True Identity by Immunohistochemistry - pathinformatics.com

1 326 Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et alUndifferentiated TumorTrue Identity by ImmunohistochemistryArmita Bahrami, MD; Luan D. Truong, MD; Jae Y. Ro, MD, PhD Context. Undifferentiated tumor refers to a hetero-geneous group of neoplasms with little or no evidence ofdifferentiation on routine light microscopic To identify the true Identity of undifferen-tiated tumors by immunohistochemical Sources. Review of the pertinent literature andthe authors For treatment and prognostic evaluation,it is crucial to delineate whether an undifferentiated neo-plasm is epithelial, mesenchymal, melanocytic, or hema-topoietic in nature.

2 Application of a screening panel todemonstrate the expression of markers of major lineages isfundamental for determination of the broad category ofneoplasia. Because poorly differentiated carcinomas and inparticular sarcomatoid carcinomas are known to be het-erogeneous in their antigen expression, several epithelialmarkers in combination may be required to establish thecarcinomatous nature of tumor. A diagnostic misinterpre-tation as a consequence of occasional aberrant or unex-pected antigen expression is best avoided by using a broadpanel that includes both antibodies that are anticipated tobe positive and those that are expected to be negative.

3 Inthis treatise, the immunohistochemical dissection of undif-ferentiated tumors on the basis of their morphologic fea-tures is outlined, supplemented with algorithmic immu-nohistochemical analysis for each morphologic category ofsmall round cell tumors, carcinomatous tumors, sarcoma-tous (or sarcoma-like) tumors, and tumors with histologi-cally overlapping features, including hematolymphoid ma-lignancies, melanoma, and sarcomas with epithelioid ap-pearance. The utility of several organ- or tissue-specificmarkers in the context of undifferentiated tumors is re-viewed.(Arch Pathol Lab ;132:326 348)The termundifferentiated tumorhas been used in refer-ence to a heterogeneous group of tumors with littleor no evidence ofdifferentiation.

4 Some maylink this ter-minology to morphologically undifferentiated neoplasmsthat cannot be otherwise classified, even with the appli-cation of Immunohistochemistry . In our view, however,such tumors are extremelyrare and in most instances fur-ther sampling or application of ancillary tests should helpto recognize them as a specific tumor type. For such rea-son, in this review we apply the termundifferentiatedtotumors lacking evidence of lineage differentiation on thebasis of routine light microscopic morphology undifferentiated malignant tumor represents eithera metastasis of unknown origin or a primary neoplasiawithout obvious cell line of differentiation.

5 It should benoted that undifferentiated tumor generally implies ahigh-grade malignancy, frequently associated with pleo-morphic to anaplastic appearance. Therefore, low-gradeneoplasms but without an obvious lineage of differentia-tion (eg, monomorphicspindled cell tumors) or low-gradetumors not infrequently encountered in the context of me-Accepted for publication June 4, the Departments of Pathology, Baylor College of Medicine (DrsBahrami and Truong) and Weill Medical College of Cornell University,The Methodist Hospital (Drs Truong and Ro), Houston, authors have no relevant financial interest in the products orcompanies described in this : Jae Y.

6 Ro, MD, PhD, Department of Pathology, Weill Med-ical College of Cornell University, The Methodist Hospital, 6565 FanninSt, Houston, TX 77030 (e-mail: of unknown origin are not included in this treatment purposes, it is crucial to determine wheth-er an undifferentiated neoplasm is epithelial, mesenchy-mal, or hematopoietic. In general, the diagnosis of lym-phoma for an undifferentiated tumor predicts a betterclinical outcome compared with that of of immunohistochemical procedures foridentifica-tion of the true Identity of undifferentiated tumors hasbeen proved by studies in which approximately 90% oftumors posing diagnostic difficulties by morphologycould be accurately classified by exploiting 3 Even in undifferentiated tumors, subtle features of ep-ithelial versus mesenchymal differentiation can often beappreciated, which assist the immunohistochemical ap-proach to these tumors.)

7 Hints for epithelial differentiationinclude epithelioid cells (round to oval cells) with nestingarrangement and a desmoplasticstroma with feeding ves-sels separating tumor cell nests (Figure 1). In contrast,mesenchymal differentiation is suggested by a diffuse ar-rangement ofspindled cells (Figure 2), without reactivestroma, but with feeding vessels in between tumor tumors, however, may not fitinto either of these 2categories because of their overlapping histologic features(Figure 3), for example,sarcomatoid carcinoma, melano-ma, lymphoma, neuroendocrine tumors, and sarcomawith epithelioid dissection of undifferentiated tu-mors is also helped by categorizing them into small roundArch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al327 Figure of undifferentiated carcinomatous tumorcomposed of epithelioid cells with nesting arrangement and a des-moplastic stroma separating tumor cell nests (hematoxylin-eosin, orig-inal magnification 10).

8 Figure of undifferentiated sarcomatous tumorcomposed of spindled cells with a diffuse arrangement with no reactivestroma in between tumor cells (hematoxylin-eosin, original magnifi-cation 20). Figure of undifferentiated tumor with overlap-ping histologic features, displaying epithelioid cells without nesting ar-rangement (hematoxylin-eosin, original magnification 20).blue cell tumors (SRCTs) or large cell tumors. The lattergroup is further divided into (1) carcinomatous tumors,(2) sarcomatous or sarcoma-like tumors, and (3) tumorswith overlapping features. Each category entertains abroad list of entities from epithelial, mesenchymal, he-matopoietic, or melanocytic lineage in the differential the following section, the immunohistochemical pro-cedure for a broad lineage determination of undifferenti-ated tumors is discussed, followed by immunohistochem-ical analysis of each individual category of SRCTs, carci-nomatous tumors, sarcomatous (or sarcoma-like) tumors,and tumors with overlapping features, supplementedwith diagnostic algorithms.

9 It isemphasized that the out-lined algorithmic immunohistochemical approach is nei-ther meant to be comprehensive nor intended to be anabsolute method for immunohistochemical dissection ofthese tumors. In reality, each tumor requires an individ-ually constructed panel composed of carefully selectedantibodies that recognize all reasonablediagnostic possi-bilities in the context of the tumor s morphology, anatomicsite, and clinical/radiologic LINEAGE DETERMINATIONThe immunohistochemical evaluation of undifferentiat-ed tumors should first aim at determination of the broadcategory of neoplasia, that is, carcinoma, sarcoma, lym-phoma, or melanoma.

10 A screening panel todemonstratethe expression of markers of major lineages (ie, epithelial,mesenchymal, lymphoid, and melanocytic) often providesthe first clue to the nature of an undifferentiated certain circumstances, adjuvant immunostains are add-ed; thus, placental alkaline phosphatase (PLAP) andOCT3/4, markers for germ cell tumors (GCTs), may beincluded for tumors in younger men in view of the highincidence of GCTs inthis age group. Based on the resultof the screening panel, a more detailed or specific panelis commonly followed to further subclassify the tumor orconfirm a particular Markers for Epithelial low-molecular-weight cytokeratins(LMW CKs), including CK8, CK18, and CK19, recognizedby the antibodies CAM or 35BH11, and a cocktail ofkeratins (pankeratin)