Poorly differentiated neoplasms of unknown primary site: diagnostic usefulness of a molecular cancer classifier assay

Our plain-English summary of Poorly differentiated neoplasms of unknown primary site: diagnostic usefulness of a molecular cancer classifier assay, by F.A. Greco, W.J. Lennington, D.R. Spigel, et al (Molecular Diagnosis & Therapy, 2015).

The study

• Authors: F.A. Greco, W.J. Lennington, D.R. Spigel, J.D. Hainsworth
• Journal: Molecular Diagnosis & Therapy
• Published: 2015;19(2):91-7
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: Definition of the lineage of poorly differentiated neoplasms (PDNs) presenting as cancer of unknown primary site (CUP) is important since many of these tumors are treatment-sensitive. Gene expression profiling and a molecular cancer classifier assay (MCCA) may provide a new method of diagnosis when standard pathologic evaluation and immunohistochemical (IHC) staining is unsuccessful.

Patients And Methods: Thirty of 751 CUP patients (4%) seen from 2000-2012 had PDNs without a definitive lineage diagnosed by histology or IHC (median 18 stains, range 9-46). Biopsies from these 30 patients had MCCA (92-gene reverse transcriptase-polymerase chain reaction mRNA) performed. Additional IHC, gene sequencing, fluorescent in situ hybridization for specific genetic alterations, and repeat biopsies were performed to support MCCA diagnoses, and clinical features correlated. Seven patients had MCCA performed initially and received site-specific therapy.

Results: Lineage diagnoses were made by MCCA in 25 of 30 (83 %) patients, including ten carcinomas (three germ cell, two neuroendocrine, five others), eight sarcomas [three peritoneal mesotheliomas, one primitive neuroectodermal tumor (PNET), four others], five melanomas, and two lymphomas. Additional IHC and genetic testing [BRAF, i(12)p] supported the MCCA diagnoses in 11 of 16 tumors. All seven patients (two germ cell, two neuroendocrine, two mesothelioma, one lymphoma) responded to site-specific therapy based on the MCCA diagnosis, and remain alive (five progression-free) from 25+ to 72+ months.

Conclusion: The MCCA provided a specific lineage diagnosis and tissue of origin in most patients with PDNs unclassifiable by standard pathologic evaluation. Earlier use of MCCA will expedite diagnosis and direct appropriate first-line therapy, which is potentially curative for several of these tumor types.

In plain English

This was a retrospective case review. Of 751 patients with cancer of unknown primary site seen from 2000 to 2012 at the Sarah Cannon Cancer Center and Tennessee Oncology clinics in Nashville and Middle Tennessee, 30 (4%) had poorly differentiated tumors whose basic type could not be identified by standard pathology and extensive immunohistochemical staining. The authors tested biopsies from these 30 patients with a 92-gene molecular cancer classifier assay. The article did not examine asbestos exposure. The assay gave a diagnosis in 25 of 30 specimens (83%): ten carcinomas, eight sarcomas (including mesothelioma in three), five melanomas and two lymphomas. Four results were indeterminate, and one sample had too little tissue. Further testing supported the assay result in 11 of 16 tumors examined. In one patient the assay said sarcoma, but staining confirmed mesothelioma. Seven patients were treated according to the assay result. All seven were reported alive, and five were progression-free. The authors concluded the test can identify tumor type and origin in most such patients. They noted that newer stains might have resolved some cases.

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: Retrospective case review of patients with cancer of unknown primary site, with gene expression testing of archived and some new biopsies
• Who was studied: 751 patients with cancer of unknown primary site seen 2000 to 2012 at the Sarah Cannon Cancer Center and Tennessee Oncology clinics (Nashville and Middle Tennessee). The study group was the 30 (4%) whose tumor lineage could not be determined by standard pathology and immunohistochemistry.
• Exposure: No asbestos or other environmental or occupational exposure was studied. What was evaluated was a diagnostic test: a 92-gene molecular cancer classifier assay (RT-PCR mRNA, CancerTYPE ID).
• Main results:
  • The assay made a lineage diagnosis in 25 of the 30 biopsy specimens (83%).
  • The assay result was indeterminate in four tumors, and one had insufficient tissue.
  • Of the 25 assay diagnoses, ten (40%) were carcinoma.
  • Sarcoma was diagnosed in eight (32%) patients, including mesothelioma in three.
  • Among the 16 tumors with additional testing, further studies and clinical features confirmed or supported the assay diagnosis in 11.
  • In patient 2 the assay gave the general lineage, sarcoma, but staining confirmed the specific diagnosis of mesothelioma.
  • In patient 3 (woman aged 55), whose assay diagnosis was mesothelioma, additional staining (calretinin, WT-1) did not support that diagnosis.
  • In patient 22, the assay said lymphoma, but further testing showed granulocytic sarcoma/CML (chloroma).
  • Seven patients were treated according to the assay diagnosis.
  • All seven treated patients were reported alive.
  • Five of the treated patients (two germ cell tumors, two neuroendocrine carcinomas, one lymphoma) responded favorably and remained progression-free.
  • Patient 2, treated as mesothelioma, had a partial response to initial chemotherapy followed by progressive tumor.
• The authors' conclusion: The authors concluded that in this uncommon group, gene expression profiling can diagnose the tumor lineage and tissue of origin in most patients.
• Limitations the authors state:
  • The study was retrospective.
  • Some of the 30 cases might have been resolved with immunohistochemical stains now available.
  • In most patients the assay was done months to years after the original diagnosis, so it could not guide their treatment.

Topics

Medical terms in this study, explained in our Lexicon: Neoplasm, Histology, Carcinoma, Sarcoma, Peritoneal Mesothelioma, Mesothelioma, First-line Therapy.

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