Undifferentiated Tumor: True Identity by Immunohistochemistry

Archives of Pathology & Laboratory Medicine,  Mar 2008  by Bahrami, Armita,  Truong, Luan D,  Ro, Jae Y

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Context.-"Undifferentiated tumor" refers to a heterogeneous group of neoplasms with little or no evidence of differentiation on routine light microscopic morphology.

Objective.-To identify the true identity of undifferentiated tumors by immunohistochemical analysis.

Data Sources.-Review of the pertinent literature and the authors' experience.

Conclusions.-For treatment and prognostic evaluation, it is crucial to delineate whether an undifferentiated neoplasm is epithelial, mesenchymal, melanocytic, or hematopoietic in nature. Application of a screening panel to demonstrate the expression of markers of major lineages is fundamental for determination of the broad category of neoplasia. Because poorly differentiated carcinomas and in particular sarcomatoid carcinomas are known to be heterogeneous in their antigen expression, several epithelial markers in combination may be required to establish the carcinomatous nature of tumor. A diagnostic misinterpretation as a consequence of occasional aberrant or unexpected antigen expression is best avoided by using a broad panel that includes both antibodies that are anticipated to be positive and those that are expected to be negative. In this treatise, the immunohistochemical dissection of undifferentiated tumors on the basis of their morphologic features is outlined, supplemented with algorithmic immunohistochemical analysis for each morphologic category of small round cell tumors, carcinomatous tumors, sarcomatous (or sarcoma-like) tumors, and tumors with histologically overlapping features, including hematolymphoid malignancies, melanoma, and sarcomas with epithelioid appearance. The utility of several organ- or tissue-specific markers in the context of undifferentiated tumors is reviewed.

(Arch Pathol Lab Med. 2008;132:326-348)

The term undifferentiated tumor has been used in reference to a heterogeneous group of tumors with little or no evidence of differentiation. Some may link this terminology to morphologically undifferentiated neoplasms that cannot be otherwise classified, even with the application of immunohistochemistry. In our view, however, such tumors are extremely rare and in most instances further sampling or application of ancillary tests should help to recognize them as a specific tumor type. For such reason, in this review we apply the term undifferentiated to tumors lacking evidence of lineage differentiation on the basis of routine light microscopic morphology alone.

An undifferentiated malignant tumor represents either a metastasis of unknown origin or a primary neoplasia without obvious cell line of differentiation. It should be noted that undifferentiated tumor generally implies a high-grade malignancy, frequently associated with pleomorphic to anaplastic appearance. Therefore, low-grade neoplasms but without an obvious lineage of differentiation (eg, monomorphic spindled cell tumors) or low-grade tumors not infrequently encountered in the context of metastasis of unknown origin are not included in this discussion.

For treatment purposes, it is crucial to determine whether an undifferentiated neoplasm is epithelial, mesenchymal, or hematopoietic. In general, the diagnosis of lymphoma for an undifferentiated tumor predicts a better clinical outcome compared with that of carcinoma.1 The value of immunohistochemical procedures for identification of the true identity of undifferentiated tumors has been proved by studies in which approximately 90% of tumors posing diagnostic difficulties by morphology could be accurately classified by exploiting immunohistochemistry.1-3

Even in undifferentiated tumors, subtle features of epithelial versus mesenchymal differentiation can often be appreciated, which assist the immunohistochemical approach to these tumors. Hints for epithelial differentiation include epithelioid cells (round to oval cells) with nesting arrangement and a desmoplastic stroma with feeding vessels separating tumor cell nests (Figure 1). In contrast, mesenchymal differentiation is suggested by a diffuse arrangement of spindled cells (Figure 2), without reactive stroma, but with feeding vessels in between tumor cells. Some tumors, however, may not fit into either of these 2 categories because of their overlapping histologic features (Figure 3), for example, sarcomatoid carcinoma, melanoma, lymphoma, neuroendocrine tumors, and sarcoma with epithelioid cells.

Immunohistochemical dissection of undifferentiated tumors is also helped by categorizing them into small round blue cell tumors (SRCTs) or large cell tumors. The latter group is further divided into (1) carcinomatous tumors, (2) sarcomatous or sarcoma-like tumors, and (3) tumors with overlapping features. Each category entertains a broad list of entities from epithelial, mesenchymal, hematopoietic, or melanocytic lineage in the differential diagnosis.

In the following section, the immunohistochemical procedure for a broad lineage determination of undifferentiated tumors is discussed, followed by immunohistochemical analysis of each individual category of SRCTs, carcinomatous tumors, sarcomatous (or sarcoma-like) tumors, and tumors with overlapping features, supplemented with diagnostic algorithms. It is emphasized that the outlined algorithmic immunohistochemical approach is neither meant to be comprehensive nor intended to be an absolute method for immunohistochemical dissection of these tumors. In reality, each tumor requires an "individually constructed panel" composed of carefully selected antibodies that recognize all reasonable diagnostic possibilities in the context of the tumor's morphology, anatomic site, and clinical/radiologic findings.