Human Pathology

About the journal

Publisher: W B Saunders
Published: 1970 to the present, United States
Language: English
ISSN: 0046-8177 (print), 1532-8392 (electronic)
Its record in the NLM Catalog

2020s

TRAF7 mutations and immunohistochemical study of uterine adenomatoid tumor compared with malignant mesothelioma. H. Itami, T. Fujii, T. Nakai, et al. 2021;111:59-66. PubMed · Publisher

Abstract

Adenomatoid tumors (ATs) are benign mesothelial tumors with a good prognosis and usually occur in female and male genital tracts, including in the uterus. ATs are genetically defined by tumor necrosis factor receptor-associated factor (TRAF) 7 mutations, and a high number of AT cases show immunosuppression. On the other hand, malignant mesotheliomas (MMs) are malignant mesothelial tumors with a very poor prognosis. Genetic alterations in TRAF, methylthioadenosine phosphorylase(MTAP), and BRCA-associated nuclear protein 1 (BAP1) in ATs derived from the uterus and MMs of pleural or peritoneal origin were compared by gene sequence analysis or immunohistochemical approaches. Formalin-fixed paraffin-embedded tissues derived from patients were used for immunohistochemical staining of L1 cell adhesion molecule (L1CAM), BAP1, MTAP, and sialylated protein HEG homolog 1 (HEG1) in 51 uterine AT cases and 34 pleural or peritoneal MM cases and for next-generation sequencing of the TRAF7 gene in 44 AT cases and 21 MM cases. ATs had a significantly higher rate of L1CAM expression than MMs, whereas MMs had a significantly higher rate of loss of MTAP and BAP1 expression than ATs. There was no difference in the rate of HEG1 expression between the tumor types. Most of the ATs (37/44; 84%) had somatic mutations in TRAF7, but none of the MMs had somatic mutations in TRAF7 (0/21; 0%). In addition, a low number of AT cases were associated with a history of immunosuppression (9/51; 17.6%). TRAF7 mutation is one of the major factors distinguishing the development of AT from MM, and immunosuppression might not be associated with most AT cases.

Copyright © 2021 Elsevier Inc. All rights reserved.
Appendageal tumors and tumor-like lesions of the testis and paratestis: a 32-year experience at a single institution. K.I. Al-Obaidy, F.I. Alruwaii, T.M. Ulbright, et al. 2020;103:25-33. PubMed · Publisher

Abstract

The testicular hilum and paratestis contain several embryologically diverse anatomic structures, including the spermatic cord, tunica vaginalis, epididymis, rete testis, and several other embryonic remnants. Several benign and malignant lesions arise from these morphologically distinct structures, and owing to their proximity, it is challenging to classify and subsequently stage these tumors. Herein, we conducted a retrospective review of the paratesticular appendageal and rete testis tumors and tumor-like lesions diagnosed at our department from 1985 to 2016. Soft-tissue lesions/tumors were excluded. A total of 146 paratesticular appendageal and rete testis tumors and tumor-like lesions were identified. Most were benign (n = 107; 73%). Adenomatoid tumor (26%) was the most common benign tumor, followed by different types of cysts (19%), mesothelial hyperplasia (18%), serous cystadenoma (5.5%), and rete testis adenoma (4%). Malignant lesions comprised 23% of the cases, with mesothelioma the most common (15%), followed by adenocarcinoma of the rete testis (4%), serous cystadenocarcinoma (2%), and papillary and clear cell adenocarcinoma of the epididymis (2%). Finally, serous borderline tumors and melanotic neuroectodermal tumor (retinal anlage tumors) comprised the remaining 4% of cases. In conclusion, a wide range of benign and malignant lesions can arise from the paratesticular region. Awareness of these lesions and their histologic spectrum is crucial to avoid diagnostic pitfalls and to allow pathologists to establish a correct diagnosis and subsequent treatment plan.

Copyright © 2020. Published by Elsevier Inc.
Histopathological features of epithelioid malignant pleural mesotheliomas in patients with extended survival. J. Paajanen, S. Laaksonen, E. Kettunen, et al. 2020;98:110-119. PubMed · Publisher

Abstract

Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, wherein the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. To study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival more than five years (LTSs) and compared the findings with 84 tumors from a reference group (RG) with average survival. We analyzed the tumors considering previously published histopathological prognostic features and attempted to identify additional morphological features predictive of extended survival. Most of the LTS tumors presented with nuclear grade I (n = 34, 90%) and a tubulopapillary growth pattern (n = 30, 70%). One LTS tumor had necrosis. In contrast, nuclear grade II (n = 49, 61%) and solid growth pattern (n = 59, 70%) were more frequent in the RG, and necrosis was present in 16 (19%) tumors. We also evaluated the association of asbestos lung tissue fiber burden quantified from autopsy samples with histopathological features and found that elevated asbestos fiber was associated with higher nuclear grade (P < 0.001) and the presence of necrosis (P = 0.021). In univariate survival analysis, we identified the following three novel morphological features associated with survival: exophytic polypoid growth pattern, tumor density, and single mesothelium layered tubular structures. After adjustments, low nuclear grade (P < 0.001) and presence of exophytic polypoid growth (P = 0.024) were associated with prolonged survival. These results may aid in estimating DMM prognosis.

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
The potential utility of GATA binding protein 3 for diagnosis of malignant pleural mesotheliomas. S. Prabhakaran, A. Hocking, C. Kim, et al. 2020;105:1-8. PubMed · Publisher

Abstract

Malignant pleural mesothelioma is associated with asbestos exposure and poor outcomes. The usefulness of immunohistochemistry for diagnosis of sarcomatoid mesothelioma, especially the desmoplastic type, is limited, and more effective markers are required. GATA binding protein 3 (GATA3) has been suggested as a diagnostic marker for sarcomatoid mesothelioma. The potential usefulness of GATA3 for prognostication and its clinical and pathological correlations in different subtypes of mesothelioma have not been evaluated. We investigated the immunohistochemical labeling and associations for GATA3, BRCA1-associated protein 1 (BAP1), and Ki67 labeling in three major histological types of pleural malignant mesotheliomas. We examined 149 clinically annotated malignant mesotheliomas and assessed associations of GATA3 expression with clinical variables and prognosis. In addition, we labeled 10 cases of fibrous pleuritis with GATA3, all of which were negative. GATA3 was positive in 75 of 149 (50%) mesotheliomas, with the highest incidence of labeling seen in the sarcomatoid subtype (73%), compared with the biphasic (50%) and epithelioid (40%), mesotheliomas. A total of eight desmoplastic mesotheliomas showed labeling with GATA3. Patients whose tumors had sarcomatoid histology showed poorer survival than those with the other subtypes (p < 0.001), but overall GATA3 labeling did not have a statistically significant association with survival (p = 0.602). There was no association of GATA3 labeling and BAP1 status or Ki67 index. Our study includes the largest cohort of mesotheliomas that has been labeled for GATA3 to date. GATA3 is a useful marker for sarcomatoid mesothelioma, including the desmoplastic subtype. Discordance in GATA3 and BAP1 labeling of epithelioid and sarcomatoid components in the biphasic subtype is not uncommon.

Copyright © 2020 Elsevier Inc. All rights reserved.

2010s

Chronic follicular pleuritis: a B cell-rich form of nonspecific pleuritis/fibrosis. S.A. Yousem. 2019;90:14-19. PubMed · Publisher

Abstract

The parietal pleura is often biopsied in patients with idiopathic pleural effusion, and in up to 40% of cases, a diagnosis of nonspecific pleuritis/fibrosis (NSP) is rendered. The histology of this reaction has not been well described including a pattern of B cell lymphoid hyperplasia described as "chronic follicular pleuritis (CFP)". Thirty-two cases of NSP were studied, of which 13 (41%) corresponded to CFP with the remainder displaying a fibrinous and organizing pleuritis with varying degrees of collagenization. CFP had similar etiologies as NSP with long term follow-up, including cardiac disease, pericarditis, asbestos exposure, and occult malignancy. The importance of recognizing a previously undescribed B cell/plasma cell pleural inflammatory response in reactive pleural disease is discussed.

Copyright © 2019 Elsevier Inc. All rights reserved.
Clinicopathologic study of deciduoid mesothelioma using SMARCB1/INI1 immunohistochemistry and fluorescence in situ hybridization. T. Kawai, S. Ogata, H. Nakashima, et al. 2019;93:23-29. PubMed · Publisher

Abstract

Deciduoid mesothelioma is a rare variant of epithelioid mesothelioma. Malignant rhabdoid tumors, renal medullary carcinoma, and some synovial sarcomas show a loss of SMARCB1/INI1 protein, a member of the SWI/SNF chromatin-remodeling complex. All of those tumors are known to have rhabdoid cells. Some mesothelioma cases, such as those of the deciduoid type, have also been reported to possess such rhabdoid features. Since this topic has not been studied in malignant mesothelioma, we analyzed the immunohistochemical expression of SMARCB1/INI1 in malignant mesotheliomas [45 epithelioid type (including 9 deciduoid type), 12 biphasic type, and 17 sarcomatoid type]. We employed (a) SMARCB1/INI1 immunohistochemistry, using an antibody to the INI1 gene product and (b) Fisher exact test, logistic regression analysis, the Kaplan-Meier method, and the Wilcoxon test for survival analysis for prognostic factor evaluation (SAS 9.4; SAS Institute, Cary, NC). The results showed that 17 of 74 (23%) malignant mesothelioma cases (epithelioid: 24%; biphasic; 8%; sarcomatoid; 29%) had reduced SMARCB1/INI1 expression. Reduced SMARCB1/INI1 expression appeared to be more frequent in the deciduoid type (67%), of which there were admittedly only a few cases, than in either the epithelioid type (14%) or biphasic type (8%), whether or not rhabdoid cells were present, but not different between the deciduoid and sarcomatoid types. However, there was no statistically significant difference in prognosis between malignant mesotheliomas with reduced versus preserved SMARCB1/INI1 protein expression. The results suggest that in differential diagnosis, cases with reduced SMARCB1/INI1 protein expression should not be excluded from a diagnosis of malignant mesothelioma.

Copyright © 2019 Elsevier Inc. All rights reserved.
Mesothelioma of the tunica vaginalis testis. K.J. Butnor, E.N. Pavlisko, T.A. Sporn, et al. 2019;92:48-58. PubMed · Publisher

Abstract

Malignant mesothelioma (MM) arising from the serosal membranes of the tunica vaginalis testis (TVT) is rare. Most examples in the published medical literature are individual case reports. This study presents the clinicopathological findings of mesothelioma of the TVT in one of the largest series to date. Individuals with mesothelioma of the TVT were identified from a database of more than 4000 mesothelioma cases, and their clinicopathological features were recorded. Eighteen men with MM and 2 with well-differentiated papillary mesothelioma of the TVT were identified, which represented 0.6% of males with mesothelioma in study population. The median age at diagnosis was 72 years (range, 32-85 years). A neoplasm was not suspected preoperatively in 12 of the 17 (71%) men whose clinical presentation was known, 7 of whom presented with hydrocele and 5 with inguinal hernia. The other 5 had a clinically recognized mass. Seven of the men underwent herniorrhaphy; 7, radical orchiectomy; 3, hydrocelectomy; and 3, paratesticular mass biopsy or excision as the initial diagnostic procedure. Twelve of the MM cases were epithelioid and 6 were biphasic. Among the 6 men with MM who had ≥6 months of follow-up, 1 was alive with no evidence of disease at 6 months, and 5 were known to have died of disease 8-74 months (median = 31.5 months) following diagnosis. Three men with MM had received either chemotherapy or radiation therapy. Of the 2 men initially diagnosed with well-differentiated papillary mesothelioma, 1 was alive without evidence of disease 5 years after diagnosis, while the other had findings more compatible with MM with peritoneal involvement 2 years following initial diagnosis. In 15 of the 18 cases of MM (83%), there was documented occupational or paraoccupational exposure to asbestos, the average duration of which was 33 years (range, 2-46 years). Information regarding the presence or absence of pleural plaques was available in 5 of the MM cases, and pleural plaques had been found in 4. Lung tissue was not available for fiber analysis in any of the cases. One additional case originally diagnosed at another institution as MM of the TVT was reclassified as adenocarcinoma following performance of additional immunohistochemical testing. TVT is a rare site of MM, the diagnosis of which is often unsuspected preoperatively. Like its counterparts at other serosal sites, MM of the TVT is an aggressive tumor with a poor prognosis that evidence would suggest is etiologically associated with asbestos in at least some cases.

Copyright © 2019 Elsevier Inc. All rights reserved.
Primary peritoneal epithelioid mesothelioma of clear cell type with a novel VHL gene mutation: a case report. A. Smith-Hannah, R. Naous. 2019;83:199-203. Case report PubMed · Publisher

Abstract

Clear cell variant of epithelioid mesothelioma is an extremely rare tumor with only isolated cases reported so far in the peritoneum. Here, we report a case of peritoneal epithelioid mesothelioma, clear cell variant, in a 63-year-old female patient with a novel VHL gene mutation and an unusual indolent clinical course. The patient, who has no clinical history of asbestos exposure, presented with a 27.2-cm upper abdominal mass and a 5.5-cm liver lesion. Retrospective review of the patient's abdominal computed tomographic scan 4 years ago showed 2 small abdominal lesions that were felt clinically to represent hemangiomas. These were retrospectively considered to have grown in size and represented the current abdominal mass. Both masses were subsequently biopsied and showed a proliferation of monomorphic epithelioid cells with distinct cell membranes, fine chromatin, and clear to finely vacuolated pale eosinophilic cytoplasm arranged in nests and solid sheets. Immunohistochemical staining confirmed it to be malignant mesothelioma. Clear cell variant of peritoneal epithelioid mesothelioma should always be considered in patients with an abdominal or pelvic mass with clear cell features. Given the rarity of such entity, its clinical course and prognosis remains unclear.

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
Tumor PD-L1 expression in malignant pleural and peritoneal mesothelioma by Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx assays. D.B. Chapel, R. Stewart, L.V. Furtado, et al. 2019;87:11-17. PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is an aggressive neoplasm with poor prognosis. The Dako PD-L1 22C3 and 28-8 pharmDx assays are approved by the US Food and Drug Administration (FDA) as companion and complementary diagnostics for the anti-PD-1 drugs pembrolizumab and nivolumab, respectively. Data from multiple clinical trials indicate that immunotherapy has antitumor activity in advanced malignant pleural (MPM) and peritoneal mesothelioma (MPeM). However, large studies of PD-L1 expression in MM using the FDA-approved anti-PD-L1 assays are lacking. We stained tissue microarray sections (N = 125; 112 MPM and 13 MPeM) using 2 FDA-approved clinical immunohistochemical makers for PD-L1 expression: Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx. Overall, 22% (27/125) of MMs were positive using the 22C3 assay, whereas 27% (32/117) were positive using the 28-8 assay, using a tumor proportion score cutoff of 1%. Tumor cell PD-L1 expression was strongly correlated with PD-L1 expression on tumor-associated immune cells. No significant difference in PD-L1 expression was observed by patient sex, age, treatment history, pathologic stage, or histologic subtype. However, the proportion of cases positive for PD-L1 expression was higher among MPeM compared to MPM (P = .007 for 22C3 assay; P = .04 for 28-8 assay). PD-L1 is expressed in a substantial proportion of MM cases, as measured by FDA-approved companion assays for widely used immunotherapeutic drugs. PD-L1 expression is particularly prevalent in MPeM. These findings support large clinical studies to further examine PD-L1 as a biomarker for a subset of MM patients that may benefit from immunotherapy.

Copyright © 2019 Elsevier Inc. All rights reserved.
Aberrant Pax-8 expression in well-differentiated papillary mesothelioma and malignant mesothelioma of the peritoneum: a clinicopathologic study. D. Xing, N. Banet, R. Sharma, et al. 2018;72:160-166. PubMed · Publisher

Abstract

Serous ovarian neoplasms can overlap morphologically with peritoneal mesothelial proliferations, including well-differentiated papillary mesothelioma (WDPM) and malignant epithelioid mesothelioma (MM). Accurate histologic classification of these neoplasms is important for clinical management. The Pax-8 protein is commonly used for differentiating peritoneal MM from serous carcinoma, but the diagnostic value of Pax-8 for distinguishing WDPM from borderline or low-grade serous tumors is unknown. We used immunohistochemistry staining to assess Pax-8 expression in 33 WDPMs, 34 peritoneal MMs, 48 pleural MMs, 11 adenomatoid tumors, 5 peritoneal inclusion cysts, and 51 benign/reactive mesothelium specimens. Staining was noted in 20 WDPMs (61%), with 17 showing strong and diffuse nuclear staining and 3 patchy/focal staining. Calretinin was expressed in 33 cases (100%), whereas focal BerEP4 staining was noted in 2 of 29 cases (7%). In contrast, 4 peritoneal MM (12%) were Pax-8 positive (3 diffuse and 1 focal staining). All adenomatoid tumors and peritoneal inclusion cysts were negative for Pax-8. Of the 48 pleural MM cases, 2 (4%) showed focal weak to moderate nuclear labeling for Pax-8, and 2 cases (4%) of reactive mesothelium demonstrated focal and scattered Pax-8 staining. Pax-8 appears to be a useful marker for distinguishing MM from gynecologic malignancies but is not reliable for distinguishing WDPM from borderline or low-grade gynecologic lesions.

Copyright © 2017 Elsevier Inc. All rights reserved.
BAP1 loss is unusual in well-differentiated papillary mesothelioma and may predict development of malignant mesothelioma. H.E. Lee, J.R. Molina, W.R. Sukov, et al. 2018;79:168-176. Case report PubMed · Publisher

Abstract

Literature on BRCA1-associated protein 1 (BAP1) expression status in well-differentiated papillary mesothelioma (WDPM) is limited. In the present study, we examined the prevalence of BAP1 loss in WDPM by immunohistochemistry with clinical correlation, along with CDKN2A deletion status by fluorescence in situ hybridization (FISH). Eight patients diagnosed as having WDPM were identified from the surgical pathology file. Adenomatoid tumors (n = 8) and malignant mesothelioma (MM) (n = 39) were included for comparison. BAP1 immunohistochemistry was performed on representative block(s) from each case. CDKN2A FISH was also performed in the WDPMs and adenomatoid tumors. Clinical information was obtained from the medical records. Three of 8 WDPM patients showed synchronous or metachronous MM. All 3 cases showed BAP1 loss in both WDPM and the matched MM. Single-nucleotide polymorphism genomic microarray (n = 3) demonstrated a similar genetic profile in the WDPM and MM components, which supports their clonal relationship. The remaining 5 WDPM cases had intact BAP1 expression and had no evidence of disease on follow-up imaging studies at 1 to 71 months (median, 35 months). All 8 adenomatoid tumors had intact BAP1 expression, whereas 17 of 39 MM had BAP1 loss. CDKN2A FISH was negative for deletion in 4 WDPMs tested (including the case that developed MM) and all 8 adenomatoid tumors. In our study, WDPM did not show CDKN2A deletion in any case. BAP1 loss was also absent in all pure WDPM cases but was identified in all WDPM with synchronous or metachronous MM. Similar genetic landscape in WDPM and MM components suggested their clonal relationship.

Copyright © 2018 Elsevier Inc. All rights reserved.
Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma. S. Inaguma, J. Lasota, Z. Wang, et al. 2018;71:1-7. PubMed · Publisher · Free full text

Abstract

Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4. The PD-L1 (CD274)/PD-1 (PDCD1, CD279) pathway is crucial for the modulation of immune responses in normal cells. Nevertheless, pathologic activation of the PD-L1/PD-1 pathway participates in immune evasion by tumor cells. Many PD-L1-expressing tumor cells have been identified in different types of cancer, including malignant mesothelioma. In this study, 175 well-characterized primary diffuse pleural mesotheliomas, including the epithelioid (n = 148), biphasic (n = 15), and sarcomatoid (n = 12) histotypes, were evaluated immunohistochemically for cancer stem cell markers (ALCAM, ALDH1, and SALL4) and PD-L1 expression. Twenty-five percent of the mesotheliomas (43/175) expressed ALCAM, whereas ALDH1 and SALL4 positivity was seen in 1% to 2% of cases. Thirty-three percent of the analyzed tumors (57/175) contained PD-L1-positive cells. Overall survival was significantly decreased in the cohort of patients with ALCAM- or PD-L1-positive tumors (both P < .01). Furthermore, the multivariate Cox hazards regression analysis identified ALCAM and PD-L1 (both P < 0.01) as potential independent risk factors. Thus, a combination of these 2 markers might be useful for prognostication and planning the treatment of patients with malignant pleural mesothelioma.

Copyright © 2017 Elsevier Inc. All rights reserved.
IMP3 as a prognostic biomarker in patients with malignant peritoneal mesothelioma. S. Hui, Z. Guo-Qi, G. Xiao-Zhong, et al. 2018;81:138-147. PubMed · Publisher

Abstract

Malignant peritoneal mesothelioma (MPeM) is an incurable cancer with poor prognosis, and several biomarkers have been suggested for screening of MPeM. The aim of our study was to evaluate the prognostic significances of IMP3 and Fli-1 in MPeM. Diagnostic biopsies of 44 MPeM patients were centrally collected and were immunohistochemically analyzed for expression of IMP3, Fli-1, and Ki-67. Labeling was assessed by 2 pathologists. Complete clinical information and follow-up were obtained from patients' records. Carcinomas expressed Fli-1 in 42 (95.5%) of 44 specimens, and IMP3 in 23 (52.3%) of 44 specimens. Spearman ρ analysis revealed that Fli-1 expression was related to both histologic type and Ki-67 labeling index (Ki-67LI; r = -0.500, P < .05; r = 0.358, P < .05), and IMP3 expression was related to Ki-67LI (r = 0.401, P < .05). A Kaplan-Meier analysis and univariate Cox regression analysis showed that tumor-directed treatment, a lower peritoneal carcinomatosis index, stage I, lower Ki-67LI, and lower level of IMP3 expression had a statistically significantly positive effect on overall survival; Fli-1 did not affect overall survival in the univariate analysis (hazard ratio [HR], 1.026; P = .904). A Kaplan-Meier analysis showed the correlation between IMP3-Fli-1 and overall survival, whereas univariate and multivariate Cox regression analyses did not confirm the correlation. Cox regression analysis revealed that IMP3 expression (HR, 2.311 [95% confidence interval, 1.190-4.486]; P = .013) and no tumor-directed treatment (HR, 0.189 [95% confidence interval, 0.086-0.416]; P = .000) retained independent prognostic significance, both with negative effect on OS. IMP3, along with tumor-directed treatment protocols, is a powerful prognosticator in patients with MPeM.

Copyright © 2018 Elsevier Inc. All rights reserved.
The diagnostic role of BAP1 in serous effusions. B. Davidson, M. Tötsch, J. Wohlschlaeger, et al. 2018;79:122-126. PubMed · Publisher

Abstract

The aim of this study was to analyze the diagnostic role of BAP1 in effusion cytology. Effusions (n = 258), consisting of 53 malignant mesotheliomas and 205 other cancers, the majority carcinomas (62 breast, 60 ovarian, 31 lung, 51 carcinomas of other origin, 1 melanoma), were analyzed for BAP1 expression using immunohistochemistry. BAP1 was lost in 46 (87%) mesotheliomas compared with 4 (2%) of 205 other cancers (P < .001), resulting in sensitivity and specificity of 87% and 98%, respectively. There was no significant difference between peritoneal (n = 14) and pleural (n = 39) mesotheliomas. The 4 carcinomas with loss of BAP1 included 1 ovarian, 1 breast, 1 uterine cervical, and 1 gastric carcinoma. The present study supports the role of BAP1 as a highly sensitive and specific marker for malignant mesothelioma in serous effusions and argues for inclusion of this test in all specimens in which this diagnosis is considered.

Copyright © 2018 Elsevier Inc. All rights reserved.
BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma. S.M. McGregor, J. McElherne, A. Minor, et al. 2017;60:86-94. PubMed · Publisher

Abstract

BRCA-associated protein 1 (BAP1) immunohistochemistry (IHC) and CDKN2A (p16) fluorescence in situ hybridization (FISH) have shown clinical utility in confirming the diagnosis of malignant pleural mesothelioma (MPM), but the role for using these 2 markers to guide clinical management is not yet clear. Although p16 loss is predictive of poor prognosis, there is controversy as to whether BAP1 loss is predictive of a more favorable prognosis; how these results interact with one another has not been explored. We performed CDKN2A FISH on a previously published tissue microarray on which we had performed BAP1 IHC, revealing combined BAP1/p16 status for 93 MPM cases. As expected, BAP1 IHC in combination with CDKN2A FISH resulted in high sensitivity (84%) and specificity (100%) for MPM, and p16 loss was an independent predictor of poor survival (hazard ratio, 2.2553; P = .0135). There was no association between BAP1 loss and p16 loss, as 26%, 28%, 30%, and 16% of overall cases demonstrated loss of BAP1 alone, loss of p16 alone, loss of both BAP1 and p16, or neither abnormality, respectively. Although multivariate analysis demonstrated that BAP1 IHC is not an independent predictor of prognosis, when viewed in combination with homozygous CDKN2A deletion, risk stratification was evident. More specifically, patients with CDKN2A disomy and loss of BAP1 expression had improved outcomes compared with those with CDKN2A disomy and retained BAP1 expression (hazard ratio, 0.2286; P = .0017), and this finding was notably evident among epithelioid cases. We conclude that BAP1 IHC provides prognostic information within the context of CDKN2A FISH that may have clinical utility beyond diagnosis.

Copyright © 2016 Elsevier Inc. All rights reserved.
Cytokeratin 5/6 expression, prognosis, and association with estrogen receptor α in high-grade serous ovarian carcinoma. E.T. Taube, C. Denkert, J. Sehouli, et al. 2017;67:30-36. PubMed · Publisher

Abstract

High-grade serous ovarian carcinoma remains one of the most lethal malignancies in women. For histopathologic differentiation from mesothelioma cytokeratin, 5/6 immunohistochemistry is widely used. Another preferred marker for differential diagnosis to mesothelioma is estrogen receptor α (ER-α). In this study, we determined the rate of cytokeratin 5/6-positive cells in primary high-grade serous carcinoma. A cohort of 215 patients with high-grade serous ovarian carcinoma was evaluated immunohistochemically for the protein expression of cytokeratin 5/6. Most tumors demonstrated at least partly positive for cytokeratin 5/6 (n=148; 68.3%), showing different staining patterns from scattered stained cells to a diffuse staining, at times with a distinctive tumor-stroma border motif. Sixty-seven (31%) were entirely negative. No correlation of cytokeratin immunoreactivity score (IRS) with conventional staging parameters could be demonstrated. From the different IRS values for cytokeratin 5/6, IRS=12 (n=6; 2.9%) seemed to indicate a worse prognosis, albeit not statistically significant. An association with ER-α expression could not be detected but the combination of cytokeratin 5/6 IRS=12 and ER-α negativity resulted in a significant negative prognostic marker (overall survival: P=.003 and progression-free survival: P<.0001). We substantiate cytokeratin 5/6 protein expression as a frequent feature of high-grade serous ovarian carcinoma with various staining patterns, an important fact for the routine differential diagnosis with mesothelioma. Furthermore, cytokeratin 5/6 in combination with ER-α proved to be a negative prognostic marker, wherefore we suggest further investigation of its biological significance and possible manifestation of a basal differentiation.

Copyright © 2017 Elsevier Inc. All rights reserved.
Loss of BRCA1-associated protein 1 (BAP1) expression is rare in non-small cell lung cancer. D. Owen, B.S. Sheffield, D. Ionescu, et al. 2017;60:82-85. PubMed · Publisher

Abstract

BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene involved in regulation of the cell cycle, cellular differentiation, repair of DNA damage, and apoptosis. In the distinction of malignant mesothelioma from benign mesothelial proliferations, immunohistochemical loss of BAP1, the protein expressed by the BAP1 gene, has proven highly specific for malignant mesothelioma. However, few studies have investigated the rate of BAP1 loss in tumors that commonly metastasize to the pleura. Our objective is to determine the rate of BAP1 loss in non-small cell lung cancer (NSCLC). Immunohistochemistry for BAP1 was performed using tissue microarrays containing 133 confirmed cases of NSCLC (80 of lung adenocarcinoma and 53 of squamous cell carcinoma). Cases were interpreted as showing BAP1 loss if nuclear staining was completely absent in all tumor cells and present in stromal and inflammatory cells that served as internal controls. Cases showing no BAP1 staining in the internal controls were excluded. After exclusion of 32 cases for technical reasons, only 1 case of pulmonary adenocarcinoma of 101 cases of NSCLC (69 adenocarcinoma and 32 squamous cell carcinoma; 1.0% of cases) showed BAP1 loss. We conclude that loss of BAP1 expression is a rare event in NSCLC. Therefore, BAP1 is a potentially useful addition to the immunohistochemical markers used to distinguish mesothelioma from pleural metastasis of NSCLC.

Copyright © 2016 Elsevier Inc. All rights reserved.
Reproducibility for histologic parameters in peritoneal mesothelioma. D.J. Hartman, A. Borczuk, S. Dacic, et al. 2017;67:54-59. PubMed · Publisher

Abstract

Histologic subtype is recognized as a prognostic factor in malignant pleural mesothelioma. Specifically, epithelial morphology is associated with a better prognosis than other subtypes, and the same association is observed in peritoneal malignant mesothelioma. Recently, prognostic differences based on morphologic subtypes of epithelial peritoneal malignant mesothelioma were reported. Herein, we report the interobserver variability across four pathologists at three institutions. The authors independently reviewed 67 cases of malignant peritoneal epithelioid mesotheliomas and subclassified them according to their epithelial subtype: papillary, tubulopapillary, trabecular, micropapillary, solid and/or pleomorphic. The cases were also evaluated by each author for several other histopathologic parameters including depth of invasion, nuclear grade, lymphocytic host response, mitotic count/index, presence of lymphovascular invasion, and stromal desmoplasia. The interobserver agreement for histopathologic parameters was highest for mitotic rate (κ=0.36) and primary epithelial subtype (κ=0.32). The interobserver variability for solid subtype pattern was moderate (κ=0.49). We found that the interobserver variability for most histopathologic parameters is poor.

Copyright © 2017 Elsevier Inc. All rights reserved.
The differential diagnosis between pleural sarcomatoid mesothelioma and spindle cell/pleomorphic (sarcomatoid) carcinomas of the lung: evidence-based guidelines from the International Mesothelioma Panel and the MESOPATH National Reference Center. A.M. Marchevsky, N. LeStang, K. Hiroshima, et al. 2017;67:160-168. Meta-analysis · Systematic review PubMed · Publisher

Abstract

Immunohistochemistry is used to distinguish sarcomatoid malignant mesotheliomas (SMM) from spindle cell and pleomorphic carcinomas (SPC) but there are no guidelines on how to interpret cases that show overlapping or equivocal immunohistochemical findings. A systematic literature review of the immunophenotype of these lesions was performed and the experience with 587 SMM and 46 SPC at MESOPATH was collected. Data were analyzed with Comprehensive Meta-Analysis 2.0 software (Biostat, Englewood, NJ). There were insufficient data to evaluate the differential diagnosis between SPC and localized SMM or peritoneal SMM. Meta-analysis showed considerable overlap in the immunophenotype of these neoplasms and significant data heterogeneity amongst many of the results. Survival data from MESOPATH patients showed no significant differences in overall survival between SMM and SPC patients. Best available evidence was used to formulate several evidence-based guidelines for the differential diagnosis between pleural SMM and SPC. These guidelines emphasize the need to correlate the histopathological findings with clinical and imaging information. Diffuse SMM can be diagnosed with certainty in the presence of malignant spindle cell pleural lesions showing immunoreactivity for cytokeratin and mesothelial markers and negative staining for epithelial markers. Criteria for the interpretation of various other combinations of immunoreactivity for cytokeratin and mesothelial and/or epithelial markers are proposed. Localized sarcomatoid mesotheliomas can only be diagnosed in the presence of spindle cell malignancies that exhibit immunoreactivity for cytokeratin and mesothelial markers and negative immunoreactivity for epithelial lesions, in patients that show no multifocal or diffuse pleural spread and no evidence for extrapleural lesions.

Copyright © 2017. Published by Elsevier Inc.
CD24 is highly useful in differentiating high-grade serous carcinoma from benign and malignant mesothelial cells. B. Davidson. 2016;58:123-127. PubMed · Publisher

Abstract

CD24 was previously shown to be overexpressed in high-grade serous carcinoma (HGSC) effusions compared to malignant mesothelioma (MM) in gene expression array analysis. The present study validated this observation in a large series consisting of both effusions and surgical specimens. Effusions (n = 206; 100 HGSC, 16 ovarian carcinomas of other histological types, 54 breast carcinomas, 36 MM) and surgical specimens (n = 182; 117 ovarian carcinomas, 65 MM) were analyzed for CD24 expression using immunohistochemistry. CD24 was expressed in 105/116 (91%) ovarian carcinoma and 16/54 (30%) breast carcinoma effusions, while it was uniformly absent in MM (0/36; 0%; P < .001). Reactive mesothelial cells were CD24-negative in all carcinoma specimens. Comparative analysis of 117 solid primary (n = 43) and metastatic (n = 74) ovarian carcinomas and 65 solid MM specimens showed CD24 expression in 46% (54/117) of the former compared to 3% (2/65) of the latter (P < .001). Comparative analysis of ovarian carcinomas at different anatomic sites showed significantly higher CD24 expression in effusions compared to solid ovarian and metastatic lesions (P < .001), with similar results when analysis was limited to HGSC (P < .001). In conclusion, CD24 is a highly sensitive and specific marker of ovarian carcinoma in the differential diagnosis from MM and reactive mesothelium in effusions. CD24 is similarly a specific marker in surgical specimens, though with lower sensitivity. The overexpression of CD24 in ovarian carcinoma effusions compared to solid lesions may be due to the acquisition of cancer stem cell characteristics.

Copyright Â© 2016 Elsevier Inc. All rights reserved.
GATA-3 and FOXA1 expression is useful to differentiate breast carcinoma from other carcinomas. D.G. Davis, M.T. Siddiqui, G. Oprea-Ilies, et al. 2016;47(1):26-31. PubMed · Publisher

Abstract

GATA-3, a member of the GATA family of zinc-finger DNA binding proteins, and FOXA1, a member of the forkhead transcription factor family, are both associated with estrogen receptor expression. Both GATA-3 and FOXA1 are useful markers for breast carcinoma, but their expression in the different breast cancer subtypes and other neoplasms has not been thoroughly evaluated. We examined the expression of GATA-3 and FOXA1 in estrogen receptor-positive, Her2/neu-positive, and triple-negative breast carcinomas as well as in 10 other common carcinomas, including hepatocellular, colonic, pancreatic, gastric, endometrial (endometrioid), lung, prostatic, renal cell, urothelial, and ovarian serous carcinomas. Primary and metastatic melanomas and mesotheliomas were also evaluated. GATA-3 and FOXA1 staining of estrogen receptor-positive breast carcinomas was seen in 96.6% and 96.2%, respectively. In triple-negative breast carcinomas, GATA-3 and FOXA1 staining was seen in 21.6% and 15.9%, respectively. Among the other tumors, GATA-3 staining was only seen in urothelial carcinoma (70.9%) and FOXA1 staining was only seen in prostatic (87.5%), urothelial (5.1%) carcinomas, and mesotheliomas (40.0%). In conclusion, GATA-3 and FOXA1 are excellent breast carcinoma markers; however, their utility is limited in the triple-negative subtype. The utility of FOXA1 in diagnosing prostatic carcinoma and mesothelioma warrants further investigation.

Copyright © 2015 Elsevier Inc. All rights reserved.
Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array. P. Chirac, D. Maillet, F. Leprêtre, et al. 2016;55:72-82. PubMed · Publisher

Abstract

Malignant peritoneal mesotheliomas (MPM) are rare, accounting for approximately 8% of cases of mesothelioma in France. We performed comparative genomic hybridization (CGH) on frozen MPM samples using the Agilent Human Genome CGH 180 K array. Samples were taken from a total of 33 French patients, comprising 20 men and 13 women with a mean (range) age of 58.4 (17-76) years. Asbestos exposure was reported in 8 patients (24.2%). Median (range) overall survival (OS) was 39 (0-119) months. CGH analysis demonstrated the presence of chromosomal instability in patients with MPM, with a genomic pattern that was similar to that described for pleural mesothelioma, including the loss of chromosomal regions 3p21, 9p21, and 22q12. In addition, novel genomic copy number alterations were identified, including the 15q26.2 region and the 8p11.22 region. Median OS was associated with a low peritoneal cancer index (P=.011), epithelioid subtype (P=.038), and a low number of genomic aberrations (P=.015), all of which constitute good prognostic factors for MPM. Our results provide new insights into the genetic and genomic background of MPM. Although pleural and peritoneal mesotheliomas have different risk factors, different therapeutics, and different prognosis; these data provide support to combine pleural and peritoneal mesothelioma in same clinical assays.

Copyright © 2016 Elsevier Inc. All rights reserved.
Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas. C. Combaz-Lair, F. Galateau-Sallé, A. McLeer-Florin, et al. 2016;52:9-18. PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with no effective therapy. However PD-L1/PD-1 immunity checkpoint therapies gave encouraging results; TLR3 is a programmed death factor, which triggering up-regulates PD-L1. As PD-1/PD-L1 blocking antibodies could restore antitumor immune responses alone or in combination with TLR3 agonists, we investigated PD-L1/PD-1 and TLR3 expressions in MPM to select patients for immunotherapy. Sixty-eight pleural surgical specimens, including 58 MPM (epithelioid, n = 34; biphasic, n = 11; sarcomatoid, n = 13) and 10 benign lesions, were studied. PD-L1 expression was assessed using E1L3N and SP142 clones in tumor cells (TCs) and in tumor-infiltrating lymphocytes (TILs) (positivity threshold of 1%), and compared with overall survival. PD-1, CD3 and CD8 expression by TILs, and TLR3 expression by TCs were analyzed concomitantly. PD-L1 was more expressed by sarcomatoid subtype than by other MPM (62% versus 23% and 9% for E1L3N; 38% versus 11% for SP142) (P = .01 and .04, respectively). Specificity and sensitivity of E1L3N and SP142 were of 53% and 98%, and 90% and 86%, respectively. PD-L1 expression by TILs and TCs correlated for SP142 (P = .023), and PD-L1 SP142 expression by TCs was associated with shorter overall survival (P = .016). TLR3 was expressed in most MPM, but weakly in sarcomatoid MPM. We confirm by comparing two commercially available antibodies that PD-L1 expression is higher in sarcomatoid MPM and correlates with a shorter survival. Whereas TLR3 agonists could be tested in MPM expressing TLR3, the sarcomatoid subtype could benefit from anti-PD-L1/PD-1 therapies alone or in combination.

Copyright © 2016 Elsevier Inc. All rights reserved.
Loss of BAP1 expression is very rare in peritoneal and gynecologic serous adenocarcinomas and can be useful in the differential diagnosis with abdominal mesothelioma. J. Andrici, J. Jung, A. Sheen, et al. 2016;51:9-15. PubMed · Publisher

Abstract

Gynecologic and primary peritoneal serous carcinoma may be difficult to distinguish from abdominal mesotheliomas clinically, morphologically, and immunohistochemically. BAP1 double-hit inactivation and subsequent loss of protein expression have been reported in more than half of all abdominal mesotheliomas. We therefore sought to investigate the expression of BAP1 in serous carcinoma and explore its potential utility as a marker in the differential diagnosis with mesothelioma. We searched the computerized database of the Department of Anatomical Pathology, Royal North Shore Hospital, Australia, for all cases of gynecologic and peritoneal serous carcinomas and mesotheliomas diagnosed between 1998 and 2014. Immunohistochemistry for BAP1 was then performed on tissue microarray sections. Cases with completely absent nuclear staining in the presence of a positive internal control in nonneoplastic cells were considered negative. If staining was equivocal (eg, absent nuclear staining but no internal control), staining was repeated on whole sections. Loss of BAP1 expression was found in only 1 of 395 (0.3%) serous carcinomas but in 6 of 9 (67%) abdominal mesotheliomas (P < .001) and 131 of 277 (47%) thoracic mesotheliomas (P < .001). We conclude that BAP1 loss occurs extremely infrequently in gynecologic and peritoneal serous adenocarcinomas, whereas it is very common in mesotheliomas including abdominal mesothelioma. Therefore, although positive staining for BAP1 cannot be used to exclude a diagnosis of mesothelioma, loss of BAP1 expression can be used to very strongly support a pathological diagnosis of abdominal mesothelioma over serous carcinoma.

Copyright © 2015 Elsevier Inc. All rights reserved.
MMP-7 is a highly specific negative marker for benign and malignant mesothelial cells in serous effusions. B. Davidson, H.T. Stavnes, E. Hellesylt, et al. 2016;47(1):104-8. PubMed · Publisher

Abstract

The aim of this study was to analyze the diagnostic role of MMP-7 in effusion cytology. Effusions (n = 356), consisting of 307 carcinomas (184 ovarian, 55 breast, 32 lung, 36 carcinomas of other origin) and 49 malignant mesotheliomas, were analyzed for MMP-7 expression using immunohistochemistry. MMP-7 was expressed in 124/307 (40%) carcinomas and was uniformly absent in malignant mesotheliomas (0/49; 0%; P < .001). Reactive mesothelial cells were similarly MMP-7 negative in all carcinoma specimens. In carcinomas, expression was most frequent in tumors of ovarian and other female genital (cervical and endometrial) origin (P < .001). The sensitivity and specificity of this marker in the differential diagnosis between high-grade serous carcinoma and malignant mesothelioma were 46% and 100%, respectively. In conclusion, MMP-7 expression is highly specific, though only of moderate sensitivity, for the diagnosis of carcinoma in the differential diagnosis from both benign and malignant mesothelial cells.

Copyright © 2015 Elsevier Inc. All rights reserved.
The diagnostic utility of reduced immunohistochemical expression of SMARCB1 in synovial sarcomas: a validation study. J. Ito, N. Asano, A. Kawai, et al. 2016;47(1):32-7. PubMed · Publisher

Abstract

Synovial sarcoma is a malignant mesenchymal neoplasm of uncertain histogenesis, characterized by a specific SS18-SSX fusion. The diagnosis of synovial sarcoma can be challenging based on morphology and conventional immunohistochemistry alone, and identification of the fusion gene by molecular genetics may be necessary for diagnosis. Several recent studies have demonstrated the diagnostic utility of the reduced expression of SMARCB1 in synovial sarcomas as measured using immunohistochemistry. Therefore, we undertook a validation study using synovial sarcomas and other spindle or round cell tumors that could enter differential diagnosis of monophasic or poorly differentiated synovial sarcomas. Among 36 synovial sarcomas that were successfully evaluated, the expression of SMARCB1 was diffusely reduced in 33 cases (92%) at variable degrees. In contrast, the expression of SMARCB1 was not reduced in any of the 93 evaluable non-synovial sarcoma tumors (5 thymomas, 5 sarcomatoid mesotheliomas, 10 schwannomas, 9 mesenchymal chondrosarcomas, 20 solitary fibrous tumors, 19 Ewing sarcomas, and 25 malignant peripheral nerve sheath tumors). A few schwannomas and malignant peripheral nerve sheath tumors showed mosaic or complete loss of SMARCB1 expression. Reduced expression of SMARCB1 immunoreactivity was therefore found to be highly sensitive and specific for synovial sarcoma, and can be useful for rapidly and accurately confirming the diagnosis of synovial sarcoma. This reduction in SMARCB1 expression likely reflects the BAF47 ejection mechanism of the SS18-SSX fusion product and can therefore be viewed as an indirect visualization of this fusion product.

Copyright © 2015 Elsevier Inc. All rights reserved.
BAP1 facilitates diagnostic objectivity, classification, and prognostication in malignant pleural mesothelioma. S.M. McGregor, R. Dunning, E. Hyjek, et al. 2015;46(11):1670-8. PubMed · Publisher

Abstract

BRCA-associated protein 1 (BAP1) has emerged as a promising biomarker for malignant pleural mesothelioma (MPM). Loss of BAP1 expression can occur by a variety of mechanisms, but reports on incidence are variable and the clinical significance is unclear. In order to investigate the diagnostic and prognostic significance of BAP1, we constructed a tissue microarray consisting of 111 MPM cases and performed BAP1 immunohistochemistry. BAP1 was lost in 77% of epithelioid cases (n=58) but was retained in all sarcomatoid cases (n=10); 49% of biphasic cases showed loss (n=43), and BAP1-negative cases demonstrated loss of staining in both the epithelioid and sarcomatoid components. All non-neoplastic mesothelial tissues (n=20) retained BAP1, resulting in a sensitivity, specificity, positive predictive value, and negative predictive value of 61%, 100%, 100%, and 32%, respectively. Moreover, BAP1 expression in spindled mesothelium enabled discrimination of reactive and malignant cells, thus providing a more objective means of distinguishing epithelioid from biphasic morphology compared to histology alone. Nonetheless, BAP1 staining was patchy in some benign mesothelial neoplasms, which raises concern for using BAP1 in small biopsies. Kaplan-Meier analysis demonstrated a significant improvement in overall survival with BAP1 loss, but this did not reach significance in multivariate analysis accounting for histologic subtype. When only epithelioid cases were analyzed there was a trend toward increased survival, but it did not reach significance. We conclude that BAP1 loss is frequent in epithelioid MPM, which is in turn associated with improved survival, and that it can have additional clinical significance by facilitating histologic classification.

Copyright © 2015 Elsevier Inc. All rights reserved.
Metachronous cardiac and cerebral sarcomas: case report with focus on molecular findings and review of the literature. A. Guerriero, P. Giovenali, R. La Starza, et al. 2015;46(3):482-7. Case report · Review PubMed · Publisher

Abstract

Although multiple primary malignancies are relatively rare, they have increased in frequency over the last decades, partly because of advances in diagnosis and therapy. This report describes for the first time the case of a patient with past occupational exposure to asbestos and no family history of cancer who developed 2 rare primary malignancies: a cardiac sarcoma and a gliosarcoma 11 months later. Molecular-cytogenetic studies did not identify common lesions to these 2 rare metachronous sarcomas. The gliosarcoma was associated with monosomy 10 and underlying PTEN monoallelic loss, which has been recurrently observed. In the cardiac sarcoma, MDM2 amplification and CDKN2AB/9p21 biallelic deletion suggested intimal sarcoma. No causal relationship was found between cardiac sarcoma and asbestos exposure, although MDM2 abnormalities were linked to malignant mesothelioma.

Copyright © 2015 Elsevier Inc. All rights reserved.
Prognostic factors in malignant pleural mesothelioma. B. Davidson. 2015;46(6):789-804. Review PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a clinically aggressive tumor originating from mesothelial cells, which line the serosal cavities. Recent years have seen extensive research aimed at identifying new therapeutic targets, predictive markers and prognostic factors in this disease. These include both serum and tissue markers, and are related to multiple cellular pathways which affect cell survival, proliferation, apoptosis, angiogenesis, interaction with the immune response and DNA repair. Several of these molecules may become relevant for pathologists as part of the effort to select patient sub-populations for targeted therapy in the future. This review summarizes current data in this area and discusses their potential clinical relevance.

Copyright © 2015 Elsevier Inc. All rights reserved.
Diagnostic utility of immunohistochemistry in distinguishing between epithelioid pleural mesotheliomas and breast carcinomas: a comparative study. N.G. Ordóñez, A.A. Sahin. 2014;45(7):1529-40. PubMed · Publisher

Abstract

Epithelioid mesotheliomas and breast carcinomas can present a variety of morphologic patterns. Because of this, breast carcinomas that metastasize to the pleura and lung may be confused with mesotheliomas. The aim of the present study is to compare the immunohistochemical markers currently available for the diagnosis of these 2 malignancies and to determine the best panel of markers that can be used to assist in discriminating between them. Sixty epithelioid mesotheliomas and 80 breast carcinomas (40 triple negative and 40 estrogen receptor positive) were investigated for expression of the positive mesothelioma markers calretinin, keratin 5/6, mesothelin, podoplanin, thrombomodulin, and WT1; the positive carcinoma marker claudin 4; and the breast-associated markers gross cystic disease fluid protein 15 (GCDFP-15), mammaglobin, and GATA3. All of the epithelioid mesotheliomas reacted for calretinin and keratin 5/6, 93% for WT1; 88% for podoplanin; 77% for thrombomodulin; 23% for GATA3; and 0% for claudin 4, GCDFP-15, and mammaglobin, respectively. Of the triple-negative breast carcinomas, 100% expressed claudin 4; 5%, keratin 5/6; 30%, GATA3; 18%, mammaglobin; 15%, GCDFP-15; 56%, mesothelin; 38%, calretinin; 18%, thrombomodulin; 5%, WT1; and 3%, podoplanin. Among the estrogen receptor-positive breast carcinomas, 100% were claudin 4 and GATA3 positive; 70% expressed GCDFP-15; 63%, mammaglobin; 13%, calretinin; 13%, thrombomodulin; 8%, WT1; 5%, keratin 5/6; 3%, mesothelin; and 0%, podoplanin. It is concluded that podoplanin and WT1 are the best positive mesothelioma markers for differentiating epithelioid mesotheliomas from breast carcinomas. An accurate differential diagnosis can be reached with the use of these two markers in combination with the breast-associated markers GCDFP-15, mammaglobin, and GATA3.

Copyright © 2014 Elsevier Inc. All rights reserved.
Insulin-like growth factor II messenger RNA-binding protein 3 expression in gastrointestinal mesenchymal tumors. H. Yamamoto, K. Arakaki, K. Morimatsu, et al. 2014;45(3):481-7. PubMed · Publisher

Abstract

Insulin-like growth factor II messenger RNA-binding protein 3 (IMP3) is a recently identified biomarker demonstrated to be useful in diagnosis and prognostic prediction for several kinds of malignant tumors. However, the clinicopathologic and diagnostic value of IMP3 in mesenchymal tumors of the gastrointestinal tract is not clear. In this study, we examined the immunohistochemical expression of IMP3 in gastrointestinal stromal tumor (GIST) (n = 150), malignant melanoma (n = 17), malignant mesothelioma (n = 6), leiomyosarcoma (n = 6), inflammatory myofibroblastic tumor (IMT) (n = 12), desmoid fibromatosis (n = 8), leiomyoma (n = 20), and schwannoma (n = 20). Focal (≥10%) or diffuse (≥50%) expression with strong staining for IMP3 was judged as positive. We found that malignant melanomas (16/17 cases, 94.1%), malignant mesotheliomas (5/6 cases, 83.3%), IMTs (7/12 cases, 58.3%), and leiomyosarcomas (2/6 cases, 33.3%) were positive for IMP3. Among IMTs and leiomyosarcomas, IMP3-positive cases were histologically and/or clinically aggressive subtypes. Other kinds of tumors, including GIST, desmoid fibromatosis, leiomyoma and schwannoma, were essentially negative for IMP3. Our results suggest that IMP3 may be an ancillary tool in identifying aggressive abdominal mesenchymal tumors other than GIST.

© 2014.
Application of immunohistochemistry in the diagnosis of epithelioid mesothelioma: a review and update. N.G. Ordóñez. 2013;44(1):1-19. Review PubMed · Publisher

Abstract

A large number of immunohistochemical markers that can assist in the differential diagnosis of epithelioid mesotheliomas are currently available. Because these markers are expressed differently in the various types of carcinomas that can metastasize to the serosal membranes and can potentially be confused with epithelioid mesothelioma, their selection for inclusion in a diagnostic panel largely depends on the differential diagnosis, as well as on which ones work the best in a given laboratory. Traditionally, the panels used in the differential diagnosis of epithelioid mesothelioma have consisted of a combination of positive mesothelioma markers and broad-spectrum carcinoma markers. At present, a wide variety of organ-associated carcinoma markers such as thyroid transcription factor-1 and napsin A for the lung, PAX 8 and PAX 2 for the kidney, and Müllerian-derived tumors; gross cystic disease fluid protein-15 and mammaglobin for the breast; and CDX2 for intestinal differentiation are available, which can assist in establishing the site of origin of an adenocarcinoma when included in a diagnostic panel. This article provides updated information on the composition of the panels of markers recommended in the various differential diagnoses.

Copyright © 2013 Elsevier Inc. All rights reserved.
Peripheral lymphadenopathy as the initial manifestation of malignant mesothelioma in a child. Y.S. Gong, Y.T. Rong, W.C. Han, et al. 2013;44(4):664-9. Case report PubMed · Publisher

Abstract

Peripheral lymphadenopathy is a rare presentation in malignant mesothelioma. We describe a unique case of malignant mesothelioma arising in an 11-year-old boy, for whom peripheral lymphadenopathy was the initial manifestation of the disease. The final diagnosis was confirmed by a broad panel of immunohistochemical markers. Literature review disclosed only 2 cases in childhood that initially presented with peripheral lymphadenopathy. Pathologists should be aware of this rare biologic behavior of malignant mesothelioma to reach the correct and prompt diagnosis.

Copyright © 2013 Elsevier Inc. All rights reserved.
Proton magnetic resonance metabolomic characterization of ovarian serous carcinoma effusions: chemotherapy-related effects and comparison with malignant mesothelioma and breast carcinoma. R. Vettukattil, T.E. Hetland, V.A. Flørenes, et al. 2013;44(9):1859-66. PubMed · Publisher

Abstract

Malignant serous effusions are a common manifestation of advanced cancer, associated with significant morbidity and mortality. The aim of this study was to identify the metabolic differences between ovarian serous carcinoma effusions obtained pre- and post-chemotherapy, as well as to compare ovarian carcinoma (OC) effusions with breast carcinoma and malignant mesothelioma specimens. The supernatants of 115 effusion samples were analyzed by high-resolution magnetic resonance spectroscopy in vitro and multivariate analysis. The samples comprised pleural and peritoneal effusions from 95 OC, 10 breast carcinomas, and 10 malignant mesotheliomas. Among the OC, 8 were paired peritoneal specimens obtained pre- and post-chemotherapy from the same patient. OC had elevated levels of ketones (aceto-acetate and β-hydroxybutyrate) and lactate compared to malignant mesotheliomas and breast carcinomas, whereas the latter had more glucose, alanine, and pyruvate. Multivariate analysis of paired effusions in OC showed a significant increase in glucose and lipid levels in the post-treatment spectra (P = .039). Magnetic resonance spectroscopy is a promising technique for comprehensive and comparative studies of metabolites in malignant serous effusions, and our study shows that small metabolites associated with effusions might improve our understanding of tumor biology and disease progression and has diagnostic potential in this differential diagnosis.

Copyright © 2013 Elsevier Inc. All rights reserved.
Expression of the Ets transcription factor EHF in serous ovarian carcinoma effusions is a marker of poor survival. K. Brenne, D.A. Nymoen, T.E. Hetland, et al. 2012;43(4):496-505. PubMed · Publisher

Abstract

The EHF (Ets homologous factor) gene was previously shown to be overexpressed in ovarian/primary peritoneal serous carcinoma compared to malignant mesothelioma using gene expression arrays. The objective of this study was to validate this finding at the mRNA level in a larger series. We analyzed the diagnostic role of EHF in 98 ovarian serous carcinoma effusions, 23 malignant mesothelioma specimens (20 effusions, 3 surgical specimens), and 28 primary ovarian serous carcinomas using quantitative real-time polymerase chain reaction. Expression levels of EHF in ovarian carcinoma were additionally investigated for association with clinicopathologic parameters and survival. Quantitative real-time polymerase chain reaction analysis showed significantly higher expression of EHF mRNA in ovarian carcinoma effusions and in primary ovarian carcinoma compared to malignant mesothelioma effusions (P < .001 for both). EHF mRNA expression was additionally higher in primary ovarian carcinomas compared to effusions of this cancer (P < .001). In univariate analysis for all patients with effusions, higher EHF mRNA levels were associated with a trend for shorter progression-free survival (P = .066), which became significant in analysis of 45 patients with primary diagnosis pre-chemotherapy effusions (P = .01). In Cox multivariate analysis, EHF mRNA expression was an independent predictor of poor progression-free survival for all patients and patients with primary diagnosis pre-chemotherapy effusions (P = .033 and P = .009, respectively). EHF mRNA levels differentiate ovarian carcinoma from malignant mesothelioma and may thus be of diagnostic value in this setting. EHF may be a novel prognostic marker in ovarian carcinoma.

Copyright Â© 2012 Elsevier Inc. All rights reserved.
SCARA3 mRNA is overexpressed in ovarian carcinoma compared with breast carcinoma effusions. A.J. Bock, D.A. Nymoen, K. Brenne, et al. 2012;43(5):669-74. PubMed · Publisher

Abstract

Scavenger receptor class A, member 3 (SCARA3) was previously found to be overexpressed in ovarian/primary peritoneal carcinoma (OC/PPC) compared with breast carcinoma effusions by global gene expression analysis. The present study aimed to validate this finding applying quantitative PCR and analyzing the association between SCARA3 expression and clinicopathologic parameters in a large OC cohort. SCARA3 messenger RNA (mRNA) expression was analyzed in 127 effusions (103 ovarian/peritoneal/fallopian tube carcinomas, 9 breast carcinomas, 15 malignant mesotheliomas [MM]), and 30 solid primary OCs. The association between OC SCARA3 levels and clinicopathologic parameters was investigated. SCARA3 mRNA was expressed in all effusions, irrespective of tumor type. However, transcript levels were significantly higher in OC compared with breast carcinoma (P < .001) and MM (P = .011) effusions. Primary OCs and effusions had comparable expression levels. Higher SCARA3 expression was found in disease recurrence postchemotherapy compared with primary diagnosis prechemotherapy OC effusions (P = .001), and this difference was significant for treatment with both platinum agents (P = .006) and paclitaxel (P = .002). SCARA3 levels in effusions and primary carcinomas were unrelated to patient age, tumor grade, FIGO stage, residual tumor volume after surgery, response to chemotherapy, or survival (P > .05 for all). In conclusion, SCARA3 mRNA by quantitative PCR is highly expressed in OC and may aid in differentiating this tumor from other cancers, particularly breast carcinoma, in effusions. The consistently high SCARA3 levels in both primary carcinomas and metastatic cells in effusions, and its up-regulation along disease progression from diagnosis to recurrence, suggest a role in ovarian cancer biology.

Copyright © 2012 Elsevier Inc. All rights reserved.
Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature. Y. Karamurzin, Z. Zeng, Z.K. Stadler, et al. 2012;43(10):1677-87. Case report · Review PubMed · Publisher

Abstract

Immunohistochemical detection of DNA mismatch repair proteins and polymerase chain reaction detection of microsatellite instability have enhanced the recognition of mismatch repair-deficient neoplasms in patients with Lynch syndrome and, consequently, led to the identification of tumors that have not been included in the currently known Lynch syndrome tumor spectrum. Here, we report 4 such unusual tumors. Three of the 4, a peritoneal mesothelioma, a pancreatic acinar cell carcinoma, and a pancreatic well-differentiated neuroendocrine tumor, represented tumor types that, to the best of our knowledge, have not been previously reported in Lynch syndrome. The fourth tumor was an adrenocortical carcinoma, which has rarely been reported previously in Lynch syndrome. Three of our 4 patients carried a pathogenic germ-line mutation in a mismatch repair gene. The unusual tumor in each of the 3 patients showed loss of the mismatch repair protein corresponding to the mutation. The fourth patient did not have mutation information but had a history of colonic and endometrial carcinomas; both lacked MSH2 and MSH6 proteins. Interestingly, none of the 4 unusual tumors revealed microsatellite instability on polymerase chain reaction testing, whereas an appendiceal carcinoma from 1 of the study patients who was tested simultaneously did. The recognition of such tumors expands the repertoire of usable test samples for the workup of high-risk families. As yet, however, there are no data to support the inclusion of these tumors into general screening guidelines for detecting Lynch syndrome, nor are there data to warrant surveillance for these tumors in patients with Lynch syndrome.

Copyright © 2012 Elsevier Inc. All rights reserved.
Latent TGF-β binding proteins (LTBPs) 1 and 3 differentially regulate transforming growth factor-β activity in malignant mesothelioma. P. Vehviläinen, K. Koli, M. Myllärniemi, et al. 2011;42(2):269-78. PubMed · Publisher

Abstract

Malignant mesothelioma is an aggressive cancer of the pleura with poor prognosis. There is a need to identify new biomarkers and therapeutic targets for this invasive and fatal disease. Transforming growth factor β (TGF-β) can promote mesothelioma tumorigenesis through multiple mechanisms. Latent TGF-β binding proteins (LTBPs) regulate TGF-β activation by targeting the growth factor into the extracellular matrix from where it can be released and activated. We investigated here the expression patterns of different LTBP isoforms in malignant mesothelioma tissues and in 2 established malignant mesothelioma cell lines. All LTBPs were expressed, but LTBP-3 was the main isoform in healthy pleura and in cultured nonmalignant mesothelial cells. We observed down-regulation of LTBP-3 expression in malignant mesothelioma, which was associated with high P-Smad2 levels indicative of TGF-β activity specifically in the tumor tissue. Small interfering RNA-mediated suppression of LTBP-3 expression in mesothelioma cells increased the secretion of TGF-β activity. Immunoreactivity of LTBP-1, on the other hand, was markedly strong in the tumor stroma, which showed significantly lower levels of P-Smad2. A strong negative correlation between LTBP-1 and P-Smad2 immunoreactivity was found, implying that LTBP-1 is not likely to contribute directly to the increased levels of TGF-β activity in malignant mesothelioma. Current results suggest that LTBPs 1 and 3 may have specific roles in malignant mesothelioma pathogenesis through the regulation of TGF-β activation in the tumor tissue and the structure of the tumor stroma.

Copyright Â© 2011 Elsevier Inc. All rights reserved.
The use of insulin like-growth factor II messenger RNA binding protein-3 in diagnostic pathology. J.J. Findeis-Hosey, H. Xu. 2011;42(3):303-14. Review PubMed · Publisher

Abstract

The histologic distinction between reactive processes and malignant neoplasms and between low-grade and high-grade tumors is not always straightforward and is sometimes extremely challenging. This is especially the case when the diagnostic material is a small biopsy specimen or a cytology specimen with scant cellularity. In addition, suboptimal processing and crush artifact may limit accurate diagnosis. A reliable diagnostic biomarker that preferentially highlights malignant processes and high-grade tumors would be very valuable in segregating these entities from reactive processes and low-grade lesions. Recent extensive studies have shown that an oncoprotein, insulin like-growth factor II messenger RNA binding protein-3, is not only a prognostic biomarker but also a diagnostic molecule. This review focuses on discussing the value of insulin like-growth factor II messenger RNA binding protein-3 in diagnostic pathology, with a focus on utilization of insulin like-growth factor II messenger RNA binding protein-3 in the discrimination of benign effusions from malignant effusions, malignant mesothelioma from mesothelial hyperplasia, carcinoids from high-grade neuroendocrine carcinomas, low-grade dysplasia from high-grade dysplasia, hepatocellular carcinoma from hepatic adenoma, cholangiocarcinoma and metastatic pancreatic ductal carcinoma from benign bile duct lesions, melanoma from nevi, and follicular thyroid carcinoma from follicular adenoma of the thyroid, as well as examining insulin like-growth factor II messenger RNA binding protein-3 expression in lymphomas of germinal center origin.

Copyright © 2011 Elsevier Inc. All rights reserved.
IMP3/L523S, a novel immunocytochemical marker that distinguishes benign and malignant cells: the expression profiles of IMP3/L523S in effusion cytology. K. Ikeda, G. Tate, T. Suzuki, et al. 2010;41(5):745-50. PubMed · Publisher

Abstract

Differentiating reactive mesothelial cells from metastatic carcinoma and malignant mesothelioma is critical in effusion cytology. Numerous immunohistochemical/cytochemical reports use various antibodies in effusion samples, and most antibodies differentiate metastatic adenocarcinoma from malignant mesothelioma, but no antibodies help distinguish malignant mesothelioma from reactive mesothelial cells. A mouse monoclonal antibody (IMP3/L523S) against KOC is a 580-amino acid oncofetal RNA-binding protein containing 4 K homology domains. IMP3/L523S has been identified in several human malignant tumors. The immunocytochemical staining profile of IMP3 was determined in 95% alcohol-fixed cytologic effusion specimens. A total of 229 cases of pleural and peritoneal effusion cytospecimens were evaluated for the study, including 39 benign effusions with reactive mesothelial cells and 190 metastatic malignant effusions. IMP3 immunoreactivity was observed in 2 (5.1%) of 39 cases of reactive mesothelial cells, 138 (72.6%) of 190 cases of malignant effusion, 4 (36.4%) of 11 cases of malignant mesothelioma, 106 (75.7%) of 140 cases of metastatic adenocarcinoma, and 8 (100%) of 8 cases of squamous cell carcinoma. The overall specificity for the diagnosis of malignancy was 94.9%, whereas the sensitivity was 72.6%. In the peritoneal effusions, the sensitivity for the diagnosis of metastatic adenocarcinoma to distinguish reactive mesothelial cells was 92.3%. In conclusion, IMP3 staining is present in many carcinomas and is not a useful marker for distinguishing between carcinomas arising in different organs. However, the IMP3 antibody is a highly specific marker for malignant lesions, and thus, IMP3 staining is useful for distinguishing neoplastic cells from reactive mesothelial cells in effusion samples.

Copyright 2010 Elsevier Inc. All rights reserved.
Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter. K. Tan, K. Kajino, S. Momose, et al. 2010;41(9):1330-8. PubMed · Publisher

Abstract

Gene methylation leads to malignant progression in some tumors. The mechanism by which mesothelin is expressed in malignant mesothelioma (MM) is not well understood. MM is histologically divided into 3 subtypes, that is, the epithelioid, sarcomatoid, and biphasic types, and it was shown that mesothelin expression was restricted to the epithelioid type and the epithelioid component of the biphasic type of MM. However, its regulatory mechanism of expression has not been clarified. Here, we studied the expression of mesothelin by immunohistochemistry along with the methylation status of 20 CpG sites in the promoter of the mesothelin gene (MSLN) in 118 lung specimens, including 39 MM, 41 lung carcinoma, 26 nonneoplastic pulmonary lesions, and 12 normal lung tissue samples by the methylation-sensitive single nucleotide primer extension technique. We confirmed that mesothelin was expressed in the epithelioid type and epithelioid component of the biphasic type of MM but neither in the sarcomatoid type nor sarcomatous component of the biphasic type. Surprisingly, the MSLN promoter was significantly hypomethylated in the MM cases regardless of its subtype, compared with the other pulmonary lesions and normal lung tissue samples. These findings suggested that hypomethylation of the MSLN promoter may be specifically associated with the formation of MM, regardless of its expression status, and that the expression of mesothelin protein was lost in the sarcomatoid type by some unknown posttranscriptional regulatory mechanism. We also identified 4 CpG sites, among the 20 sites studied, to be more specifically hypomethylated in MM cases.

Copyright 2010 Elsevier Inc. All rights reserved.
Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. J.A. Bishop, R. Sharma, P.B. Illei. 2010;41(1):20-5. PubMed · Publisher

Abstract

Recent advances in the treatment of pulmonary adenocarcinoma have increased the need for accurate typing of non-small cell carcinomas. Immunohistochemistry for thyroid transcription factor-1 is widely used in the diagnosis of pulmonary adenocarcinomas because it marks approximately 75% of lung adenocarcinomas and is negative in most squamous cell carcinomas and adenocarcinomas of other organs. Napsin A is an aspartic proteinase involved in the maturation of surfactant protein B. It is detected in the cytoplasm of type 2 pneumocytes and alveolar macrophages and is a putative marker for pulmonary adenocarcinomas. We performed immunohistochemistry for napsin A and thyroid transcription factor-1 using tissue microarrays of 95 adenocarcinomas, 48 squamous cell carcinomas, 6 neuroendocrine tumors of the lung, as well as 5 colonic, 31 pancreatic, and 17 breast adenocarcinomas, 38 malignant mesotheliomas, 118 renal cell carcinomas, and 81 thyroid tumors. The tissue microarrays also included 15 different benign tissues. Pulmonary adenocarcinomas were napsin A positive in 79 (83%) of 95 cases compared with 69 (73%) of 95 cases that were thyroid transcription factor-1 positive. There were 13 napsin A-positive/thyroid transcription factor-1-negative and 2 thyroid transcription factor-1-positive/napsin A-negative tumors, increasing the number of cases that were positive with at least one of the markers to 81 (85%) of 95. The limited number of neuroendocrine tumors tested was napsin A negative. All squamous cell carcinomas, adenocarcinomas of the colon, pancreas and breast, and mesotheliomas were negative for both markers. Of the renal tumors, napsin A was positive in most of papillary renal cell carcinomas (79%), about one third (34%) of clear cell renal cell carcinomas, and in a single case of chromophobe renal cell carcinoma (3%). In the thyroid, only 2 cases of papillary thyroid carcinoma (5%), both with tall cell morphology, were positive for napsin A, whereas all other papillary and follicular carcinomas were negative. As expected, all renal tumors were thyroid transcription factor-1 negative, and all thyroid tumors, except for one papillary carcinoma, were thyroid transcription factor-1 positive. Napsin A is a sensitive marker for pulmonary adenocarcinoma and is also expressed in a subset of renal cell carcinomas, particularly of the papillary type, as well as in rare cases of papillary thyroid carcinomas. The combined use of napsin A and thyroid transcription factor-1 results in improved sensitivity and specificity for identifying pulmonary adenocarcinoma in primary lung tumors and in a metastatic setting.

2000s

PRK1 distribution in normal tissues and carcinomas: overexpression and activation in ovarian serous carcinoma. M.T. Galgano, M. Conaway, A.M. Spencer, et al. 2009;40(10):1434-40. PubMed · Publisher · Free full text

Abstract

Protein kinase C-related kinases are regulated by phosphatidylinositol-3-kinase and Rho family GTPases. The isoform PRK1 has been characterized in detail in prostate cancer, but not in other carcinomas. We analyzed our prior microarray data for PRK1 gene expression in 175 carcinomas and evaluated tissue microarrays for protein expression in 251 carcinomas and a comprehensive group of normal tissues. We also used immunoblotting to determine the levels and phosphoactivation status of PRK1, PRK2, and PDK1 in 12 ovarian serous carcinomas, SKOV3 cells, and 3 samples of normal ovarian surface epithelium (OSE). The highest average level of PRK1 messenger RNA was observed in ovarian serous carcinomas compared with all other carcinomas, including those of the prostate, bladder/ureter, breast, colon, stomach/esophagus, kidney, liver, pancreas, and lung (P = .05). By immunohistochemistry, PRK1 was observed in selected normal cells, including epithelium from the gynecologic tract and hematolymphoid elements. All serous ovarian and endometrial endometrioid adenocarcinomas and mesotheliomas were immunoreactive for PRK1. The findings in nonserous ovarian and most carcinomas from the prostate, breast, and pancreas were also positive but less consistently so. In comparison with OSE, the serous carcinomas typically had greater pPRK1/total PRK1 (P = .02) as well as greater pPDK/total PDK (P = .01). The relative phosphorylation status of these 2 kinases correlated within each sample. In summary, PRK1 is present in various malignancies, but especially in serous carcinomas, where the increased activation status of PRK1 and its upstream regulator, PDK, as compared with normal OSE suggests a role in ovarian cancer development or progression.
Twenty-five years of fiber analysis: what have we learned?. V.L. Roggli, R.T. Vollmer. 2008;39(3):307-15. PubMed · Publisher

Abstract

Asbestos exposure has resulted in a variety of diseases, including asbestosis, carcinoma of the lung (LC), pleural plaques, and malignant mesothelioma (MM). We hypothesized that there have been significant changes in the mineral fiber content of lung tissue from individuals with these diseases over the past 25 years. Asbestos content was measured in lung tissue samples from 819 individuals using light microscopy (to measure asbestos body concentrations) and scanning electron microscopy (to measure types and concentrations of mineral fibers). Cases were divided chronologically according to those occurring in the first half (group 1) versus those occurring in the second half (group 2). The study included 419 cases of MM, 206 cases of asbestosis, and 340 cases of LC. The median asbestos body count (in asbestos bodies per gram) decreased from group 1 to group 2 for each disease: MM, 480 to 350; asbestosis, 24700 to 19200; and LC, 1600 to 174 (reference range, 0-20). A similar trend was observed for fiber counts by scanning electron microscopy. Amosite was the most frequently detected asbestos fiber type and decreased in frequency of detection and median concentration from group 1 to group 2. Crocidolite showed an increased detection frequency from group 1 to group 2 across all 3 disease categories. The decrease in asbestos body and amosite concentrations over time is consistent with the banning of asbestos from insulation products in 1972. The source for the increased detection of crocidolite was not identified and needs further investigation.
Mesothelioma with clear cell features: an ultrastructural and immunohistochemical study of 20 cases. N.G. Ordóñez. 2005;36(5):465-73. PubMed · Publisher

Abstract

Mesotheliomas with clear cell morphology are rare and only a few individual case reports have been documented in the literature. The author reports a series of 20 epithelioid mesotheliomas with clear features, 17 of which originated in the pleura and 3 in the peritoneum. Eighteen of the patients were men and 2 were women. Twelve patients had a history of asbestos exposure. Electron microscopy and special histochemical stains demonstrated that the cytoplasmic clearing seen in hematoxylin and eosin-stained sections resulted from multiple factors that can occur either singly or in combination. The most frequent cause of the cytoplasmic clearing was the accumulation of large amounts of intracytoplasmic glycogen. Another but somewhat less common factor was the accumulation of large amounts of lipid, which occurred alone or with glycogen. Other less common causes were marked mitochondrial swelling, the presence of numerous intracytoplasmic vesicles, and a large number of intracytoplasmic lumens. The value of immunohistochemistry in helping to distinguish epithelioid mesotheliomas from some carcinomas with clear cell morphology is emphasized. In addition, it was determined that because electron microscopy was decisive in establishing the cause of the cytoplasmic clearing in most of the cases, tissue for electron microscopy should routinely be procured for ultrastructural studies.
Asbestos bodies: clues to the mechanism of asbestos toxicity?. A.B. Kane. 2003;34(8):735-6. Comment · Editorial PubMed · Publisher

Summary

This editorial commented on a study by Ghio and colleagues, in the same issue of Human Pathology, of asbestos bodies coated with calcium oxalate crystals. The author summarized the diseases associated with asbestos exposure, noted that asbestos bodies in sputum or lung tissue are a histopathologic hallmark of exposure, and outlined fiber properties linked to biologic reactivity, including surface iron. Ghio and colleagues had described 3 patients with occupational asbestos exposure whose sputum and lungs contained such bodies; 2 had asbestosis and 1 was diagnosed with diffuse malignant mesothelioma at autopsy. In in vitro assays using uncoated crocidolite fibers or asbestos bodies from digested human lung, ascorbate was oxidized to oxalate in the presence of H2O2, a reaction inhibited by the iron chelator deferoxamine. The author called this a novel mechanism that may contribute to the pathogenicity of asbestos fibers. Oxidation of ascorbate, an important antioxidant in the lung lining fluid, could contribute to redox cycling of iron and deplete antioxidant defenses, enhancing oxidant-induced lung injury. She suggested the mechanism may contribute to the progressive nature of asbestosis and to the increased incidence of lung cancer and mesothelioma even after exposure ceases. She added that, if it is confirmed in animal models and further human studies, it could lead to a new strategy for chemoprevention.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Oxalate deposition on asbestos bodies. A.J. Ghio, V.L. Roggli, J.H. Richards, et al. 2003;34(8):737-42. Case report PubMed · Publisher

Abstract

We report on a deposition of oxalate crystals on ferruginous bodies after occupational exposure to asbestos demonstrated in 3 patients. We investigated the mechanism and possible significance of this deposition by testing the hypothesis that oxalate generated through nonenzymatic oxidation of ascorbate by asbestos-associated iron accounts for the deposition of the crystal on a ferruginous body. Crocidolite asbestos (1000 microg/mL) was incubated with 500 micromol H(2)O(2) and 500 micromol ascorbate for 24 hours at 22 degrees C. The dependence of oxalate generation on iron-catalyzed oxidant production was tested with the both the metal chelator deferoxamine and the radical scavenger dimethylthiourea. Incubation of crocidolite, H(2)O(2), and ascorbate in vitro generated approximately 42 nmol of oxalate in 24 hours. Oxalate generation was diminished significantly by the inclusion of either deferoxamine or dimethylthiourea in the reaction mixture. Incubation of asbestos bodies and uncoated fibers isolated from human lung with 500 micromol H(2)O(2) and 500 micromol ascorbate for 24 hours at 22 degrees C resulted in the generation of numerous oxalate crystals. We conclude that iron-catalyzed production of oxalate from ascorbate can account for the deposition of this crystal on ferruginous bodies.
Nup88 (karyoporin) in human malignant neoplasms and dysplasias: correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysis. V.E. Gould, A. Orucevic, H. Zentgraf, et al. 2002;33(5):536-44. PubMed · Publisher

Abstract

Nuclear pore complexes (NPCs) are elaborate macromolecular structures that regulate the bidirectional nucleocytoplasmic traffic system. In vertebrate cells, NPCs include a family of 50 to 100 proteins termed nucleoporins (Nups). The 88-kD Nup has been found to be linked in a dynamic subcomplex with the oncogenic CAN/Nup214. Applying a polyclonal antiserum to Nup88 on paraffin sections, we found that it immunoreacts with numerous malignant neoplasms. All carcinomas reacted irrespective of site, type, or degree of differentiation; often, high-grade carcinomas stained more strongly and extensively. Some sarcomas (e.g., fibrosarcomas, leiomyosarcomas, liposarcomas, and rhabdomyosarcomas) reacted intensely; melanomas, gliomas, mesotheliomas, and malignant lymphomas also stained. In situ carcinomas of the colon, stomach, breast, and prostate stained convincingly, as did in situ melanomas; some samples of fetal tissues also reacted. Cytologic smears of some of the aforementioned tumors also stained. In selected samples, enhanced immunostaining of tissue sections and cytologic smears correlated strongly and consistently with immunoblot data. Immunoblots of the same tumors with antibodies to 2 other Nups (Nup214 and Nup153) showed no comparable enhancement. Therefore, it seems that in some malignant tumors, Nup88 overexpression is not parallelled by an overexpression of other Nups. Benign tumors, hyperplasias, and normal tissues showed weak and sporadic staining or absence of staining; immunoblots of the same samples yielded weak signals. Occasional highly proliferative hyperplastic-reactive processes showed focal staining. Thus, our correlative histologic, cytologic, and molecular data indicate that Nup88 may be viewed as a potentially useful, broadly based histodiagnostic and molecular marker of many malignancies and premalignant dysplasias, and further suggest that in some malignant tumors, Nup88 may be selectively overexpressed as compared with other Nups. Thus, we propose that Nup88 be designated as karyoporin.

Copyright 2002, Elsevier Science (USA). All rights reserved.
Overexpression of gamma-glutamylcysteine synthetase in human malignant mesothelioma. K. Järvinen, Y. Soini, K. Kahlos, et al. 2002;33(7):748-55. PubMed · Publisher

Abstract

Mesothelioma is a fatal tumor resistant to all treatment modalities for reasons that are still unresolved. Glutathione (GSH)-associated pathways are induced by oxidants and cytotoxic drugs, and they are also involved in the progression and resistance of some tumor cells in vitro. The rate-limiting enzyme in GSH biosynthesis is gamma-glutamylcysteine synthetase (gamma GCS). However, the expression of this enzyme has not been systematically investigated in malignant tumors, and there are no studies of gamma GCS in biopsy specimens of malignant mesothelioma. We investigated the immunohistochemical distribution and expression of both subunits of gamma GCS in healthy pleural mesothelium, pleural mesothelioma tumor biopsy samples (34 cases), and mesothelioma cells in culture (7 cell lines). Nonmalignant mesothelium showed no immunoreactivity for either subunit in any of the cases. The heavy (catalytic) subunit of gamma GCS was highly immunostained in 29 and weakly positive in 5 cases. High-moderate and weak immunoreactivity of the light (regulatory) subunit of gamma GCS was found in 15 and 7 tumors, respectively, whereas 12 cases showed no reactivity. There was no correlation with either catalytic or regulatory subunit expression and patient survival. There was, however, a significant correlation between the heavy chain and multidrug resistance protein (MRP) 2 (P =.048), whereas no correlation was observed between the light chain and MRP1 or MRP2. Treatment of cultured mesothelioma cells with buthionine sulfoximine (BSO), to inhibit gamma GCS, significantly potentiated cisplatin-induced cytotoxicity mainly by nonapoptotic mechanism when assessed by counting the living cells, TUNEL (terminal deoxytransferase-mediated dUTP nick-end labeling) assay, and caspase-3 cleavage. In conclusion, gamma GCS is highly positive in most cases of malignant mesothelioma and may play an important role in the primary drug resistance of this tumor in vivo.

Copyright 2002, Elsevier Science (USA). All rights reserved.
Calretinin, thrombomodulin, CEA, and CD15: a useful combination of immunohistochemical markers for differentiating pleural epithelial mesothelioma from peripheral pulmonary adenocarcinoma. C.E. Comin, L. Novelli, V. Boddi, et al. 2001;32(5):529-36. PubMed · Publisher

Abstract

The distinction between pleural epithelial mesothelioma and peripheral lung adenocarcinoma involving the pleura is still an important diagnostic problem for surgical pathologists. The aim of our study was to identify the most specific and sensitive markers for the positive identification of mesothelioma to select a limited, appropriate panel of antibodies to differentiate between mesothelioma and adenocarcinoma. Forty-two cases of epithelial mesotheliomas and 23 cases of pulmonary adenocarcinomas were stained with the following antibodies: anticalretinin, antithrombomodulin, anti-CD44H, and monoclonal antibody HBME-1. We also studied the value of other markers in current use: cytokeratins AE1/AE3 and CAM5.2, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), Ber-EP4, B72.3, and CD15. Of the mesotheliomas, 42 stained for calretinin, 39 (92.8%) for thrombomodulin, 42 stained for CD44H, and 41 (97.6%) stained for HBME-1. Among negative markers, 4 (9.5%) mesothelioma cases stained for CEA, 5 (11.9%) stained for Ber-EP4, 6 (14.2%) stained for B72.3, and 2 (4.7%) stained for CD15. Of the lung adenocarcinomas, 2 (8.7%) cases showed reactivity for calretinin, 5 (21.7%) for thrombomodulin, 13 (56.5%) for CD44H, all for HBME-1, 22 (95.6%) for CEA, 22 (95.6%) for Ber-EP4, 8 (34.7%) for B72.3, and all for CD15. In conclusion, calretinin and thrombomodulin were the most specific positive mesothelial markers, whereas CD44H and HBME-1 showed high sensitivity but very low specificity. Among negative markers, we advocate the use of CEA and CD15 which were the most specific in differentiating mesotheliomas from adenocarcinomas.
Expression of the retinoblastoma-related gene Rb2/p130 is downregulated in atypical endometrial hyperplasia and adenocarcinoma. T. Susini, D. Massi, M. Paglierani, et al. 2001;32(4):360-7. PubMed · Publisher

Abstract

The retinoblastoma-related gene Rb2/p130 encodes a protein that is a negative cell-cycle regulator normally expressed in a number of adult tissues. This protein shares many structural and functional features with the product of the retinoblastoma gene, one of the best-studied tumor-suppressor genes, and plays a fundamental role in growth control. The Rb2/p130 gene product associates with specific members of the E2F family and various cyclins, displaying a growth-suppressive activity specific for the G(0)/G(1) phases. It has been reported that Rb2/p130 is involved in the pathogenesis and progression of lung cancer and mesothelioma. We previously demonstrated for the first time that reduced immunohistochemical expression of Rb2/p130 was a strong independent predictor of poor outcome in endometrial cancer. The aim of the present study was to evaluate Rb2/p130 expression in normal, hyperplastic, and neoplastic endometrial lesions to determine whether the protein plays a significant role in endometrial carcinogenesis. We evaluated Rb2/p130 expression by immunohistochemistry staining in 102 specimens chosen to represent a spectrum of endometrial changes, including proliferative endometrium (n = 18), secretory endometrium (n = 18), simple or complex hyperplasia without atypia (n = 18), atypical hyperplasia (n = 18), and invasive carcinoma (n = 30). We found that Rb2/p130 was highly expressed in proliferative endometrium and in hyperplasia without atypia, the mean percentage of stained nuclei being 66% and 60%, respectively, but was downregulated in secretory endometrium, atypical hyperplasia, and carcinoma, with mean scores of 38%, 25%, and 22%, respectively. When categorized on a semiquantitative scale (negative v 1% to 50% v >50% positivity), endometrial cancer displayed significantly less staining than all other endometrial samples (P <.001). Poorly differentiated carcinomas (n = 9) showed a significantly lower immunoreactivity for Rb2/p130 than did well-differentiated carcinomas (n = 11; P =.005) and moderately differentiated carcinomas (n = 10; P =.03). In addition, atypical hyperplasia showed a significantly lower immunoreactivity than either proliferative endometrium (P =.003) or hyperplasia without atypia (P = 0.02). Our findings of a progressive decrease in Rb2/p130 expression from hyperplastic endometrium through atypical hyperplasia to poorly differentiated carcinomas suggest the involvement of this negative cell-cycle regulator in endometrial carcinogenesis. Furthermore, immunostaining for Rb2/p130 may prove diagnostically useful in the often difficult distinction between hyperplastic and atypical hyperplastic endometrium. HUM PATHOL 32:360-367.

Copyright 2001 by W.B. Saunders Company
Malignant epithelioid vascular tumors of the pleura: report of a series and literature review. P.J. Zhang, V.A. Livolsi, J.J. Brooks. 2000;31(1):29-34. Case report · Review PubMed · Publisher

Abstract

Primary malignant vascular tumors of the pleura are rare. The significance and difficulty of distinction between pleural epithelioid hemangioendothelioma (EHE) and angiosarcoma have not yet been addressed. A new series of pleural angiosarcoma is reported, and the relevant literature is reviewed. Five cases were identified from files of the authors' institutions and personal consultation cases (J.J.B.). Twenty-six cases of primary malignant vascular tumors of the pleura were identified in the literature. In a total of 31 cases, 22 were from the West and 9 from Japan. Patients were 22 to 79 years old (average, 57), and the male/female ratio was 9:1. Prior chronic pyothorax was identified only in cases reported from Japan. History of exposure to radiation or asbestos was noted in a few Western cases. The most common presentation was pleural thickening and effusion. Almost all of the patients died of disease shortly after diagnosis. A spectrum of histology ranging from characteristic high-grade epithelioid to relatively low-grade EHE-like features was observed in our cases and can be found in previous reports. Most cases showed variable spotty cytokeratin immunoreactivity. Endothelial markers (factor 8, CD34, or CD31) were invariably positive. Pleural angiosarcomas are often epithelioid and can be easily mistaken for mesothelioma or carcinoma clinically and histologically. Awareness of this rare tumor should prompt the use of endothelial markers when faced with a questionable mesothelioma. When cytokeratin is negative, or focal with strong vimentin reactivity, a vascular tumor should be suspected and confirmed with vascular markers. Because of their invariably aggressive behavior, all epithelioid vascular tumors of the pleura should be considered highly malignant regardless of the presence of EHE-like histological features.
NCAM (neural cell adhesion molecules) expression in malignant mesotheliomas. S. Lantuéjoul, M.H. Laverrière, N. Sturm, et al. 2000;31(4):415-21. PubMed · Publisher

Abstract

Neural cell adhesion molecules (NCAM) are adhesion molecules expressed by neural and neuroendocrine tumors and a few biphasic tumors such as synovialosarcomas and breast phyllode tumors. To investigate NCAM expression in mesotheliomas, we studied 26 cases of epithelioid (n = 12), biphasic (n = 11), and sarcomatoid (n = 3) malignant mesotheliomas (MM), in comparison with normal mesothelium, and 50 primary non-small cell lung carcinomas (NSCLC) (25 adenocarcinomas [ADC] and 25 squamous cell carcinomas [SCC]), using electron microscopy as a gold standard for recognition of MM. NCAM reactivity using 123C3 antibody was compared with that of NE markers such as chromogranin A and synaptophysin. Although normal mesothelium remains negative, NCAM was expressed in 19 of 26 MM (73%) with a membranous staining on frozen or paraffin sections. In 6 of 12 epithelioid MM, the tumor cells expressed NCAM, whereas in 5 cases stromal fibroblasts showed a strong but focal staining. In 11 biphasic MM, 4 presented an NCAM reactivity of both epithelioid and spindle cell components, whereas in 7, only fusiform component was NCAM positive. Two of 3 sarcomatoid MM showed an NCAM expression. Chromogranin expression was never seen, whereas synaptophysin was noticed in 2 cases. No case of NSCLC showed membranous 123C3 staining, whereas 2 ADC weakly expressed synaptophysin. We conclude that NCAM expression in MM is reminiscent of its expression in mesoderm during fetal life and consistent with that reported in other biphasic tumors. These data show that NCAM expression occurs in 73% of MM, highly exceeding that observed in lung cancer.

1990s

Expression of E-cadherin in bone and soft tissue sarcomas: a possible role in epithelial differentiation. H. Sato, T. Hasegawa, Y. Abe, et al. 1999;30(11):1344-9. PubMed · Publisher

Abstract

The cadherin-mediated cell-cell adhesion system is now known to play a critical role in both the morphogenesis of cancer cells and suppression of their invasion. However, the pattern of expression of E-cadherin, the major cadherin of epithelial cells in bone and soft tissue sarcomas, remains unclear. This prompted us to study E-cadherin expression in a variety of bone and soft tissue sarcomas. Using the monoclonal antibody HECD-1, raised against the extracellular domain of E-cadherin, we observed immunoreactivity in 1 pleomorphic rhabdomyosarcoma, 2 of 5 diffuse mesotheliomas, 4 of 5 clear cell sarcomas, 1 of 5 epithelioid sarcomas, and 10 synovial sarcomas. Other types of bone and soft tissue sarcoma (4 osteosarcomas, 4 chondrosarcomas, 3 primitive neuroectodermal tumors, 1 fibrosarcoma, 4 malignant fibrous histiocytomas, 5 liposarcomas, 4 leiomyosarcomas, 6 alveolar and 5 embryonal rhabdomyosarcomas, 4 angiosarcomas, 4 malignant peripheral nerve sheath tumors, 2 extraskeletal myxoid chondrosarcomas, 2 extraskeletal osteosarcomas, and 3 alveolar soft part sarcomas) were completely negative for E-cadherin. Our findings indicate that E-cadherin is expressed in certain kinds of soft tissue sarcomas, especially those with epithelioid features, suggesting that E-cadherin plays a role in the constitution of their architecture.
Hyperplastic mesothelial cells in lymph nodes: report of six cases of a benign process that can stimulate metastatic involvement by mesothelioma or carcinoma. P. Argani, J. Rosai. 1998;29(4):339-46. PubMed · Publisher

Abstract

We report six cases of hyperplastic mesothelial cells located in the sinuses of lymph nodes. All patients but one had a concurrent serosal fluid collection (two pericardial, two pleural, one abdominal) at the time of the lymph node biopsy. All effusions cleared with treatment of the underlying disorder, which included lymphoproliferative processes, congestive heart failure, and inflammatory diseases (Dressler syndrome, vasculitis, and glomerulonephritis). Four cases were associated with vascular prominence of the involved nodal sinuses, a feature that may reflect the cause of the underlying effusion or support the transient persistence of benign mesothelial cells in lymph nodes. Two cases were characterized by distention of the nodal sinuses by sheets of mitotically active mesothelial cells. The differential diagnosis includes metastatic carcinoma, keratin-positive dendritic cells native to lymph nodes, and metastatic malignant mesothelioma. Because the latter shares both clinical and morphological features with cases of benign mesothelial cells in lymph nodes, we believe that this distinction may not always be possible in a given biopsy specimen and therefore that careful clinical follow-up is required in such cases.
Prognosis in malignant mesothelioma related to MIB 1 proliferation index and histological subtype. T.W. Beer, R. Buchanan, A.W. Matthews, et al. 1998;29(3):246-51. PubMed · Publisher

Abstract

The aims of this study were to evaluate the use of the proliferation marker MIB 1 and histological subtype as indicators of prognosis in malignant mesothelioma. Sections from 41 cases of malignant mesothelioma were histologically subtyped on hematoxylin and eosin sections and stained immunohistochemically for the proliferation marker MIB 1. A proliferation index was derived and the results compared with patient survival data. A statistically significant difference was found between the survival of patients having a low and high MIB 1 index (P < .001). Patients with tumors having a low MIB 1 index lived significantly longer than those with a high MIB 1 index. Patients with the spindle cell histological subtype of malignant mesothelioma had significantly shorter survival times than those with the epithelioid or mixed tumors (P < .01). The MIB 1 proliferation index and histological tumor subtype are useful markers of prognosis in malignant mesothelioma.
Ultrastructural features of diffuse malignant mesotheliomas. T.D. Oury, S.P. Hammar, V.L. Roggli. 1998;29(12):1382-92. Review PubMed · Publisher

Abstract

The distinction of malignant mesothelioma from tumors metastatic to the serosal membranes can often be made based on the results of histochemical or immunohistochemical studies. However, in some cases, these techniques are inadequate to make a firm diagnosis. In these instances, electron microscopic studies with the observation of a constellation of characteristic ultrastructural findings may permit an unequivocal diagnosis of mesothelioma.
Value of the MOC-31 monoclonal antibody in differentiating epithelial pleural mesothelioma from lung adenocarcinoma. N.G. Ordóñez. 1998;29(2):166-9. PubMed · Publisher

Abstract

MOC-31 is a monoclonal antibody that has recently become commercially available that recognizes an epithelial-associated, transmembrane glycoprotein often expressed in epithelial tumors. Although some authors have indicated that MOC-31 immunostaining can assist in distinguishing epithelial mesotheliomas from metastatic adenocarcinomas to the pleura, others have concluded that this marker has no value in separating these conditions. To determine whether MOC-31 immunostaining can assist in discriminating epithelial pleural mesothelioma from lung adenocarcinoma or from other carcinomas metastatic to the pleura, 38 epithelial pleural mesotheliomas, 40 pulmonary adenocarcinomas, 55 nonpulmonary adenocarcinomas, six squamous cell carcinomas of the lung (SCCLs), three small-cell lung carcinomas (SCLCs), 19 bronchial carcinoids (BCs), and 15 transitional cell carcinomas (TCCs) were studied. Reactivity was obtained in two (5%) of the mesotheliomas, in all 40 (100%) pulmonary adenocarcinomas, in 45 (82%) nonpulmonary adenocarcinomas, in six (100%) SCCLs, three (100%) SCLCs, 15 (83%) BCs, and 10 (67%) TCCs. The staining in the two positive mesotheliomas was restricted to a few cells, in contrast to the pulmonary adenocarcinomas and most of the other carcinomas where it was often strong and diffuse. It is concluded that MOC-31 can be useful in separating epithelial pleural mesothelioma from pulmonary adenocarcinoma or from other epithelial malignancies involving the pleura.
Differential expression of N-cadherin in pleural mesotheliomas and E-cadherin in lung adenocarcinomas in formalin-fixed, paraffin-embedded tissues. A.C. Han, A. Peralta-Soler, K.A. Knudsen, et al. 1997;28(6):641-5. PubMed · Publisher

Abstract

The differential diagnosis of pleural mesotheliomas and lung adenocarcinomas presents a continued challenge in the practice of surgical pathology. Paraffin immunohistochemistry (IHC) using different panels of antibodies can be helpful in some cases, but, as yet, no antigen is expressed specifically in mesotheliomas nor in adenocarcinomas. Using well characterized monoclonal antibodies (MAb) that recognized distinct mesenchymal and epithelial adhesion proteins, N-cadherin (13A9 MAb) and E-cadherin (E9 MAb), respectively, we found previously that in frozen-section IHC mesotheliomas and adenocarcinomas had distinct cadherin phenotypes: mesotheliomas were positive for N-cadherin, and lung adenocarcinomas were positive for E-cadherin. Using antigen-retrieval methods, we successfully extended our study to formalin-fixed, paraffin-embedded tissue sections. Tumors from 28 patients (14 originally diagnosed as mesotheliomas, and 14 diagnosed as adenocarcinomas) were stained with 13A9 MAb and E9 MAb. Review of hematoxylin-eosin sections excluded from analysis one case previously diagnosed as mesothelioma, which represented a hemangiopericytoma. Of the remaining 27 cases, 12 of 13 mesotheliomas were positive for N-cadherin and negative for E-cadherin. The exception was a multifocal microscopic papillary tumor of apparent mesothelial origin, which was negative for both N-cadherin and E-cadherin. Conversely, 13 of 14 adenocarcinomas were E-cadherin positive and N-cadherin negative except for one adenocarcinoma with focal N-cadherin expression. One case of a poorly differentiated adenocarcinoma invading skeletal muscle was negative for both 13A9 and E9. These studies confirmed the utility of the cadherin antibodies in distinguishing pleural mesotheliomas from lung adenocarcinomas. The reactivity of the cadherin-specific antibodies with antigens in paraffin sections make them powerful and reliable markers in the practice of diagnostic surgical pathology.
Immunolocalization of integrins in the normal lung and in pulmonary carcinomas. G.K. Koukoulis, W.H. Warren, I. Virtanen, et al. 1997;28(9):1018-25. PubMed · Publisher

Abstract

Cryosections of normal adult lung (n = 7) and pulmonary epithelial tumors, including squamous (n = 8), adeno (n = 8), bronchioloalveolar (n = 5), and large cell (n = 4) carcinomas (SCC, ACC, BAC, LCC), carcinoids (Cd, n = 7), and neuroendocrine carcinomas (NEC) of variable grades (n = 14) were immunostained by the avidin-biotin peroxidase (ABC) method with monoclonal antibodies to the alpha1-6 and alpha(v) and the beta1-4 integrin subunits. Normal adult alveolar septae showed variably intense immunoreactivity for alpha1,3,6 and beta1, whereas reactions for alpha5 and alpha(v) were weaker and uneven; the remaining integrin subunits were not detected. Bronchial and bronchiolar epithelium showed variably intense staining for alpha2.3,6,v and beta1,4. Reactions were often, though not invariably, basally polarized. SCC, ADC, and LCC showed variably intense reactions for alpha2.3,6,v and beta1,4. BAC were strongly and uniformly stained for alpha1.3 and beta1. In Cd, alpha1,2,3,v and beta1 reactions were noted, whereas in NEC, weak alpha1,3 and beta1 staining was detected with only traces of alpha6 and alpha(v). We conclude that alveolar epithelial cells do not express the hemidesmosome-associated, laminin-binding integrin alpha6beta4 of the bronchial epithelium but rather the alpha1beta1 and alpha3beta1, collagen IV, and laminin receptors, respectively. SCC, ADC, and sampled LCC express an integrin repertory qualitatively similar to that of the bronchial epithelium. Distinct from the latter, the integrin repertory of BAC parallels that of the alveolar epithelium by its strong expression of the multipotential alpha1beta1 and alpha3beta1 integrins. NEC tumors do not display the laminin receptors alpha6beta4 and alpha6beta1 shown by SCC and ADC but express instead alpha1beta1, a collagen IV-laminin receptor rarely found in epithelial neoplasms except for BAC. In NEC tumors, integrins, especially alpha2, decrease with dedifferentiation. Notably distinct from epithelial mesotheliomas, the major fibronectin-binding integrin alpha5beta1 was not found in any type of lung carcinoma.
Increasing role of immunopathology in diagnosis of malignant mesothelioma. K. Sheibani. 1997;28(6):639-40. Comment · Editorial PubMed · Publisher
Metastatic malignant mesothelioma presenting as colonic polyps. A.V. Masangkay, M. Susin, R. Baker, et al. 1997;28(8):993-5. Case report PubMed · Publisher

Abstract

A 66-year-old male engineer diagnosed with malignant pleural mesothelioma 4 years previously had thoracotomy, radiotherapy, and chemotherapy. He was followed regularly with chest computed tomography (CT) scan and had been asymptomatic. During one of his physical examinations, routine sigmoidoscopy showed incidental colonic polyps which were biopsied. Subsequently, recurrence of pleural mesothelioma and peritoneal involvement by mesothelioma was documented. Two of the polyps showed metastatic malignant mesothelioma in the lamina propia which strongly resembled adenocarcinoma histologically causing difficulty in making definitive diagnosis. Review of the literature disclosed no previously documented similar occurrence. This case shows the importance of clinical history and ancillary laboratory procedures such as immunohistochemistry and electron microscopy to avoid diagnostic pitfalls.
Pleural mesotheliomas have an integrin profile distinct from visceral carcinomas. G.K. Koukoulis, J. Shen, R. Monson, et al. 1997;28(1):84-90. PubMed · Publisher

Abstract

Cryosections of epithelial, sarcomatoid, and biphasic malignant mesotheliomas (EMM, n = 11; SMM, n = 5; BMM, n = 6) of the pleura were immunostained with monoclonal antibodies to integrin subunits alpha 1-6 and v, and beta 1-4. Localization patterns were compared with those known to occur in pulmonary and other adenocarcinomas (PADC, ADC). EMM and the epithelial component of BMM (ecBMM) expressed alpha 1,3,5,6, and v and beta 1 and 4. SMM and the sarcomatoid elements of BMM (scBMM) reacted variably for alpha 1,3,5,6 and v, and beta1. Reactions for alpha3, found in all tumors, were strongest in EMM, ecBMM, and PADC. Our findings indicate that EMM and ecBMM parallel PADC and most ADC in their expression of alpha6 beta4, underscoring that this laminin integrin receptor is intimately associated with these neoplastic epithelial phenotypes. Also, our observations on alpha3 beta1 suggest that this cell-cell adhesion-mediating integrin is related to the epithelial phenotype. Notably, all malignant mesotheliomas (MM), including those with distinct glandular structures, expressed the alpha5 beta1 fibronectin receptor, thus paralleling most sarcomas and differing from PADC and most other ADC. We conclude that irrespective of architectural and cytologic variants, transformed mesothelial cells possess an integrin repertory that differs significantly from that of most ADC, including those of the lung. These findings set mesothelium apart from epithelia and may prove helpful as adjunct tools for the differential diagnosis between EMM and AD.
E-cadherin in mesothelioma. M. Jeffers. 1996;27(11):1245-6. Comment · Letter PubMed · Publisher
Lepidic intrapulmonary growth of malignant mesothelioma presenting as recurrent hydropneumothorax. H. Wu, G. Tino, F.H. Gannon, et al. 1996;27(9):989-92. Case report PubMed · Publisher

Abstract

We report a case of malignant mesothelioma with unusual clinical and histological findings. The patient presented with recurrent hydropneumothorax and minimal pleural thickening on chest computed tomography (CT). Histologically, the pleura was involved by the malignant mesothelioma, albeit to a limited degree. Unexpectedly, the lung parenchyma from two different lobes showed focal nests of mesothelioma cells filling the alveolar spaces and growing on the luminal surface of the alveolar septa, closely resembling the multicentric growth pattern of bronchioloalveolar adenocarcinoma. Immunohistochemical and ultrastructural studies confirmed that the pulmonary lesions were an extension of the malignant mesothelioma. This case illustrates clinically, the importance of a high index of suspicion for malignancy in older patients with unexplained recurrent hydropneumothorax; and histologically the potential of malignant mesothelioma to invade the lung at an early stage of growth.
Expression of muscle actins in diffuse mesotheliomas. I.T. Kung, V. Thallas, E.J. Spencer, et al. 1995;26(5):565-70. PubMed · Publisher

Abstract

Ultrastructural examinations have shown myofibroblastoid differentiation in sarcomatoid/desmoplastic mesotheliomas, but immunohistochemical expression of muscle actins seldom has been documented. We examined 10 sarcomatoid, 12 epithelial, and five biphasic mesotheliomas immunohistochemically for the expression of muscle-specific actin (MSA) and smooth muscle actin (SMA) and compared it with that in 12 specimens of lung cancer. All of the sarcomatoid mesotheliomas were found to be positive for both MSA and SMA. The epithelial cells in nine epithelial and two biphasic mesotheliomas were positive for MSA, but SMA was only positive in one epithelial mesothelioma. Conversely, the lung cancers were negative for both MSA and SMA in the epithelial cells, except for one specimen that was weakly positive for MSA. The stromal cells in both the epithelial mesotheliomas and lung cancers were negative for cytokeratin but were positive for MSA and SMA, whereas the sarcomatoid and biphasic mesothelioma spindle cells were positive for all three antibodies. We concluded that sarcomatoid mesothelioma was positive for MSA and SMA, which is in support of its myofibroblastic differentiation, and that positivity for MSA in some epithelial mesotheliomas might be of diagnostic value in differentiation from lung cancers.
Keratins 7 and 20 as diagnostic markers of carcinomas metastatic to the ovary. C.C. Wauters, F. Smedts, L.G. Gerrits, et al. 1995;26(8):852-5. PubMed · Publisher

Abstract

The most common carcinomas metastatic to the ovary that mimic ovarian primaries are colonic adenocarcinomas and endometrial carcinomas. Conventional histochemical staining procedures, even in combination with additional immunohistochemical assays, are of limited value in distinguishing between these metastases and primary ovarian carcinomas. In this study we investigated whether the application of monoclonal antibodies against keratins 7, 8, and 20 could help in differentiating between these categories. The reactivity patterns of 40 carcinomas metastatic to the ovary were compared with those of their primary carcinomas on the one hand and with various primary ovarian carcinomas and mesotheliomas on the other. Colon cancer metastatic to the ovary was keratin 7 negative and keratin 20 positive in 94% of the cases; in contrast, all primary ovarian carcinomas were keratin 7 positive and keratin 20 negative, with the exception of two cases of mucinous cystadenocarcinoma. Ovarian metastases of gastric cancer usually contained keratins 7 and 20. Metastases of endometrial cancer to the ovary and primary ovarian carcinomas usually showed similar keratin expression. We propose that keratin 7 and 20 antibodies may be of help to distinguish between primary ovarian carcinomas and carcinoma metastases in the ovary.
The differential expression of N-cadherin and E-cadherin distinguishes pleural mesotheliomas from lung adenocarcinomas. A. Peralta Soler, K.A. Knudsen, M.C. Jaurand, et al. 1995;26(12):1363-9. PubMed · Publisher

Abstract

Malignant mesotheliomas are highly aggressive tumors that develop most frequently in the pleura of patients chronically exposed to asbestos. The distinction between malignant mesotheliomas and tumors of epithelial origin, particularly peripheral lung adenocarcinoma, can be difficult despite the use of immunocytochemical markers and other diagnostic tools. During embryonic development the cadherin cell-cell adhesion molecules participate in the segregation of cells into different tissues. As a result of complex mechanisms of tissue selectivity, N-cadherin is expressed by the developing pleural mesothelial cells and E-cadherin is expressed by the epithelial cells of the lung. Thus, we postulated that N-cadherin could be used as a marker of mesothelial cells and mesothelial tumors, in contrast to adenocarcinomas of the lung that are tumors of epithelial origin. We studied the expression of N-cadherin, E-cadherin and two cadherin-associated proteins, alpha-catenin and beta-catenin, in 19 pleural mesotheliomas, 16 lung adenocarcinomas and in 2 mesothelioma cell lines using specific monoclonal antibodies and immunohistochemical methods. Our results show that all mesotheliomas express high levels of N-cadherin, regardless of their histological type, in contrast to lung adenocarcinomas which expressed E-cadherin but no N-cadherin. The cadherin-associated proteins, alpha-catenin and beta-catenin, were present in both mesotheliomas and adenocarcinomas. Our results show that pleural mesotheliomas can be distinguished from lung adenocarcinomas based on the differential expression of N-cadherin and E-cadherin, using specific monoclonal antibodies and immunocytochemistry.
Immunopathology of malignant mesothelioma. K. Sheibani. 1994;25(3):219-20. Comment · Editorial PubMed · Publisher

Summary

This editorial discussed the use of immunopathology to tell malignant mesothelioma apart from adenocarcinoma involving the pleura or peritoneum. It accompanied a study by Zeng et al in the same issue. The author noted that clinical and radiologic findings may not always help, that not all adenocarcinomas are mucin positive, and that the ultrastructural features of mesothelioma seen by electron microscopy are usually found only in well-differentiated epithelial tumours. He summarised Zeng et al's findings: all the human mesothelioma cell lines they studied reacted strongly with anticytokeratin and vimentin, and none expressed factor VIII, CEA or Leu-M1. In the author's experience, a panel of keratin, Leu-M1, Ber-EP4 and CEA was the most useful and cost-effective, though occasional cases needed more markers. Keratin staining helped separate sarcomatoid mesothelioma from keratin-negative sarcomas but not epithelial mesothelioma from adenocarcinoma. Leu-M1 staining was often focal, which could cause problems in small biopsies. In an earlier series, Ber-EP4 was expressed in 87% of adenocarcinomas but showed focal reactivity in only one of 115 mesotheliomas. The author also commented on CEA antibodies, the K-1 antibody, DNA ploidy analysis and experimental genetic markers. He concluded that until a mesothelioma-specific marker is identified, mesothelioma will remain a diagnosis of exclusion. The editorial did not discuss asbestos exposure.

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Malignant peritoneal mesothelioma in a 17-year-old boy with evidence of previous exposure to chrysotile and tremolite asbestos. A. Andrion, S. Bosia, L. Paoletti, et al. 1994;25(6):617-22. Case report PubMed · Publisher

Abstract

We describe a case of malignant peritoneal mesothelioma arising in a 17-year-old boy. The diagnosis was based on a comprehensive study including light microscopy, histochemistry, immunohistochemistry, evaluation of the clinical course, and autopsy examination. Analytical transmission electron microscopy showed a concentration of 510,000 asbestos fibers/g dry lung tissue. The fibers were represented by chrysotile (62%) and tremolite (38%) asbestos. About 40% of the total fibers were longer than 5 microns. The presence of tremolite fibers was probably due to environmental exposure to contaminated cosmetic talc. This is the first reported case of pathologically proven exposure to asbestos dust in malignant mesothelioma of childhood and adolescence.
The search for the optimal immunohistochemical panel for the diagnosis of malignant mesothelioma. L.M. Weiss, H. Battifora. 1993;24(4):345-6. Comment · Editorial PubMed · Publisher

Summary

In this editorial, the authors commented on a study by Brown et al, published in the same issue of Human Pathology. That study examined immunohistochemical markers for distinguishing malignant pleural epithelioid mesothelioma from pulmonary adenocarcinoma. The authors noted that most antibodies used in this differential diagnosis recognized epitopes found more often in adenocarcinoma, so a diagnosis of mesothelioma rested largely on negative results. They stated that Brown et al showed that anti-CEA, B72.3 and Leu-M1, used together as a panel, were highly effective in distinguishing most cases. They listed factors to keep in mind when applying the findings. Sensitivity may vary between laboratories. The same monoclonal antibodies would need to be used. The results applied only to pleural epithelioid mesothelioma versus lung adenocarcinoma. The results also depended on the original diagnoses, which for 14 mesotheliomas rested only on histologic, immunohistochemical and clinical data. They added that scoring any unequivocal focal staining as positive meant that staining patterns could not be used, such as the membranous pattern of HMFG-2 and EMA in mesothelioma. They summarized other studies of Ber-EP4 and Lewis blood group antigens. In one study, Ber-EP4 stained 87% of 83 adenocarcinomas but only one of 115 mesotheliomas. They concluded that they looked forward to future studies following Brown et al's model in the search for the ideal diagnostic panel.

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Desmoplastic malignant mesothelioma masquerading as sclerosing mediastinitis: a diagnostic dilemma. T.B. Crotty, T.V. Colby, P.C. Gay, et al. 1992;23(1):79-82. Case report PubMed · Publisher

Abstract

A 48-year-old woman presented with dyspnea, chest discomfort, and left vocal cord paralysis that developed 2 months after a flu-like illness. Radiographic examination showed prominence of mediastinal soft tissues and an ill-defined left upper lobe infiltrate. Dense mediastinal sclerosis was found at thoracotomy, and biopsy samples taken from the sclerotic areas showed densely hyalinized fibrotic tissue. Necrotizing granulomas containing organisms resembling Histoplasma capsulatum were present within mediastinal lymph nodes. Based on these findings, a diagnosis of sclerosing mediastinitis was made. During the next year, the patient's respiratory function deteriorated, and biopsy samples taken during a second thoracotomy 1 year later were again interpreted as sclerosing mediastinitis. The patient died postoperatively; at autopsy, the sclerotic mass involving the mediastinum was composed of a mixture of dense fibrosis and sarcomatous tissue. The final diagnosis was localized mediastinal desmoplastic malignant mesothelioma. We report it here because of its unusual clinical presentation, which mimicked sclerosing mediastinitis.
Peripheral biphasic adenocarcinoma of the lung: light microscopic and immunohistochemical findings. P.T. Cagle, L.C. Alpert, P.A. Carmona. 1992;23(2):197-200. Case report PubMed · Publisher

Abstract

We report two cases of peripheral biphasic adenocarcinoma primary in the lung. To our knowledge, peripheral adenocarcinoma of the lung with a spindle-cell component has not been described previously. Diffuse positive cytokeratin and negative vimentin immunostaining of the spindle-cell components support an epithelial differentiation of the malignant spindle cells. Although study of additional cases is needed, our initial findings suggest that immunohistochemical staining pattern may help distinguish these neoplasms from other biphasic neoplasms primary or secondary to the lung, such as carcinosarcoma or malignant mesothelioma.
Thrombomodulin staining of mesothelioma cells. C.L. Collins, L.M. Fink, S.M. Hsu, et al. 1992;23(8):966. Comment · Letter PubMed · Publisher
A comparative immunohistochemical study of peritoneal and ovarian serous tumors, and mesotheliomas. N. Khoury, U. Raju, J.D. Crissman, et al. 1990;21(8):811-9. PubMed · Publisher

Abstract

The distinction between serous neoplasms of the peritoneum in women and conventional mesothelioma can be difficult. In order to determine any significant immunohistochemical differences, formalin-fixed, paraffin-embedded sections of 10 peritoneal serous tumors (PST), 10 ovarian serous tumors (OST), and 10 epithelial mesotheliomas were evaluated with a panel of 10 antibodies directed against carcinoembryonic antigen (CEA: polyclonal, monoclonal), high molecular weight keratin (34 beta E12), low molecular weight keratin (35 beta H11), Leu-M1, TAG-72 (monoclonal antibody B72.3), human milk fat globulin (HMFG-2), vimentin, placental alkaline phosphatase (PLAP), and S-100 protein. The antibodies CEA, Leu-M1, and B72.3 had the most discriminatory value in differentiating serous tumors from mesothelioma. Eighty-five percent of PSTs and OSTs (17 of 20) were positive with CEA, Leu-M1, and/or B72.3. None of the mesotheliomas stained for CEA or Leu-M1; three mesotheliomas had very focal positivity with B72.3 (1% or less). Vimentin, PLAP, HMGF-2, keratin, and S-100 had no significant discriminatory value. Epithelial mucin was present in 80% of serous tumors, while the mesotheliomas lacked epithelial mucin. Leu-M1, CEA, and/or B72.3 positivity in a peritoneal tumor supports a diagnosis of serous tumor. However, since some PST do not stain for any of the three antibodies and the focal nature of positive reactions in some cases may be difficult to interpret, exclusion of mesotheliomas is enhanced by the use of mucin stains.
Is there a "genetic model" in the genesis of malignant pleural mesothelioma?. J.A. Precerutti, M. Mayorga, L. Dalurzo, et al. 1990;21(9):983. Case report · Comment · Letter PubMed · Publisher

Summary

This letter to the editor, from physicians at Hospital Italiano in Buenos Aires, Argentina, responded to the article "Familial Mesothelioma: A Report of Two Families" by Hammar et al. It reported a case that the authors believed reinforced a possible genetic component in the genesis of malignant pleural mesothelioma. The patient was a 40-year-old woman who developed right thoracic pain. A chest x-ray showed pleural effusion, and percutaneous pleural biopsy disclosed malignant pleural mesothelioma (epithelial type), confirmed after thoracotomy. The patient had never been exposed to asbestos, and microscopic examination of the surgical material did not reveal asbestos fibers. Her father and her paternal aunt had died of pleural mesothelioma at ages 60 and 65. The patient's grandfather had worked with asbestos for years, and both his children had lived with him at that time, so they were exposed indirectly during their youth. The father had stopped his exposure many years before the patient was born, and the authors stated she was not exposed at all. The authors concluded that three cases of mesothelioma in one family, two after indirect exposure and one without any contact, raised the possibility that genetic factors may be important in some mesotheliomas. In a published reply, Hammar compared the case with one in his own report. He suggested that people with a certain genetic makeup, such as a particular HLA type, might be more susceptible to asbestos. He proposed surveying a large group of mesothelioma patients for HLA haplotype frequencies.

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Malignant epithelioid pleural mesothelioma versus peripheral pulmonary adenocarcinoma: a histochemical, ultrastructural, and immunohistologic study of 103 cases. M.R. Wick, T. Loy, S.E. Mills, et al. 1990;21(7):759-66. PubMed · Publisher

Abstract

The distinction between malignant epithelioid pleural mesothelioma (MEPM) and peripheral adenocarcinoma of the lung with pleural invasion (PAL) continues to represent a diagnostic challenge in selected cases. In order to provide comparative data on histologic, histochemical, and immunohistochemical features of these neoplasms, we analyzed 51 ultrastructurally categorized MEPMs and 52 PALs with the periodic acid-Schiff-diastase (PAS-D), mucicarmine, and colloidal iron stains, and a panel of immunohistologic reagents. Antibodies to cytokeratin, vimentin, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), Leu M1, the B72.3 antigen, blood group isoantigens (BGI), placental alkaline phosphatase, amylase, S100 protein, and Clara cell antigen were used, as applied to paraffin sections with the avidin-biotin-peroxidase complex technique. Ultrastructural studies revealed long, branching microvilli in MEPM cells in all cases, with length-to-diameter ratios (LDR) of 10:1 or more. In contrast, PAL manifested short, nonbranching microvilli with LDR of 8:1 or less. Reactivity with PAS-D and mucicarmine stains was strictly confined to PAL, and hyaluronidase-sensitive colloidal iron-positivity was restricted to MEPM. However, only 63% and 41% of these respective neoplasms demonstrated such histochemical reactivity. Immunohistologic results correlated well with electron microscopic classification. All MEPMs and PALs were reactive for cytokeratin; in addition, the majority of tumors in each group expressed EMA, and a minority were reactive for vimentin. In adenocarcinomas of the lung, Leu M1 was observed in all cases, CEA was apparent in 96%, B72.3 labeled 84%, and BGI were present in 67%; all PALs expressed at least two of these determinants, but none was seen in any mesothelioma. The other markers included in this study also were observed in some PAL cases, but not in MEPM. These findings suggest that immunohistology parallels electron microscopy in efficacy in the diagnostic separation of MEPM and PAL. Using antibodies to Leu M1, CEA, and the B72.3 antigen, reactivity for at least two of these three markers appears to exclude a diagnosis of pleural mesothelioma. The other glycoproteinaceous, oncoplacentofetal, and cytoplasmic antigens we studied can be used to reinforce such a determination, since their distribution is confined to adenocarcinomas.
Serous surface carcinoma of the peritoneum: a clinicopathologic study of 22 cases. L.D. Truong, M.L. Maccato, H. Awalt, et al. 1990;21(1):99-110. PubMed · Publisher

Abstract

Serous surface carcinoma (SSC) of the peritoneum is defined as a primary tumor histologically indistinguishable from serous carcinoma of the ovary, diffusely involving the peritoneal surface but sparing or only superficially invading the ovaries. In this study of 22 cases of SSC, it was found that the main clinical manifestations of SSC were abdominal pain and enlargement. In most cases, SSC evenly involved the entire mesothelial surface but rarely was predominant in or even limited to the pelvis. It frequently invaded the submesothelium, but deep invasion into abdominal and pelvic organs or local metastasis was rare, and distant metastasis was not seen at presentation. Microscopically, SSC was a high-grade tumor frequently showing high mitotic rate, psammomas bodies, and necrosis. The tumor was usually contiguous with hyperplastic mesothelium on either ovarian surface or other locations. Tumor cells in all cases except one showed cytoplasmic or surface neutral or acidic mucin or both. Tumor cells stained positive for keratin (100% of cases), epithelial membrane antigen (100%), Leu-M1 (45%), B72.3 (85%), vimentin (35%), and carcinoembryonic antigen (25%). Electron microscopic studies of six cases showed epithelial differentiation in each. Seven patients (32%) were alive with no clinical disease at 3 to 31 months, one patient (4%) was alive with extensive local disease at 24 months, 11 patients (50%) died almost exclusively of local recurrence at 1 to 70 months, and three patients (14%) died of operative complications. It is concluded that SSC arises from peritoneal mesothelium but has epithelial phenotype. It can be morphologically differentiated from other conditions with similar laparotomy findings, such as malignant mesothelioma, benign papillary mesothelioma, cystic mesothelioma, and benign or borderline peritoneal serous tumors. The prognosis of SSC is poor, and most patients die of uncontrollable local disease.
Unusual granular reactivity for carcinoembryonic antigen in malignant mesothelioma. J.W. Stirling, D.W. Henderson, D.V. Spagnolo, et al. 1990;21(6):678-9. PubMed · Publisher

Summary

This letter to the editor, from pathologists at Flinders Medical Centre, South Australia, and Sir Charles Gairdner Hospital, Western Australia, described an unusual pattern of carcinoembryonic antigen (CEA) immunostaining in malignant mesothelioma. CEA is undetectable in most mesotheliomas and is commonly used to distinguish mesothelioma from adenocarcinoma. The authors reported that routine study of over 200 mesotheliomas with a polyclonal CEA antibody had supported this pattern. After they introduced a monoclonal CEA antibody, staining occurred in five of 45 consecutive mesotheliomas. All five showed focal to extensive coarsely granular cytoplasmic staining, often concentrated around the nucleus and of moderate to strong intensity. This staining was not seen with the polyclonal antibody. Three of the five also showed sporadic linear staining at the apical cell membrane, which was also seen with the polyclonal antibody. The tissues were two open pleural biopsies and three cell blocks from pleural effusions. Four tumours were epithelial and one was bimorphic. Immunoelectron microscopy in one case showed reaction product mainly associated with cytoplasmic vesicles, possibly Golgi-derived, and rough endoplasmic reticulum. One patient also had colon carcinoma, but all five pleural tumours had features highly characteristic of mesothelioma. The authors suggested that the antibody may recognise an epitope shared by CEA and other glycoproteins. They concluded that granular CEA immunostaining of this kind in no way invalidates a diagnosis of malignant mesothelioma.

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1980s

Familial mesothelioma: a report of two families. S.P. Hammar, D. Bockus, F. Remington, et al. 1989;20(2):107-12. Case report PubMed · Publisher

Abstract

Five reports of familial mesothelioma in which mesotheliomas occurred in two or more family members have been recorded in the medical literature. In this report, we describe two examples of familial mesothelioma. In one family, three brothers who worked in the asbestos insulation industry developed mesothelioma. In the second family, the father, who was occupationally exposed to asbestos, died from a tubulopapillary peritoneal mesothelioma 11 years before his son died from an identical histologic type of peritoneal mesothelioma. Our report, as with those previously recorded, suggests that genetic factors may be important in the genesis of some mesotheliomas.
Immunohistochemical distinction of malignant mesothelioma from pulmonary adenocarcinoma with anti-surfactant apoprotein, anti-Lewisa, and anti-Tn antibodies. M. Noguchi, T. Nakajima, S. Hirohashi, et al. 1989;20(1):53-7. PubMed · Publisher

Abstract

Nine cases of malignant mesothelioma of pure epithelial and biphasic types (five pleural, three peritoneal, and one pericardial mesotheliomas), seven cases of benign adenomatoid tumor of the uterus, and 21 cases of peripheral pulmonary adenocarcinoma of non-mucus-producing type were examined immunohistochemically for expression of keratin, vimentin, carcinoembryonic antigen (CEA), surfactant apoprotein, Lewis blood group antigens, and Tn antigen. The majority (78%) of the malignant mesotheliomas expressed keratin, but CEA and surfactant apoprotein were not detected in any mesotheliomas. On the other hand, pulmonary adenocarcinomas expressed not only keratin (100%), but also CEA (62%) and surfactant apoprotein (62%). The expression of Lewisa blood group antigen and Tn antigen was detected in 76% and 62% of the pulmonary adenocarcinomas, respectively, but only one mesothelioma was stained for Lewisa antigen. This study reveals that the majority of malignant mesotheliomas can be distinguished from pulmonary adenocarcinomas by immunohistochemcial staining for CEA, surfactant apoprotein, Lewisa antigen, and Tn antigen. Immunohistochemically, adenomatoid tumors behaved similarly to malignant mesotheliomas.
Mesothelioma versus adenocarcinoma: false-positive CEA and Leu-M1 staining due to hyaluronic acid. J.A. Robb. 1989;20(4):400. Letter PubMed · Publisher

Summary

This letter to the editor responded to an earlier observation by Triol et al that mucicarmine-positive cytoplasmic vacuoles in malignant epithelial mesotheliomas are due to hyaluronic acid. The author noted that such vacuoles may lead to an incorrect diagnosis of adenocarcinoma if hyaluronidase predigestion is not used, and that positive CEA or Leu-M1 staining is also thought to favor adenocarcinoma. He described his 43rd case of malignant mesothelioma, which was clinically, morphologically and histochemically typical of epithelial malignant mesothelioma. It had a tubulopapillary pattern and contained a marked amount of hyaluronic acid, with colloidal iron- and mucicarmine-positive cytoplasmic vacuoles that became negative after hyaluronidase predigestion. The B72.3 stain was negative. Adsorbed CEA weakly stained some cytoplasmic vacuoles, and Leu-M1 stained some epithelial cell cytoplasms. Both stains became negative after hyaluronidase predigestion, while a lung adenocarcinoma control remained positive for all three antigens. The author concluded that when unexpected CEA or Leu-M1 staining is seen in an otherwise typical epithelial mesothelioma, hyaluronidase predigestion should be used before issuing a diagnosis favoring adenocarcinoma. He also suggested that mesotheliomas reported in the literature as CEA-positive may be false-positive cases due to high hyaluronic acid content. In a printed reply, Triol and Chandler stated that his results appeared to agree with theirs.

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Minimal pathologic changes of the lung and asbestos exposure. D. Bellis, A. Andrion, L. Delsedime, et al. 1989;20(2):102-6. PubMed · Publisher

Abstract

A group of 199 autopsy subjects was investigated for minimal pathologic pulmonary changes possibly resulting from asbestos exposure. According to the standards proposed by the Pneumoconiosis Committee of the College of American Pathologists, features consistent with asbestosis grade 1 (AG1) include findings of bilateral pleural plaques, high concentrations of asbestos bodies (ABs) in digested lung tissue, and a history of occupational risk. Similar changes without evidence of ABs on histologic section and referred to as small airway lesions (SALs) present a less well-correlated association. In this study, SALs showed significant differences when compared with the features observed in subjects without possible asbestos-related pulmonary fibrotic changes. Minimal bronchioloalveolar fibrotic changes with concomitant presence of ABs can be considered a mild pneumoconiotic lesion (AG1), and SALs may be regarded as an additional indicator of asbestos exposure.
Primary papillary serous neoplasia of the peritoneum: a clinicopathologic and ultrastructural study of eight cases. U. Raju, G. Fine, K.A. Greenawald, et al. 1989;20(5):426-36. PubMed · Publisher

Abstract

The well-documented but rare primary papillary serous peritoneal tumors are difficult problems for the pathologist and the clinician. Because of their unusual location, these tumors are often classified as mesothelioma or advanced ovarian carcinoma. In this study, we report the clinicopathologic features of eight primary peritoneal serous papillary tumors and compare their histologic and ultrastructural features to 12 serous ovarian tumors and 16 epithelial mesotheliomas (two peritoneal and 14 pleural). The eight peritoneal serous papillary tumors occurred in women aged 19 to 75 years; two were serous tumors of low malignant potential (borderline) and six were serous carcinomas. The tumors were located in the mesosalpinx, left pelvis, omentum, and/or surface of the ovary. The two patients with borderline neoplasms had long disease-free survival (11 years and 20 years), while three of the four patients with carcinoma with more than 1 year of follow-up died of disease. The peritoneal serous papillary tumors were morphologically identical to serous ovarian tumors of equivalent grade. Well-differentiated papillary structures with distinct fibrovascular cores and one or several layers of columnar, crowded cells, dense overlapping nuclei with a long axis perpendicular to the surface of the papillary cores, and numerous psammoma bodies were features of the peritoneal and ovarian serous tumors. In contrast, the tubulo-alveolar, solid, or poorly defined papillary structures lined by well-spaced polygonal to cuboidal cells with abundant cytoplasm, absence of nuclear polarity, and infrequent psammoma bodies characterized the mesotheliomas. Epithelial mucin and carcinoembryonic antigen (CEA) immunoreactivity, when present, supported a diagnosis of serous tumor in these generally mucin-poor and CEA-negative neoplasms. Ultrastructurally, the cells of serous tumors had slender, straight microvilli of variable length interspersed with or without cilia, while the nonciliated cells of mesothelioma had long, exuberant, wavy microvilli. The morphologic and clinical features of the peritoneal papillary serous tumors are distinctive enough to warrant their separation from mesotheliomas.
Keratin protein immunoreactivity of sarcomatoid and mixed types of diffuse malignant mesothelioma: an immunoperoxidase study of 30 cases. A.G. Montag, G.S. Pinkus, J.M. Corson. 1988;19(3):336-42. PubMed · Publisher

Abstract

To define the role of keratin protein immunohistochemistry in the pathologic diagnosis of the sarcomatoid type of diffuse malignant mesothelioma (DMM), we examined 30 DMM (16 pure sarcomatoid type and 14 mixed sarcomatoid-epithelial type) by an indirect immunoperoxidase technique using three commercially available antibodies to keratin proteins. The sarcomatoid (spindle-cell) areas of all 30 cases of sarcomatoid DMM were immunoreactive for keratin proteins. In 14 of 16 cases of sarcomatoid DMM, 50% or more of the tumor cells were reactive with one or more antibodies; however, polyclonal bovine muzzle and monoclonal AE1/AE3 antibodies were distinctly superior to polyclonal human callus keratin antibody in the detection of spindle tumor cells. In contrast with the staining patterns observed for DMM, 39 spindle-cell malignancies and tumor-like processes of 10 histogenetic types were unreactive with the three antibodies. Those spindle-cell tumors and reactive mesothelial proliferations that may enter into the differential diagnosis of sarcomatoid DMM are discussed. We conclude that keratin protein immunohistochemistry is a sensitive and highly useful method for the pathologic diagnosis of the sarcomatoid type of DMM and its distinction from other spindle-cell neoplasms.
Congenital polycystic tumor of the atrioventricular node (endodermal heterotopia, mesothelioma): a histogenetic appraisal with evidence for its endodermal origin. G. Fine, U. Raju. 1987;18(8):791-5. PubMed · Publisher

Abstract

The small, variously designated, primary atrioventricular node tumor has been considered to be of endothelial, endodermal, or mesothelial origin. To identify its derivation, we studied seven tumors using silver staining and immunocytochemical labeling with a variety of antibodies. Cytoplasmic argyrophil granules but not argentaffin granules were found in isolated cells among the more numerous tubule-lining cells in four tumors. Serotonin and calcitonin were demonstrable in seven and six tumors, respectively, in a similar distribution to that of the argyrophil cells. A positive reaction of different distribution from that of the argyrophil cells was noted in a varying number of tubule-lining cells for carcinoembryonic antigen, epithelial membrane antigen, and blood group antigen in seven, four, and seven tumors, respectively. No activity was noted in the tumor cells for factor VIII-related antigen or a number of peptides. An endodermal rather than mesothelial or epithelial origin for the tumor is substantiated by the presence of neuroendocrine cells in the midst of the more numerous carcinoembryonic-antigen-positive lining cells of the tumor tubules.
Current pathogenetic concepts of diffuse malignant mesothelioma. J.E. Craighead. 1987;18(6):544-57. Review PubMed · Publisher
Placental-like alkaline phosphatase reactivity in human tumors: an immunohistochemical study of 520 cases. M.R. Wick, P.E. Swanson, J.C. Manivel. 1987;18(9):946-54. PubMed · Publisher

Abstract

Placental-like alkaline phosphatase (PLAP) activity has been reported in various human neoplasms of both somatic and germ cell types. The expression of PLAP was examined with a polyclonal antibody and the immunoperoxidase technique in formalin-fixed, paraffin-embedded sections of 37 germ cell neoplasms and 483 somatic tumors. The expression of keratin and epithelial membrane antigen (EMA) was concurrently assessed to determine whether these stains were helpful in distinguishing germ cell neoplasms from somatic tumors that might mimic them microscopically. All germ cell lesions were reactive for PLAP, but so were 62 somatic carcinomas, usually in female müllerian, intestinal, and lung cancers and less often in carcinomas of the breast and kidney. PLAP-reactive somatic tumors exhibited EMA and keratin positivity in the absence of prior protease digestion, whereas germ cell neoplasms failed to do so. Malignant mesotheliomas were nonreactive for PLAP, as were carcinomas of the nasopharynx, adrenals, liver, pancreas, stomach, prostate, and urinary bladder. PLAP is a highly sensitive but nonspecific immunohistologic marker of germ cell differentiation. However, non-protease-enhanced stains for keratin and EMA allow separation of germ cell and somatic carcinomas, despite their shared capacity for PLAP expression. In somatic neoplasms, PLAP immunoreactivity might be of potential use in predicting possible primary sources for metastatic tumors of unknown origin.
The distinction of adenocarcinoma from malignant mesothelioma in cell blocks of effusions: the role of routine mucin histochemistry and immunohistochemical assessment of carcinoembryonic antigen, keratin proteins, epithelial membrane antigen, and milk fat globule-derived antigen. E.S. Cibas, J.M. Corson, G.S. Pinkus. 1987;18(1):67-74. PubMed · Publisher

Abstract

The immunohistochemical profile (i.e., carcinoembryonic antigen, keratin proteins, epithelial membrane antigen, human milk fat globule-derived antigen, and mucin) of paraffin-embedded cell blocks of 20 malignant effusions from patients with malignant mesothelioma was compared with that of 39 malignant effusions from patients with metastatic adenocarcinoma to determine whether these markers distinguished between these tumor types. Twenty-three adenocarcinomas (59 per cent) stained for mucin. Immunoreactivity for carcinoembryonic antigen (CEA) was observed in 28 adenocarcinomas (72 per cent). All were immunoreactive for keratin proteins, and 29 adenocarcinomas (74 per cent), including seven that were mucin and CEA negative and exhibited a "peripheral predominant" staining pattern for keratin proteins. By contrast, none of the mesotheliomas stained for mucin or for CEA, and, although all were immunoreactive for keratin proteins, none demonstrated a peripheral predominant pattern of staining. Epithelial membrane antigen and milk fat globule-derived antigen were identified in the majority of both mesotheliomas and adenocarcinomas. Neither staining intensity nor pattern of reactivity of these markers clearly distinguished the tumors. This study of cell blocks of serous effusions suggests that staining for mucin, immunoreactivity for carcinoembryonic antigen, and a peripheral predominant pattern of reactivity for keratin proteins represent highly characteristic markers of adenocarcinomas, which identify the majority of these tumors (38 of 39) and allow their distinction from malignant mesotheliomas.
Keratin and epithelial membrane antigen immunoreactivity in nonneoplastic fibrous pleural lesions: implications for the diagnosis of desmoplastic mesothelioma. J.I. Epstein, R.E. Budin. 1986;17(5):514-9. PubMed · Publisher

Abstract

The histologic distinction between desmoplastic mesothelioma and reactive fibrosis and between biphasic desmoplastic mesothelioma and pleural metastases with desmoplasia can be difficult. The presence of such epithelial markers as keratin and epithelial membrane antigen (EMA) within the fibrous areas of a pleural lesion might be construed as evidence in support of the diagnosis of desmoplastic mesothelioma. To test this hypothesis ten desmoplastic mesotheliomas were studied with monoclonal antisera to keratin and EMA and compared with ten hyaline pleural plaques, 11 pleural scars, five benign localized fibrous mesotheliomas, and eight desmoplastic pleural metastases. Although the hyalinized fibrous areas within the desmoplastic mesotheliomas stained with keratin (ten of ten) and EMA (five of ten), the following reactive fibrous pleural lesions were also positive: plaques (four of ten keratin-positive, five of ten EMA-positive); scars (six of 11 keratin-positive, four of 11 EMA-positive); and fibrosis induced by metastases (six of eight keratin-positive, one of eight EMA-positive). Benign localized fibrous mesotheliomas were keratin- and EMA-negative. This study suggests that both benign and malignant fibrous pleural lesions may be of mesothelial origin and demonstrates the need to determine by histologic criteria whether the spindle cell component is benign or malignant before assessing the significance of its keratin or EMA immunoreactivity. The lack of keratin and EMA staining in benign localized fibrous mesotheliomas might be of use in distinguishing benign localized cellular fibrous mesotheliomas from sarcomatous mesotheliomas.
An ultrastructural comparison of mesotheliomas with adenocarcinomas of the lung and breast. M.J. Warhol, J.M. Corson. 1985;16(1):50-5. PubMed · Publisher

Abstract

The ultrastructural features of 15 mesotheliomas were compared with those of equal numbers of adenocarcinomas of the lung and of the breast in a double-blind study. Combined quantitative and qualitative features were evaluated to provide criteria for distinguishing among these three tumors, which may present as either primary or metastatic pleural tumors. mesotheliomas could be distinguished from adenocarcinomas of the lung by length of microvilli (mean ratios of length to diameter [LDR], 15.7 and 8.7, respectively; P less than 0.01) and content of tonofilaments. Length of microvilli was also useful in distinguishing mesotheliomas from breast adenocarcinomas (mean LDR, 15.7 and 6.9, respectively; P less than 0.001). Adenocarcinomas of the lung could be distinguished from adenocarcinomas of the breast by tonofilament content and the presence of intracytoplasmic lumina. Combined quantitative and qualitative criteria are essential for maximal ultrastructural discrimination among these tumors.
Asbestos body concentrations in human lung: predictions from asbestos body counts in tissue sections with a mathematical model. R.T. Vollmer, V.L. Roggli. 1985;16(7):713-8. PubMed · Publisher

Abstract

A mathematical model for predicting the concentration (Nv) of asbestos bodies (AB) in human tissue from the count (No) of these bodies in planar tissue sections is presented. The result is the equation Nv = No/[0.54 X A X (La + t)], giving the concentration of AB in numbers per gram of wet lung tissue. La, the average length (in microns) of the AB, is specific for each case; A is the area (square millimeters) of the tissue counted, and t is the thickness of the section (in microns). This equation fits experimental digestion results to a multiplicative error factor of less than 3. When an estimate of La, such as 51.6 microns, is used, the equation is less accurate but probably sufficiently accurate for the screening of lung specimens.
Morphology of small-airway lesions in patients with asbestos exposure. J.L. Wright, A. Churg. 1984;15(1):68-74. PubMed · Publisher

Abstract

The morphologic changes in the small airways of 15 patients who had been exposed to asbestos and had abnormalities of the respiratory bronchioles and alveolar ducts were examined and compared with changes in the small airways of a matched group of cigarette smokers. Lesions were evaluated using a visual grading scheme to determine pathologic severity of fibrosis, inflammation, and pigmentation in these airways. The membranous bronchioles of both asbestos-exposed and cigarette exposed patients showed the deposition of fibrous tissue and pigment; the lesions were morphologically identical, although more severe in the asbestos group (67 per cent of airways) than in the smoking group (19 per cent of airways). A distinctive lesion, consisting of fibrosis often accompanied by pigment, was found in 74 per cent of the respiratory bronchioles in the asbestos-exposed patients, compared with 6 per cent of respiratory bronchioles in the smokers. Similar changes were found in 49 per cent of alveolar ducts in the asbestos group and 1 per cent of the ducts in smoking group. Asbestos bodies were found in only 11 of 15 cases. The authors conclude that a distinctive lesion of small airways exists in some asbestos workers and that it can be identified by the finding of marked fibrosis in the walls of respiratory bronchioles and alveolar ducts. Because there is no proof that this lesion actually progresses to interstitial fibrosis (asbestosis), the authors suggest that it be termed "asbestos airways disease."
Keratin proteins and carcinoembryonic antigen in lung carcinoma: an immunoperoxidase study of fifty-four cases, with ultrastructural correlations. J.W. Said, G. Nash, G. Tepper, et al. 1983;14(1):70-6. PubMed · Publisher

Abstract

This study evaluates the use of immunoperoxidase stains for keratin and carcinoembryonic antigen (CEA) in the diagnosis of lung cancer. Immunohistochemical staining for these antigens was performed on paraffin sections from 54 lung neoplasms, and the results were correlated with the histologic, histochemical, and ultrastructural appearances of the tumors. Strong staining for keratin proteins was evident in all squamous cell carcinomas. This reaction was particularly helpful in identifying squamous differentiation in poorly differentiated areas and in cases in which tonofilaments appeared to be sparse or absent on electron microscopy. Weak focal staining for keratin was evident in only two cases of adenocarcinoma, and the difference in frequency of staining between squamous cell carcinomas and adenocarcinomas was statistically significant (P = 0.01). Carcinoembryonic antigen was variably present in all types of lung carcinoma, but staining for it was strongly positive in cases of adenocarcinoma. Positive staining for keratin with negative or focal weak staining for CEA was characteristic of mesotheliomas, which was helpful in differentiating them from adenocarcinomas. When evaluated by multiple means including immunohistochemical analysis, tumors with mixed differentiation were frequently identified and most large cell carcinomas showed evidence of glandular or squamous differentiation. Electron microscopic demonstration of neurosecretory granules was the best single diagnostic criterion for small cell anaplastic carcinomas (P = 0.01, as determined by stepwise logistic regression analysis). Also helpful in differentiating between small and large cell anaplastic carcinomas were a significantly smaller mean cell diameter in the former, as measured on electron micrographs (P = 0.05), and positive staining for keratin, which occurred significantly more often in large cell carcinomas (P = 0.03). These findings suggest that immunoperoxidase stains for keratin and CEA supplement routine histochemical and electron microscopic studies in the diagnosis of lung tumors, and may provide additional specific objective criteria for their classification.

PubMed has no abstract for this study. This is the authors' abstract, copied from the article.
Numbers of asbestos bodies on iron-stained tissue sections in relation to asbestos body counts in lung tissue digests. V.L. Roggli, P.C. Pratt. 1983;14(4):355-61. PubMed · Publisher

Abstract

Utilization of tissue digestion techniques has demonstrated the presence of large numbers of asbestos bodies within lungs of persons after occupational exposure to asbestos, and smaller numbers in the vast majority of persons with no identifiable exposure. Because of the wide variability in results of such studies among different observers, the presence of more than one asbestos body on light microscopy has been recommended recently as one of the morphologic requirements (together with peribronchiolar fibrosis) for the tissue diagnosis of asbestosis. However, data that correlate the occurrence of asbestos bodies in paraffin-embedded tissue sections with the quantification of asbestos bodies by tissue digestion techniques have not been available. The authors counted the asbestos bodies in multiple paraffin-embedded sections of lung tissues stained for iron, and compared those numbers with the asbestos body counts determined by hypochlorite digestion of wet formalin-fixed lung tissue in six cases of asbestosis or asbestos-associated neoplasia. When adjustments were made for asbestos body orientation in tissue sections, shrinkage of sections during processing, and conversion of lung volume to wet weight, the agreement between the two techniques was excellent (r = 0.98, P less than 0.001). An average of two asbestos bodies on 2 X 2 cm (4 cm2) iron-stained tissue sections 5 microns thick is equivalent to approximately 200 asbestos bodies per gram of wet fixed lung tissue.
Recent advances in pulmonary cytopathology. S.D. Greenberg. 1983;14(10):901-12. Review PubMed · Publisher

Abstract

During the past five years, advances in pulmonary cytopathology have made possible the achievement of several goals, including the diagnosis of pneumonias in immunocompromised hosts, the detection and localization of occult lung cancers in high-risk cigarette smokers, the diagnosis of lesions of the lungs and chest wall by fine-needle aspiration, and the detection of asbestos exposure by sputum cytologic studies. Significant progress has also been made in the application of cell image analysis to the detection of premalignant bronchial epithelial cells in sputum. For the most part, these advances are based on such well-known cytologic procedures as the preparation of thin and evenly distributed smears, prompt fixation, properly controlled and monitored Papanicolaou staining, and thorough screening of slides. Such diligence in laboratory techniques remains the backbone of excellence in pulmonary cytopathology. Cytologic findings should be interpreted with the clinical features of each case in mind, for the practice of pulmonary cytopathology remains an art as well as a science.
Small-airway lesions in patients exposed to nonasbestos mineral dusts. A. Churg, J.L. Wright. 1983;14(8):688-93. PubMed · Publisher

Abstract

Small-airway lesions were identified in histologic sections from the lungs of seven workers with histories of exposure to nonasbestos dusts. The lesions consisted of deposits of fibrous tissue, often accompanied by pigment, in the walls of membranous and respiratory bronchioles and alveolar ducts. Comparison with a matched population of persons with no dust exposure revealed that the changes in the respiratory bronchioles and alveolar ducts were morphologically distinctive and could be used to diagnose the lesions. Structurally, these lesions were very similar to those described in the airways of asbestos workers, although comparison with the authors' previous results indicated that the number of severely affected airways was less in the nonasbestos dust group. Mineralogic analysis indicated that these abnormalities were produced by a variety of different dusts including silica, iron oxide, and aluminum oxide, and that occult asbestos exposure, although possible in three of the cases, was most likely not a primary cause of disease. The authors suggest that this lesion, which they call mineral dust airways disease, is a nonspecific reaction of the small airways to inorganic particulates. The presence of such changes casts considerable doubt on the theory that small-airway abnormalities in asbestos workers are the earliest form of asbestosis.
Fiber counting and analysis in the diagnosis of asbestos-related disease. A. Churg. 1982;13(4):381-92. PubMed · Publisher

Abstract

Analysis of numbers and types of asbestos fibers present in lung tissue may provide insights into the pathogenesis of asbestos-induced disease, as well as diagnostic information concerning the relationship of a given lesion to asbestos exposure. This type of analysis requires extraction of fibers and asbestos bodies from lung tissue, preferably by means of a digestion-and-concentration technique, and examination with a combination of electron optical techniques, including electron diffraction and energy-dispersive x-ray spectroscopy. The combination permits definitive identification of asbestos fibers. Asbestos bodies have been shown to contain asbestos no matter what population they are found in, but they appear to be of value in ascertaining unusual exposure only when present in very large numbers. Numbers of asbestos bodies markedly underestimate total numbers of fibers present in lung. In patients from the general population, the mean number of asbestos fibers is about 1 X 10(6)/g dry lung; of this number, more than 80 per cent are fibers of chrysotile less than 5 microns long. Patients in the general population who have pleural plaques have about the same total number of fibers, but their lungs contain about a 50-fold increase in long thin amphibole fibers of commercial origin. Patients who have asbestosis and most patients who have mesothelioma have 100 to 200 X 10(6) fibers/g dry lung; the grade of asbestosis appears to be related to total fiber content. Occasional patients may develop mesotheliomas with much smaller fiber burdens. Both benign and malignant pleural diseases appear to be closely related to the presence of long thin amphibole fibers. Analysis of pulmonary fiber burden suggest that asbestos-related disease is not merely a matter of total numbers of fibers present, but that factors such as fiber type and size are equally important.
Immunoperoxidase localization of keratin proteins, carcinoembryonic antigen, and factor VIII in adenomatoid tumors: evidence for a mesothelial derivation. J.W. Said, G. Nash, M. Lee. 1982;13(12):1106-8. PubMed · Publisher

Abstract

The histogenesis of adenomatoid tumors has been a source of controversy. Although most investigators favor a mesothelial derivation, recent ultrastructural evidence suggests that some adenomatoid tumors may be vascular neoplasms. This study reports the pattern of staining of seven adenomatoid tumors with antisera to keratin, factor VIII, and carcinoembryonic antigen (CEA), using an immunoperoxidase technique. All the tumors revealed strong cytoplasmic staining for keratin with no staining for factor VIII (an endothelial cell marker) or CEA. An identical staining pattern was evident in normal and reactive mesothelial cells. These findings support a mesothelial rather than an endothelial derivation for the tumors studied.
Studies of a human mesothelioma. A.M. Behbehani, W.J. Hunter, A.L. Chapman, et al. 1982;13(9):862-6. Case report PubMed · Publisher

Abstract

Abdominal fluid from a patient with mesothelioma was cultured in vitro, and a cell line designated JMN was established. This cell line has undergone more than 100 passages. Electron microscopic, karyotypic, and heterotransplantation studies as well as the capability of collagen synthesis by this cell line indicated that it is of malignant mesothelial origin. The cell line has proved very useful for the isolation of human pathogenic viruses.
Are all adenomatoid tumors adenomatoid mesotheliomas?. C.L. Davy, C.K. Tang. 1981;12(4):360-9. Case report PubMed · Publisher

Abstract

The ultrastructure of three histologically typical adenomatoid tumors of the epididymis is presented. Two of the three tumors showed morphologic features of mesothelium similar to those reported in the literature. The third tumor demonstrated a multilayered basal lamina and Weibel-Palade bodies, both of which have been found consistently in sclerosing hemangiomas. Although the ultrastructure of the first two tumors confirms the theory of a mesothelial origin of adenomatoid tumors, the findings of the third tumor indicate that a histologically typical adenomatoid tumor may not necessarily be a mesothelioma and that electron microscopy is indispensable in establishing their nature. These findings also lead us to suggest that the term adenomatoid tumor should remain in use for light microscopic diagnosis, and that the term adenomatoid mesothelioma should be applied only when the mesothelial nature of an adenomatoid tumor is proven by electron microscopy. For those that show ultrastructural evidence of endothelial origin, the term adenomatoid angioma seems to be appropriate and accurate. It is possible that the adenomatoid angioma represents a variant of the histiocytoid hemangioma.
Histochemical and ultrastructural features of an unusual pulmonary carcinosarcoma. K.G. Zimmerman, R.E. Sobonya, C.M. Payne. 1981;12(11):1046-51. Case report PubMed · Publisher

Abstract

An autopsy case is presented in which a pulmonary carcinosarcoma filled the left chest of a 61 year old man. The extensive pleural involvement that this neoplasm exhibited has not been reported previously. By light microscopy the neoplasm initially was considered a mesothelioma because of the pattern of glands and undifferentiated sarcomatous stroma. However, by electron microscopy the sarcomatous component was found to show rhabdomyoblastic differentiation. Neither histochemical stains nor electron microscopy supported a mesothelial origin for the glandular component. Differential diagnostic considerations of pleuropulmonary neoplasms showing rhabdomyosarcomatous differentiation are discussed. This case illustrates the importance of detailed study in order to characterize and properly classify these neoplasms.
Pulmonary blue bodies. M.N. Koss, F.B. Johnson, L. Hochholzer. 1981;12(3):258-66. PubMed · Publisher

Abstract

Pulmonary blue bodies are intra-alveolar laminated basophilic concretions of uncertain etiology. Blue bodies were studied in lung biopsy specimens from 10 patients. The patients ranged in age from 47 to 69 years and were predominantly men. Three had a history of overt exposure to environmental dusts such as sawdust and asbestos, and two showed occasional ferruginous bodies in the lung, raising the possibility of pneumoconiosis. In eight cases there was interstitial pneumonitis, which resembled desquamative interstitial pneumonia by light microscopy but which was often seen to be patchy and asymmetrically distributed in the lung by chest x-ray examination. Of two other patients, one had xanthogranulomatous inflammation and the other, necrotizing granulomatous inflammation. Light and electron microscopic, histochemical, microchemical, and x-ray diffraction studies of blue bodies were also performed. Calcium carbonate is a major component of blue bodies and is responsible for their birefringence in unstained sections and ready solubility in acid solutions. Blue bodies also contain a mucopolysaccharide matrix and iron. We offer the hypothesis that blue bodies (calcium carbonate) are a product of histiocytic catabolism.
The second diagnosis: the role of the pathologist in identifying pneumoconioses in lungs excised for tumor. E.J. Mark. 1981;12(7):585-7. PubMed · Publisher

Summary

This short review in the journal's Current Topics section, written by a lung pathologist at Massachusetts General Hospital, argued that pathologists examining lungs removed for tumor should also make a 'second diagnosis' of disease in the rest of the lung, including pneumoconioses. The author recommended inflating the lung with formalin, sectioning it at 1-centimeter intervals, and taking at least three sections per lobe away from the tumor. He reviewed links between lung carcinoma and dusts, chemicals and radioactive materials. Asbestos-associated carcinomas were described as arising more often in the lower lobes and spreading more often in the pleura. He stated that no correlation was strong enough for tumor type alone to mark exposure. He advised that asbestos bodies be sought in all such lungs, noting they may be hard to find below 100 per gram of wet tissue. He described an iron stain and a rapid technique of 20 successive scrapings of the cut lung surface onto one slide. He also covered telling asbestos bodies from pseudoasbestos bodies, interstitial fibrosis as possible evidence of asbestosis, and the pleural hyaline plaque as a marker of exposure. Beryllium disease, silicosis and other dusts were also discussed. He concluded that missing exposure history, such as shipyard work, does not absolve the pathologist from a thorough search for pneumoconiosis.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

1970s

Malignant mesothelioma with minimal asbestos exposure. W.J. Chen, N.K. Mottet. 1978;9(3):253-8. Case report PubMed · Publisher

Abstract

The association of malignant mesothelioma and asbestos fibers is well established. The minimal exposure that may produce the tumor is not known. The present report documents the minimal exposure by thorough examination of occupational history and personal hobbies, and counting of the number of asbestos fibers in the lungs. The evidence for the elemental composition of asbestos fibers by electron probe (EDAX) is also presented.
Peritoneal mesothelioma. M. Kannerstein, J. Churg. 1977;8(1):83-94. PubMed · Publisher

Abstract

The cytohistology in 82 cases diagnosed as malignant peritoneal mesothelioma was correlated with available clinical and gross pathologic information. The cases were then evaluated as to ceratainty of diagnosis. The material had come from a large number of sources, most of it having been traced by a history of occupational exposure to asbestos. A relatively short interval of significant symptoms, with already existent diffuse peritoneal involvement and ascites, and an average survival time of less than a year characterized the group. The microscopic morphology formed a spectrum from highly characteristic, pure epithelial and mixed epithelial and sarcomatoid types, through nonspecific although relatively differentiated appearances, to pleomorphic analplatic proliferations. Local invasion and metastasis were common but much more limited than with tumors of other histogenesis showing comparable serous membrane involvement. Autopsy was of considerable exclusionary value although not in itself always determinative, and mucopolysaccharide histochemistry was occasionally decisive in diagnosis. Because of the microscopic versatlity of mesothelioma and the clinical and gross morphologic overlap with other neoplasms, all available data must be taken into consideration in arriving at a diagnosis. We believe that the dgree of certainty of diagnosis should be indicated by a succinct but reasonably explicit terminology.
The fine structure of so-called minute pulmonary chemodectomas. C. Kuhn, F.B. Askin. 1975;6(6):681-91. Case report PubMed · Publisher

Abstract

Electron microscopy was performed on several minute tumors of the type called chemodectomas, all from the lung of a single patient. The cells had a whorling pattern with extensive interdigitating cytoplasmic processes joined by desmosomes. Except for tangles of cytoplasmic fibrils, the tumor cells had few distinctive organelles. They had no endocrine-like granules and were not associated with nerves or basement membranes. The tumors had little resemblance to paragangliomas, but displayed a puzzling similarity to meningiomas. Our observations permit no definite conclusions as to the histogenesis of these lung tumors. Viewed in the light of recent physiologic studies, they cast doubt on the presence of special chemoreceptive paraganglia in the lung.
Epithelioid sarcoma. A clinical and pathologic study of nine cases. H. Santiago, L.K. Feinerman, R. Lattes. 1972;3(1):133-47. PubMed · Publisher

Abstract

This is a report of nine cases of epitheloid sarcoma, a term introduced recently to designate a special variant of malignant soft tissue tumor generally involving tendons, aponeuroses, and more superficial tissues of the extremities. The histologic features of this tumor, which consists of a mixture of polygonal epithelioid cells and elongated fibroblastic cells with necrotizing foci, have often misled the pathologist into diagnoses of necrotizing granuloma, malignant melanoma, angiosarcoma, or metastatic carcinoma. The tumor is definitely malignant, is difficult to eradicate by local surgical excision, and often metastasizes to lymph nodes and via the blood. The histogenesis of this tumor is still controversial, but some light and electron microscopic features suggest a possible synovial origin.

PubMed has no abstract for this study. This is the authors' abstract, copied from the article.

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