Immunoreactivity for calretinin and keratins in desmoid fibromatosis and other myofibroblastic tumors: a diagnostic pitfall

Our plain-English summary of Immunoreactivity for calretinin and keratins in desmoid fibromatosis and other myofibroblastic tumors: a diagnostic pitfall, by S. Barak, Z. Wang, M. Miettinen (The American Journal of Surgical Pathology, 2012).

The study

• Authors: S. Barak, Z. Wang, M. Miettinen
• Journal: The American Journal of Surgical Pathology
• Published: 2012;36(9):1404-9
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Calretinin is an intracellular calcium-binding EF-hand protein of the calmodulin superfamily. It plays a role in diverse cellular functions, including message targeting and intracellular calcium signaling. It is expressed in the mesothelium, mast cells, some neural cells, and fat cells, among others. Because of its relative specificity for mesothelial neoplasms, calretinin is widely used as one of the primary immunohistochemical markers for malignant mesothelioma and in differentiating it from adenocarcinoma. On the basis of our sporadic observation on calretinin immunoreactivity in desmoid fibromatosis, we systematically evaluated calretinin, keratin cocktail (AE1/AE3), and WT1 immunoreactivity in 268 fibroblastic/myofibroblastic neoplasms. Calretinin was observed in 75% (44/58) of desmoid fibromatosis, 50% (21/42) of proliferative fasciitis, 23% (8/35) of nodular fasciitis, 33% (13/40) of benign fibrous histiocytoma, 35% (22/62) of malignant fibrous histiocytoma, and 13% (4/31) of solitary fibrous tumors but not in normal connective tissue fibroblasts at various sites. Keratin AE1/AE3 immunoreactivity was also commonly (6/13) present in the large ganglion-like cells of proliferative fasciitis and sometimes in nodular fasciitis (3/35), solitary fibrous tumor (3/27), and malignant fibrous histiocytoma (9/62). Nuclear immunoreactivity for WT1 or keratin 5 positivity was not detected in myofibroblastic tumors. On the basis of these observations, it can be concluded that calretinin and focal keratin immunoreactivity is fairly common in benign and malignant fibroblastic and myofibroblastic lesions. Calretinin-positive and keratin-positive spindle cells in desmoid and nodular fasciitis or calretinin-positive ganglion-like cells in proliferative fasciitis should not be confused with elements of epithelioid or sarcomatoid mesothelioma. These diagnostic pitfalls can be avoided with careful observation of morphology, quantitative differences in keratin expression, and use of additional immunohistochemical markers such keratin 5 and WT1 to verify true epithelial and mesothelial differentiation typical of mesothelioma.

In plain English

This laboratory study examined whether stains used to help diagnose malignant mesothelioma also react with other tumors that can resemble it. The authors had seen chest wall desmoid fibromatosis presented as mesothelioma because it stained for calretinin. They stained 268 fibroblastic and myofibroblastic tumors for calretinin, and most were also stained for keratin AE1/AE3, keratin 5 and WT1. Calretinin was found in 44 of 58 desmoid fibromatosis cases (75%), 21 of 42 proliferative fasciitis (50%), 8 of 35 nodular fasciitis (23%), 13 of 40 benign fibrous histiocytomas (33%), 22 of 62 malignant fibrous histiocytomas/myxofibrosarcomas (35%) and 4 of 31 solitary fibrous tumors (13%). It was not found in normal fibroblastic tissue. Keratin AE1/AE3 staining, usually focal, was seen in 6 of 13 proliferative fasciitis cases and some other tumor types. No tumor tested showed nuclear WT1 or keratin 5 staining. The authors concluded that calretinin staining in these tumors should not be confused with mesothelioma. They said tissue appearance, the amount of keratin staining, and WT1 and keratin 5 help avoid this error. Asbestos exposure was not studied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (immunohistochemical) study of tumor tissue specimens
• Who was studied: 268 fibroblastic and myofibroblastic tumors were examined at the Laboratory of Pathology, National Cancer Institute, Bethesda, MD. They comprised 58 desmoid fibromatosis, 42 proliferative fasciitis, 35 nodular fasciitis, 40 benign fibrous histiocytomas, 31 solitary fibrous tumors and 62 malignant fibrous histiocytomas/myxofibrosarcomas. All were stained for calretinin. Table 1 reports keratin AE1/AE3, WT1 and keratin 5 results for subsets of each group (206 tumors in total). Selected normal tissues were also examined. Dates and the source of the cases were not stated.
• Exposure: No asbestos or other environmental exposure was studied. The study examined staining with antibodies to calretinin. Most tumors were also stained for other mesothelioma markers (keratin AE1/AE3, keratin 5 and WT1), and selected cases for keratins 7, 8 and 18.
• Main results:
  • In normal human tissue, calretinin was found in mesothelia, mast cells, some neural elements and variably in fat, but not in normal fibroblastic stromal tissue.
  • Desmoid fibromatosis: calretinin-positive tumor cells were found in 75% of cases (44/58).
  • Desmoid fibromatosis: tumor cells were keratin AE1/AE3 negative (0/37 in the table).
  • Proliferative fasciitis: half of cases (21/42) showed calretinin positivity in the ganglion-like cells.
  • Proliferative fasciitis: keratin AE1/AE3 positivity, usually focal, was seen in 46% (6/13) of cases.
  • Nodular fasciitis: calretinin positivity was found in 23% (8/35) of cases.
  • Nodular fasciitis: rare keratin-positive spindled cells were found in 3/35 cases.
  • Benign fibrous histiocytoma: calretinin-positive tumor cells were found in 33% (13/40) of cases.
  • Malignant fibrous histiocytomas/myxofibrosarcomas: calretinin-positive cells were found in 22/62 (35%).
  • Malignant fibrous histiocytomas/myxofibrosarcomas: small numbers of keratin AE1/AE3-positive tumor cells were found in 9/62 (15%).
  • Solitary fibrous tumors: calretinin-positive tumor cells were found in 13% (4/31).
  • No nuclear WT1 or keratin 5 immunoreactivity was found in any tumor tested. For example, none of the 37 desmoids tested showed it, although variable cytoplasmic positivity was common.
• The authors' conclusion: The authors concluded that calretinin staining is commonly found in benign myofibroblastic lesions, especially desmoid fibromatosis, nodular fasciitis and proliferative fasciitis, and in some malignant fibroblastic tumors. They said it should be understood as a feature of these tumors and not confused with malignant mesothelioma. In their view, careful attention to morphology, quantitative differences in keratin staining, and markers such as WT1 and keratin 5 help avoid this pitfall.
• Limitations the authors state:
  • The authors note that WT1 and keratin 5/6, the markers they recommend for distinguishing these tumors, may show reduced or no expression in some mesotheliomas, especially sarcomatoid ones.

Topics

Medical terms in this study, explained in our Lexicon: Calretinin, Mesothelium, Neoplasm, Mesothelioma, Adenocarcinoma, Solitary Fibrous Tumor, Fibroblast, Spindle Cell.

Related studies

• Expression of calretinin, thrombomodulin, keratin 5, and mesothelin in lung carcinomas of different types: an immunohistochemical analysis of 596 tumors in comparison with epithelioid mesotheliomas of the pleura — M. Miettinen, M. Sarlomo-Rikala (2003)
• Calretinin and other mesothelioma markers in synovial sarcoma: analysis of antigenic similarities and differences with malignant mesothelioma — M. Miettinen, J. Limon, et al. (2001)
• The value of anti-calretinin antibody in the differential diagnosis of normal and reactive mesothelia versus metastatic tumors in effusion cytology — H. Nagel, B. Hemmerlein, et al. (1998)
• Expression of calretinin in human ovary, testis, and ovarian sex cord-stromal tumors — Q.J. Cao, J.G. Jones, et al. (2001)
• Keratin protein immunoreactivity of sarcomatoid and mixed types of diffuse malignant mesothelioma: an immunoperoxidase study of 30 cases — A.G. Montag, G.S. Pinkus, et al. (1988)
• 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)

Browse more research in The American Journal of Surgical Pathology, or return to medical research.