The Changing Role of the Pathologist in the Management of the Cancer Patient

Raymond B. Nagle


1.1. The Difficult Diagnosis

The experienced surgical pathologist routinely uses paraffin embedded tissue stained with hematoxylin and eosin (H&E) to establish the correct cancer diagnosis. A number of circumstances arise, however, in which the H&E slide is insufficient to establish the correct diagnosis. This occurs in approx 4-10% of all tumors and is usually owing to the fact that the tumors are undifferentiated and the cell of origin remains elusive. These undifferentiated tumors tend to fall into three categories:

1. The large cell undifferentiated tumor.

2. The small cell undifferentiated tumor.

3. The spindle cell undifferentiated tumor.

A second circumstance is the tumor presents as a metastasis with an uncertain origin. Often these tumors are poorly differentiated adenocarcinomas in which the organ of origin cannot be ascertained from the histological pattern of the metastasis. Approximately 20% of all cancer patients present with metastasis. Studies have revealed that in as many as 4% of these patients the primary cancer is never found, even with complete autopsy examination.


Beginning in the 1980s, antibodies specific to various cell linage proteins that could be used in immunohistochemical applications became available to the pathologist. It was found that all epithelial neoplasms expressed cytoskeleton proteins of the cytokeratin family. It was discovered that there were 20 such proteins, and exact combinations of these proteins were expressed with great fidelity in various cell lines (1). These findings were adapted for diagnostic use, allowing many undifferentiated tumors to be clearly diagnosed as carcinomas after demonstrating that they expressed cytokeratins. Shortly thereafter, other proteins were discovered that also were cell lineage specific. Over the years this has evolved and now there are a great number of antibodies that are useful in classifying undifferentiated neoplasms or in defining the site of origin of metastatic neoplasms.

Examples of the use of such antibodies for identifying large cell undifferentiated neoplasms (2-4) or neoplasms of uncertain origin is shown in Fig. 1. Antibodies useful in the

From: Cancer Diagnostics: Current and Future Trends Edited by: R. M. Nakamura, W. W. Grody, J. T. Wu, and R. B. Nagle © Humana Press Inc., Totowa, NJ

Renal Cell Carcinoma - CD10 (+)

Mesothelioma - Calretinin (+), CK 5/6 (+), Thrombomodulin (+)


I— Breast Carcinoma --ER/PR (+/-), mammoglobin (+), BRST-2 (+)

"— Hepatocellular carcinoma - CK7 (-), CK20 (-),

CEA canallculi pattern, alpha fetoprotein

— Lung adeno carcinoma -- CK7 (+), CK20 (-), TTF-1 (+)

-Melanoma -- S-100 (+), Melan A (+/-), Tyrosinase (+/-), HMB45 (+/-]

Anaplastic Lymphoma -- CD 30(+), Alk-1 (+), CD15 (-) _Seminoma (dysgerminoma) -- PLAP (+)

Fig. 1. Large cell undifferentiated or neoplasms of unknown origin.


- Merkle cell carcinoma -- CK7 (-), CK20 (+), Neurofilament (+), TTF-1 (-)

- Small cell lung carcinoma - CK7 (+), CK20 (-), TTF-1 (+)

T-Cell Lymphoma - CD3 (+), CD5 (+) B-Cell Lymphoma - CD20 (+), IgG H&L (+)

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