The term undifferentiated tumor has been used in reference

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1 Undifferentiated Tumor True Identity by Immunohistochemistry Armita Bahrami, MD; Luan D. Truong, MD; Jae Y. Ro, MD, PhD 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: ) 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 me- Accepted for publication June 4, From the Departments of Pathology, Baylor College of Medicine (Drs Bahrami and Truong) and Weill Medical College of Cornell University, The Methodist Hospital (Drs Truong and Ro), Houston, Tex. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Jae Y. Ro, MD, PhD, Department of Pathology, Weill Medical College of Cornell University, The Methodist Hospital, 6565 Fannin St, Houston, TX ( tastasis 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 326 Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al

2 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. Figure 1. Photomicrograph of undifferentiated carcinomatous tumor composed of epithelioid cells with nesting arrangement and a desmoplastic stroma separating tumor cell nests (hematoxylin-eosin, original magnification 10). Figure 2. Photomicrograph of undifferentiated sarcomatous tumor composed of spindled cells with a diffuse arrangement with no reactive stroma in between tumor cells (hematoxylin-eosin, original magnification 20). BROAD LINEAGE DETERMINATION The immunohistochemical evaluation of undifferentiated tumors should first aim at determination of the broad category of neoplasia, that is, carcinoma, sarcoma, lymphoma, or melanoma. A screening panel to demonstrate the expression of markers of major lineages (ie, epithelial, mesenchymal, lymphoid, and melanocytic) often provides the first clue to the nature of an undifferentiated tumor. In certain circumstances, adjuvant immunostains are added; thus, placental alkaline phosphatase (PLAP) and OCT3/4, markers for germ cell tumors (GCTs), may be included for tumors in younger men in view of the high incidence of GCTs in this age group. Based on the result of the screening panel, a more detailed or specific panel is commonly followed to further subclassify the tumor or confirm a particular diagnosis. Screening Markers for Epithelial Lineage Cytokeratins. The low-molecular-weight cytokeratins (LMW CKs), including CK8, CK18, and CK19, recognized by the antibodies CAM 5.2 or 35BH11, and a cocktail of keratins (pankeratin), recognized by the antibody AE1/ AE3, are useful screening markers for the recognition of epithelial differentiation. Because poorly differentiated carcinomas are known to be heterogeneous in their expression of antigens recognized by epithelial markers, when a negative result is obtained with a single antibody and the diagnosis of carcinoma is still suspected, it is prudent to use additional antibodies in a backup panel. In a study of 98 poorly differentiated carcinomas, CAM 5.2 and epithelial membrane antigen (EMA) each detected epithelial differentiation of 71% of the cases, whereas a combined CAM 5.2 and EMA elucidated the epithelial nature of 99%. 4 Sarcomatoid carcinomas are in particular known to be unpredictable in regard to their CK expression; therefore, Figure 3. Photomicrograph of undifferentiated tumor with overlapping histologic features, displaying epithelioid cells without nesting arrangement (hematoxylin-eosin, original magnification 20). Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al 327

3 it is sometimes required to use several markers in combination to detect the epithelial differentiation of these tumors (see Sarcomatoid Carcinoma ). In addition, CK may not be detectable in certain carcinomas; for example, it is known that CK expression in adrenocortical carcinomas is often diminished to levels too low to be recognized following the deleterious effects of fixation. 5 7 Cytokeratin expression, most frequently with LMW CKs, has been occasionally described in a variety of sarcomas 8,9 and rarely in hematopoietic malignancies and melanocytic lesions. 9,15,16 Aberrant CK staining in nonepithelial malignancies, however, has a weak, focal, and patchy staining, which contrasts with the generally diffuse and strong staining seen in carcinomas or sarcomatoid carcinomas. Conversely, a true strong CK expression, which is frequently associated with a morphologic appearance of epithelial differentiation, is also seen in certain sarcomas 8 (see Sarcomas With Epithelioid Appearance ). Hence, caution should be taken to avoid overinterpretation of CK expression as a specific feature of epithelial tumors. Epithelial Membrane Antigen. As mentioned previously, EMA may be used as a supplement to CKs for detection of epithelial differentiation, especially in sarcomatoid carcinoma or those undifferentiated carcinomas that are negative or only focally positive for CKs. A number of epithelial tumors, including GCTs and some endocrine neoplasms such as medullary carcinoma of thyroid and adrenocortical carcinomas, lack immunoreactivity for EMA. 17 Epithelial membrane antigen is not entirely specific for carcinomas. Epithelial membrane antigen expression has been seen in some normal and neoplastic hematopoietic cells, including reactive and neoplastic plasma cells, 12 lymphocytic and histiocytic (L&H) cells in nodular lymphocyte predominant Hodgkin lymphoma, 18,19 and neoplastic cells in some T-cell lymphomas 17,19,20 ; thus, most anaplastic lymphoma kinase (ALK) positive anaplastic large cell lymphomas ( 75%) are EMA positive. 18,21 Screening Marker for Mesenchymal Lineage Vimentin. Vimentin is the sole intermediate filament characteristic of mesenchymal cells and present in virtually all sarcomas and melanomas and variably in lymphomas. 22 The antigenicity of vimentin is best preserved in frozen and alcohol-fixed tissues. 22,23 Vimentin, however, suffers poor specificity for mesenchymal neoplasms because it may be coexpressed with CK in a wide range of carcinomas (Table 1) Therefore, vimentin by itself cannot be used to differentiate mesenchymal from nonmesenchymal neoplasms. Table 1. Malignant Neoplasms With Coexpression of Vimentin and Cytokeratin Carcinoma Renal cell carcinoma Endometrial adenocarcinoma Serous ovarian carcinoma Thyroid carcinoma, papillary and anaplastic Mesothelioma (biphasic) Sarcomatoid carcinoma (spindle cell carcinoma) Sarcoma Synovial sarcoma Desmoplastic small round cell tumor Malignant rhabdoid tumor Epithelioid sarcoma Epithelioid angiosarcoma Carcinosarcoma Vimentin/CK Coexpression Frequent coexpression of vimentin with CK is seen in some carcinomas, for example, renal cell, endometrial, papillary and anaplastic thyroid, and ovarian serous (variably) carcinomas. 22,23 Consistent absence of vimentin, on the other hand, is observed in colonic, small intestinal, and prostatic adenocarcinomas or in transitional cell carcinomas. 22 The finding of vimentin/ck coexpression helps focus on certain types of epithelial tumors as possible primary sites in the evaluation of metastatic tumors. On the other hand, a number of sarcomas, in particular those with epithelioid appearance, also express CK in addition to vimentin. A selected list of malignant neoplasms frequently demonstrating vimentin/ck coexpression is provided in Table 1. Screening Markers for Malignant Melanoma S100 Protein. S100 protein is regarded as a screening marker for melanoma with more than 95% sensitivity in primary and metastatic sites. A valid positive S100 requires both nuclear and cytoplasmic staining. S100 protein, however, is also expressed in various other lesions, including peripheral nerve sheath, granular cell, cartilaginous and salivary gland tumors, chordomas, Langerhans cell histiocytosis, and occasional adenocarcinomas to varying degrees. 25 Thus, to confirm the melanocytic nature of an S100-positive neoplasm, the tumor should be also positive for one or more melanocyte-specific protein (eg, HMB-45 or MART-1/Melan-A). HMB-45. HMB-45 is a quite specific marker for melanoma, labeling 90% to 100% of conventional primary melanomas. The positivity rate declines to 80% in recurrent or metastatic melanomas and spindle cell melanomas. 26 Desmoplastic melanomas are essentially negative for HMB-45 or other specific melanoma markers. 27 HMB- 45 positivity is typically not observed in carcinomas, lymphomas, or sarcomas. Screening Marker for Hematopoietic Malignancies CD45. Although CD45 (leukocyte common antigen [LCA]) is known to have high sensitivity (97%) and specificity (nearly 100%) for lymphoid tumors, 28,29 exceptions have been documented. For example, CD45 is undetectable in most lymphoblastic lymphomas and is variably expressed in plasma cell neoplasms 29,33 35 and anaplastic large T-cell lymphomas. 36,37 CD45 immunoreactivity has been considered exquisitely specific for hematopoietic cells 28,29 ; yet, there are exceptional reports of CD45 expression in undifferentiated or neuroendocrine carcinomas. 38 Aberrant or Unpredicted Antigen Expression As stated in several previous examples, an aberrant or unexpected antigen expression should be considered as a source of diagnostic pitfall in the surgical pathology evaluation of undifferentiated tumors. A diagnostic misinterpretation 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. The occasional aberrant immunophenotyping must not undermine the 328 Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al

4 Table 2. The Immunoprofile of Small Round Cell Tumors* CK CD45 S100 CD99 Desmin Myogenin/ Myo-D1 CD56 WT1 Ewing sarcoma/primitive neuroectodermal tumor Rhabdomyosarcoma Desmoplastic small round cell tumor Poorly differentiated synovial sarcoma Mesenchymal chondrosarcoma Wilms tumor Neuroblastoma # Small cell carcinoma Hematopoietic malignancies ** Melanoma * CK indicates cytokeratin;, variable;, negative; and, positive. Often negative but occasionally positive. Nonspecific cytoplasmic immunoreactivity. Cytokeratin positive in 50%, epithelial membrane antigen positive in 100%. S100 positive in cartilaginous areas. Positive only in rhabdomyomatous Wilms tumor. # Positive only in schwannian stroma. ** Frequently negative in lymphoblastic lymphoma. Positive in most lymphoblastic lymphomas. Figure 4. Algorithmic immunohistochemical analysis for small round blue cell tumors. NE mk indicates neuroendocrine markers; SmCC, small cell carcinoma; PDSS, poorly differentiated synovial sarcoma; DSRCT, desmoplastic small round cell tumor; EWS/PNET, Ewing sarcoma/primitive neuroectodermal tumor; MC, mesenchymal chondrosarcoma; NB, neuroblastoma; SCOS, small cell osteosarcoma; MyoG, myogenin; RMS, rhabdomyosarcoma; *, positive cytoplasmic but not nuclear staining in RMS; and WT, Wilms tumor. recognized usefulness of screening markers in characterization of undifferentiated malignant neoplasms. SMALL ROUND CELL TUMORS Small round cell tumors comprise heterogeneous neoplasms composed of relatively small, round to oval, closely packed undifferentiated cells with high nuclear-cytoplasmic ratio, scant cytoplasm, and round nuclei with evenly distributed, slightly coarse chromatin and small or inconspicuous nucleoli. In spite of a similar light microscopic morphology, SRCTs include pathologic entities from vastly different lineages, including (1) epithelial tumors, for example, small cell carcinoma (SmCC) (poorly differentiated neuroendocrine carcinoma); (2) mesenchymal tumors encompassing malignant solid neoplasms of childhood and other small round cell sarcomas; and (3) tumors with overlapping features, such as lymphoma and melanoma. Because of similar routine light microscopic features of these tumors, immunohistochemistry is often mandated for a definitive diagnosis. The immunoprofile of SRCTs is provided in the following and in Table 2, and an algorithmic immunohistochemical analysis is outlined in Figure 4. Ewing Sarcoma/Primitive Neuroectodermal Tumor CD99, the product of the MIC2 gene, is a cell surface glycoprotein that is expressed in more than 95% of Ewing sarcoma/primitive neuroectodermal tumors (EWS/ PNETs) with a diffuse membranous staining pattern. CD99, however, is also expressed in several other SRCTs including lymphoblastic lymphoma/leukemia ( 90%), 31,45 acute myelogenous leukemia (43%), 46 granulocytic sarcoma (55%), 46 small cell variant of poorly differentiated synovial sarcoma (PDSS) (nearly all), mesenchymal chondrosarcoma (80% 100%), 50,51 desmoplastic small round cell tumor (DSRCT) (up to 50%), 52 and rarely in rhabdomyosarcoma (RMS). 53 CD99, however, is not expressed in neuroblastoma 42 and is only exceptionally present in blastema-rich nephroblastoma. 44,54 In contrast, CD56, a neural cell adhesion molecule (NCAM), which is positive in most SRCTs, is expressed in only 10% to 25% of EWS/PNETs and rarely in lymphoblastic lymphoma ( 10%). 58,59 Therefore, a CD99 /CD56 profile supports the diagnosis of EWS/PNET or lymphoblastic lymphoma against other SRCTs. The characteristic translocation in EWS/PNET, t(11; Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al 329

5 Figure 5. Photomicrograph of rhabdomyosarcoma showing a diffuse strong nuclear staining for myogenin (original magnification 10). 22)(q24;q12), involving the Ewing sarcoma (EWS) gene on chromosome 22 and the FLI-1 gene on chromosome 11, results in overexpression of FLI-1 protein, which can be detected immunohistochemically in more than 70% of EWS/PNETs. 40,60,61 Hence, a nuclear staining for FLI-1 protein may help distinguish Ewing family of tumors from other CD99-positive SRCTs, except for lymphoblastic lymphomas, which also stain for FLI-1 protein in 88% of cases. 60 Cytokeratin is expressed variably in EWS/PNETs (in 20% 57%); in contrast, desmin expression is extremely uncommon. 40,54,62,63 Rhabdomyosarcoma Myogenin and Myo-D1, the 2 myogenic transcriptional regulatory proteins, are equally regarded as sensitive and specific markers of skeletal muscle differentiation. 64 These markers stain the overwhelming majority ( 95%) of RMSs 53,64 66 including the primitive undifferentiated forms, regardless of morphologic evidence of skeletal muscle differentiation. 65 Although a nuclear staining is deemed as true positive (Figure 5), a cytoplasmic stain, which may be observed in nonmyogenous tumors, should be considered nonspecific. Because of the potential for cytoplasmic and high background staining with available antibodies against Myo-D1, staining for myogenin is technically preferable. 66,67 Desmin and muscle-specific actin, although highly sensitive markers for RMSs, are not specific for these tumors because they also stain smooth muscle neoplasms and DSRCTs. A strong cytoplasmic staining for WT1, not the specific nuclear staining, is observed in RMSs (in 100% of cases in 1 report). 68 Desmoplastic Small Round Cell Tumor These tumors are characterized by a polyphenotypic differentiation, including frequent coexpression of vimentin, epithelial markers (CAM 5.2, AE1/AE3, EMA), WT1, neuron-specific enolase (NSE), and desmin, 52,69,70 the latter with a cytoplasmic or characteristic paranuclear dotlike pattern. Although most DSRCTs are positive for desmin, the absence of reactivity for Myo-D1 and myogenin 52,70 differentiates them from RMSs. Because coexpression of CK and desmin is rarely seen in other SRCTs, it is probably the most specific immunohistochemical profile for DSRCT 52 (Figure 6, a through d). The characteristic genetic feature of DSRCT is a consistent association with t(11; 22)(p13;q12) that results in the fusion of Wilms tumor (WT1) and EWS genes. The antibody directed against the WT1 part of the fusion protein is positive in 70% to 100% of cases. 52,71,72 CD99 expression is variable and seen in one third to one half of DSRCTs. 52,70 Poorly Differentiated Synovial Sarcoma Although the classic bimorphic form of synovial sarcoma is usually easily recognized based on the hematoxylineosin (H&E) morphology, its poorly differentiated variants often create diagnostic difficulty. Three types of PDSS have been recognized: a small cell variant, a large cell epithelioid variant, and a high-grade spindle cell variant. 47 The small cell variant is often difficult to distinguish from other SRCTs, in particular EWS/PNET. The distinction becomes even more complicated as both PDSS and EWS/PNET are reactive for CD99 in most cases. 48,49,73 However, PDSS can be differentiated from EWS/PNET by positive staining for EMA (95% 100% of cases), CK ( 50%), CD56 (100%), and collagen IV (100%). 48,49,73 These markers are conversely negative in most EWS/ PNETs ,74 Because synovial sarcoma is nearly always negative for CD34, a positive stain for CD34 essentially excludes the diagnosis of PDSS. Most synovial sarcomas regardless of histology have the specific translocation t(x; 18)(SYT-SSX); hence, in questionable cases molecular testing may be required for definitive diagnosis. Mesenchymal Chondrosarcoma Mesenchymal chondrosarcoma is a biphasic tumor composed of highly undifferentiated small round cells, admixed with islands of hyaline-like cartilage. If the histologic tissue includes only the undifferentiated small cell component, the distinction of mesenchymal chondrosarcoma from other SRCTs especially EWS/PNET will be difficult or perhaps impossible. Although the cartilaginous areas are reactive for S100 protein, the small cell component is typically not. 50 The immunoprofile of mesenchymal chondrosarcoma includes variable expression for NSE and desmin but negative staining for CKs and myogenin. 50 CD99 is demonstrated in most cases (80% 100%) in the small cell component. 50,51 Small Cell Osteosarcoma Because of the lack of a specific immunoprofile for osteosarcoma, 75 recognition of the small cell variant of osteosarcoma from other SRCTs essentially relies on the observation of osteoid production 76 (Figure 7). Although monoclonal antibodies for osteocalcin are specific for osteoid-forming tumors, 77,78 only a minority of small cell osteosarcoma show osteocalcin reactivity. 39 Osteosarcomas are immunophenotypically heterogeneous 79 and may occasionally express desmin, smooth muscle actin, S100 protein, and rarely CK, 75,79,80 creating a potential diagnostic pitfall in their distinction from other SRCTs. Wilms Tumor Wilms tumor is classically a triphasic tumor composed of blastemal, epithelial, and stromal elements, but on occasions, particularly in small biopsy materials, it may present as a monophasic lesion with only blastemal compo- 330 Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al

6 Figure 6. Photomicrograph of desmoplastic small round cell tumor (hematoxylin-eosin, original magnifications 10 [a] and 20 [b]), showing coexpression of cytokeratin (original magnification 20 [c]) and desmin (original magnification 20 [d]). Figure 7. Photomicrograph of small cell osteosarcoma recognized by lacelike osteoid closely associated with tumor cells (hematoxylin-eosin, original magnification 20). Figure 8. Photomicrograph of Merkel cell carcinoma showing positive staining for CK20 with a distinct paranuclear dotlike pattern (original magnification 40). Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al 331

7 nent. Blastema-rich Wilms tumor, mainly composed of undifferentiated blastemal cells, may be difficult to distinguish from other SRCTs from a morphologic perspective, especially in the setting of metastatic disease. WT1, the Wilms tumor suppressor gene, located on chromosome 11p13, encodes a putative transcription factor implicated in tumorigenesis and in normal urogenital development. WT1 nuclear staining in the blastemal area is seen in 70% to 100% of cases. 54,68,81 Although the blastemal component is reactive for vimentin and desmin (partially in up to 90%), the absence of staining for myogenin and Myo-D1 discriminates blastematous Wilms tumor from RMS. 82,83 Blastemal foci are either negative or only focally positive for CK. Although rare instances of CD99 expression have been reported, staining for FLI-1 has never been observed. 54,60 Neuroblastoma Neuroblastoma is characterized by a neuronal phenotype, which is demonstrated by several markers including NSE (positive in 38% 95%), neurofilament (63%), CD56 (NCAM) (100%), synaptophysin (65% 88%), and chromogranin (60% 88%) Expression of the more specific neuroendocrine markers, including chromogranin and synaptophysin, may diminish in less differentiated tumors. 87 The following markers, which are negative in neuroblastoma, can help differentiate this tumor from EWS/ PNET (CD99 ), SmCC (CK ), lymphoma (CD45 ), melanoma (S100 ), and RMS (positive myogenous markers). 42,84,85 Because up to 35% of olfactory neuroblastomas may be CK positive, 88,89 a concomitant negative EMA may help differentiate them from SmCC. Although the tumor cells are negative for S100 protein, the presence of S100- positive dendritic cells around lobules of tumor cells is a helpful immunohistochemical feature. Small Cell Carcinoma Small cell carcinomas (poorly differentiated neuroendocrine carcinomas) represent poorly differentiated neuroendocrine neoplasms with an epithelial lineage. They may originate from a variety of locations, most commonly the lung but also from extrapulmonary sites, including nasal cavity and paranasal sinuses, breast, uterine cervix, bladder, prostate, gastrointestinal tract, pancreas, thyroid, adrenal gland, skin (Merkel cell carcinoma), and salivary glands. The histopathologic features of these tumors, regardless of the site of origin, are nearly identical. The immunodiagnosis of SmCCs rests on the immunohistochemical proof of a simultaneous epithelial and neuroendocrine differentiation. The former is reflected by reactivity for keratin, especially LMW CKs (CK8 and CK18), 57,90 and the latter by a positive neuroendocrine panel, which in order of increasing specificity includes NSE, CD56 (NCAM), synaptophysin, and chromogranin. 91,92 Against a common histologic and immunohistochemical background, SmCC from different organs may display additional immunophenotypes that help determine the primary site, because not infrequently these tumors present as metastases of unknown origin. For example, among SmCCs from different sites, including gastrointestinal origin, CK20 is positive only in Merkel cell carcinomas ( 97%) 93,94 and salivary gland SmCCs ( 60%), 93,95 often with a distinct paranuclear punctate pattern (Figure 8). Another example is positive reaction for estrogen receptor (ER) and progesterone receptor (PR), which is seen in two thirds of mammary SmCCs according to 1 report. 96 Although immunoreactivity for steroid hormone receptors, especially PR, has been occasionally observed in neuroendocrine tumors from various primary sites, 97,98 unlike breast, simultaneous expression of ER and PR is unusual for them. Thyroid transcription factor 1 (TTF-1) is a sensitive marker for lung SmCC (positive in 80% 100%) ;however, TTF-1 expression has been also observed in various extrapulmonary SmCCs in several settings (11% 80%) ,103 TTF-1, therefore, should not be considered as a sole determinant in distinguishing extrapulmonary SmCC from its pulmonary counterpart. TTF-1 expression, however, is consistently negative in Merkel cell carcinoma. 100,103 One distinctive example of organ-specific SmCC is that from the ovary. There are 2 distinct types of ovarian SmCC. One is the neuroendocrine type, which is morphologically and immunohistochemically indistinguishable from the pulmonary SmCC. The second is the hypercalcemic type, which has a distinctive immunoprofile, dissimilar to that of traditional SmCC, characterized by positive reactivity for CK, calretinin, CD10, N-terminal of WT1, p53, and occasionally parathyroid hormone; negative staining for chromogranin, CD99, desmin, inhibin, S100, and TTF-1; and variable reaction for other neuroendocrine markers. 104,105 One should be aware that extrapulmonary SmCCs do not consistently express the specific antigens of the organs of their origin. For instance, SmCCs of the prostate are negative for prostate-specific antigen (PSA) and prostate acid phosphatase (PAP), 106 and those of the urinary bladder are negative for thrombomodulin, uroplakin III, highmolecular-weight cytokeratin (HMW CK), and CK A positive CDX2, although specific to tumors of intestinal origin, is seen in only 20% of SmCCs of the colon. 108 Sinonasal undifferentiated carcinoma, a rare, highly aggressive tumor type arising in the nasal cavity and paranasal sinuses, should be considered in the differential diagnosis of both SRCTs and undifferentiated large carcinomas in the head and neck region. These tumors are generally positive for CKs but exclusively for CKs of simple epithelia, such as CK8 (100%), CK19 (50%), and CK7 (50%), and as such are negative for CK5/ They stain variably for EMA (18%), NSE (18%), and CD99 (14%) but are typically negative for chromogranin and synaptophysin. 110 Hematopoietic Malignancies A dense infiltrate of relatively small undifferentiated cells of uncertain origin may be the first presentation of a hematolymphoid malignancy. As stated previously, because lymphoblastic lymphomas may not express CD45, 30,32,111 a negative CD45 (LCA) does not totally exclude the possibility of hematopoietic malignancies. Nuclear staining for terminal deoxyribonucleotide transferase (TdT), which is a sensitive marker for both T- and B-precursor lymphoid cells, on the other hand, is considered the hallmark of lymphoblastic lymphoma. The majority (85% 90%) of lymphoblastic lymphomas derive from precursor T cells, and the rest originate from immature B cells. 18 CD43 is a sensitive, although not a specific, T-cell marker. Cytoplasmic CD3 (not surface CD3) is also frequently expressed by T-precursor lymphoblasts. CD79a is a more sensitive marker for detection of immature B cells 332 Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al

8 Table 3. Tumor-Specific Markers and Their Staining Pattern* Marker Tumor Staining Pattern TTF-1 Lung, thyroid Nuclear Thyroglobulin Thyroid Cytoplasmic HepPar-1 Hepatocellular Cytoplasmic CDX2 Colorectal/duodenal Nuclear Villin Gastrointestinal (epithelia with brush border) Apical ER/PR Breast, ovary, endometrium Nuclear GCDFP-15 Breast Cytoplasmic Mammaglobin Breast Cytoplasmic RCC marker Renal Membranous PSA Prostate Cytoplasmic PAP Prostate Cytoplasmic Uroplakin III Urothelial Membranous Inhibin Sex cord stromal, adrenocortical Cytoplasmic Melan-A Adrenocortical, melanoma Cytoplasmic Calretinin Mesothelioma, sex cord stromal, adrenocortical Nuclear/cytoplasmic WT1 Ovarian serous, mesothelioma, Wilms, desmoplastic small round cell Nuclear Mesothelin Mesothelioma Cytoplasmic/membranous D2-40 Mesothelioma, lymphatic endothelial cell marker Membranous * TTF-1 indicates thyroid transcription factor 1; HepPar-1, hepatocyte paraffin 1; ER/PR, estrogen receptor/progesterone receptor; GCDFP-15, gross cystic disease fluid protein 15; RCC, renal cell carcinoma; PSA, prostate-specific antigen; and PAP, prostate acid phosphatase. compared with CD20. Thus, if lymphoblastic lymphoma is suspected, the panel should include TdT, CD43, and CD79a, in addition to CD45. Myeloid (granulocytic) sarcomas with little or no evidence of myeloid differentiation may manifest as undifferentiated tumors, sometimes with small round cell morphology. A high index of suspicion is often required to avoid diagnostic overlook of these malignancies. Myeloblasts are usually positive for CD45 (in 75% of cases), CD43 (100%), myeloperoxidase (variably), and lysozyme (variably) but are generally negative for B- and T-lineage markers, including CD79a and CD3, respectively. 112 As mentioned previously, most lymphoblastic lymphomas 45,111 and a large fraction of myeloid sarcomas 46 express CD99. However, application of lymphoid markers usually helps to distinguish hematolymphoid malignancies from Ewing sarcomas, which are negative for these markers. Malignant Melanoma In keeping with various cytomorphologic and architectural manifestations of malignant melanoma (MM), its small cell (neuroendocrine-like) variant, which occurs more commonly within the nasal cavity and paranasal sinuses, 26 is a differential diagnostic consideration for SRCTs. Because melanoma with small cell morphology often lacks melanin pigment, immunohistochemistry plays an important role in its recognition. The immunoprofile of MM is discussed in more detail later in the section on tumors with overlapping histologic features. Herein the potential for expression of aberrant markers in small cell melanoma as a source of diagnostic confusion with other SRCTs is highlighted. These include CD99 in rare to up to 60% of cases, 113,114 WT1 (cytoplasmic but not nuclear pattern) in as many as 70%, 115 CD10 in 40% to 50%, 116,117 CD68 (a histiocytic marker) in 86%, 118 NSE in approximately 50%, 113 and neuroendocrine markers (CD56, CD57, and synaptophysin) in up to 13%. 113 Chromogranin, on the other hand, is consistently absent in melanocytic tumors. 119 UNDIFFERENTIATED CARCINOMATOUS TUMORS Undifferentiated tumors with a carcinomatous appearance are characterized by large round-oval to polygonal cells with a nesting arrangement. These histologic attributes, however, are not specific to carcinomas and may be mimicked by other tumors, including sarcomas with epithelioid appearance, melanoma, and hematopoietic malignancies. Screening panel for major lineage determination (see previous discussion) is essential for clarification of the true identity of these tumors. Tissue- or Organ-Specific Determination Once the diagnosis of carcinoma by broad lineage markers is established, immunohistochemistry may assist further by delineation of the cell line of differentiation. This is achieved by analysis of CK subtypes and other complementary or tissue- or organ-specific markers (Table 3). Although some markers are expressed almost exclusively in a specific tissue, for example, PSA and PAP for prostate and uroplakin III for urothelial epithelium, others are not strictly organ or tissue specific but may help focus the diagnosis to a specific area. It should be mentioned that because most reports on the sensitivity and specificity of markers in the literature are derived from studies that encompassed primary and metastatic tumors of various grades, it is difficult to extrapolate those parameters exclusively in respect to undifferentiated or poorly differentiated forms of tumors. Nevertheless it can be concluded from the literature that for most entities, the sensitivity of tissue-specific markers declines as the tumor grade increases. Also, although the antigenic expression of some markers appears to be robust during metastasis, for example, CDX2 for colorectal carcinoma, others, such as the renal cell carcinoma (RCC) marker, tend to reduce their sensitivity in metastatic sites. CK Profile. The CK phenotype often provides helpful clues in determination of the cell line of differentiation in both primary and metastatic carcinomas. This reflects the observation that tumors tend to recapitulate the CK profile of the normal cells from which they are derived. Although metastatic tumors may gain or lose antigens compared with primary tumors, their CK profiles usually remain the same, as demonstrated by a number of studies, including a comprehensive study of CK7 and CK20 for 384 primary tumors and their metastasis 120 and other studies focusing on CK20 expression by primary and metastatic colorectal Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al 333

9 Figure 9. Algorithmic immunohistochemical analysis of undifferentiated carcinomas. CA indicates carcinoma; adenoca, adenocarcinoma; SmCC, small cell carcinoma; SCC, squamous cell carcinoma; RCC, renal cell carcinoma; HCC, hepatocellular carcinoma;, seminoma is keratin negative, OCT3/4 positive; *NE markers, neuroendocrine markers, including synaptophysin, chromogranin, and CD56;, undifferentiated anaplastic thyroid carcinoma is often negative for thyroid transcription factor 1 (TTF-1) and thyroglobulin; and, characteristic canalicular pattern. carcinoma. 94,121,122 Coordinate expression of CK7 and CK20 defines subsets of carcinomas, as shown in Figure 9. The CK7/CK20 phenotype can be especially useful in certain clinical situations, including the differentiation between prostate (CK7 /CK20 ) and urothelial (CK7 / CK20 variable) carcinoma 123 (Figure 10); poorly differentiated squamous (CK7 ) and poorly differentiated urothelial (CK7 ) carcinoma of the urinary bladder; and metastatic colorectal carcinoma (CK7 /CK20 ) from primary nonmucinous ovarian carcinoma or primary endometrial, pulmonary, or mammary adenocarcinoma (CK7 / CK20 ). 122,124 Other CK subtypes may also have a role in defining the lineage of tumor; for example, CK19 combined with CK7 helps to differentiate between hepatocellular carcinoma (HCC) (CK7 /CK19 ) and bile duct carcinoma (CK7 / 334 Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al

10 Figure 10. Photomicrograph of urothelial carcinoma with positive staining for cytokeratin (CK) 7 (a) and CK20 (b) (original magnifications 20). Figure 11. Photomicrograph of lung adenocarcinoma with diffuse nuclear staining for thyroid transcription factor 1 (original magnification 10). Figure 12. Photomicrograph of epithelioid mesothelioma with nuclear and cytoplasmic staining for calretinin (original magnification 20). Figure 13. Photomicrograph of seminoma, showing a diffuse strong nuclear staining for OCT3/4 (original magnification 20). Figure 14. Photomicrograph of sarcomatoid carcinoma with cytokeratin expression in both sarcomatous and carcinomatous areas (original magnification 20). Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al 335

11 Table 4. Carcinoembryonic Antigen (CEA) Immunostaining in Carcinomas CEA Positive Colonic/rectal adenocarcinoma Gastric and esophageal adenocarcinoma Pancreatic adenocarcinoma Biliary tract adenocarcinoma Endocervical adenocarcinoma Lung adenocarcinoma CEA Negative Endometrial adenocarcinoma Renal cell carcinoma Prostate adenocarcinoma Ovarian serous carcinoma Adrenal carcinoma Mesothelioma CK19 ). 125 CK5/6 serves as a sensitive marker for squamous cell carcinoma (SCC) (CK5/6 ) and epithelioid mesothelioma (CK5/6 ) and helps differentiate them from pulmonary adenocarcinoma (CK5/6 ). 124, CK5/6 also labels urothelial carcinoma (in 50% 63% of cases) 124,126 and the large cell undifferentiated lung carcinoma (variably). 126,130 Figure 9 provides a selected list of specific tumors with their pertinent positive and negative markers, categorized according to their CK7/CK20 profile. The choice of tissuespecific markers to be included in an investigative panel is largely determined by the clinical impression, site of presentation, and the CK7/CK20 expression of an undifferentiated carcinoma. Carcinoembryonic Antigen. Carcinoembryonic antigen (CEA) is an oncofetal glycoprotein overexpressed by a variety of adenocarcinomas and consistently by gastrointestinal adenocarcinomas. 131,132 Table 4 summarizes reactivity for CEA in a variety of carcinomas. Use of CEA in a panel may especially assist in certain differential diagnostic considerations, for example in the distinction of endocervical (CEA positive) over endometrial (CEA negative) adenocarcinoma 133 or in the recognition of poorly differentiated colonic adenocarcinoma (CEA positive) from solid areas of ovarian serous adenocarcinoma (CEA negative). 132 Polyclonal CEA (pcea) antibodies, in contrast to CEAspecific monoclonal antibody, have cross reactivity with CEA-related antigens, including biliary glycoprotein antigen. Hepatocellular carcinoma is negative for monoclonal CEA but expresses a characteristic bile canalicular staining pattern with pcea 134 because of cross reactivity with biliary glycoprotein antigen. Carcinoembryonic antigen is also frequently used as a negative marker in the mesothelioma panel. MOC-31. MOC-31 is a cell surface glycoprotein largely found on the epithelial cells. MOC-31 helps differentiate between adenocarcinoma (MOC-31 positive) and mesothelioma (MOC-31 negative). 135,136 MOC-31 is also useful in the recognition of cholangiocarcinoma and other metastatic adenocarcinomas (MOC-31 positive) from HCC (MOC-31 negative). 137 p63. p63, a p53 homologue, is a marker for basal cells and helps maintain basal cells in squamous and other epithelial linings. 138 p63 stains the vast majority of SCCs ( 97%) and, in addition to CK5/6, is recognized as a good marker for SCC, especially the poorly differentiated forms. 102, Thus, a combined p63 /CK5/6 immunoprofile in a poorly to undifferentiated carcinoma is highly predictive of a squamous origin. 139 Because urothelial carcinoma also expresses p63 (in 70% 95% of cases) and CK5/6 (50% 63%), 126,143 a p63 /CK5/6 immunoprofile could also suggest a urothelial carcinoma. The 2 entities are nevertheless distinguished based on their different coordinate CK7/CK20. p63 expression in the lung, however, is not specific to SCC; thus, a subset of adenocarcinomas (30%) and large cell carcinomas (37%), 50% of large cell neuroendocrine carcinomas (particularly higher-grade tumors), and a variable proportion of SmCCs (0% 77%) stain for p ,142 Because p63 is consistently negative in mesothelioma, it can assist in differentiating SCC of the lung from epithelioid mesothelioma. 127,139 Neuroendocrine Markers. Neuroendocrine markers are tissue indicators of neuroendocrine neoplasms, including those with epithelial lineage (neuroendocrine carcinomas) and those with neural derivation, such as paraganglioma/pheochromocytoma and neuroblastoma. The 2 most reliable markers of neuroendocrine neoplasms, synaptophysin and chromogranin, have a comparable sensitivity; thus, they are always used together as complementary reagents for neuroendocrine lineage determination. CD56 is generally regarded as a broad-spectrum neuroendocrine marker and perhaps the most sensitive 144,145 and is instrumental in confirming the diagnosis of neuroendocrine tumors in small biopsies CD56, however, is not specific for neuroendocrine delineation because it may label occasional nonneuroendocrine tissues and their malignant counterpart (eg, follicular and papillary thyroid, renal cell, and hepatocellular carcinoma), natural killer cells, some T-cell lymphomas, and a large number of SRCTs. 92,147 Neuron-specific enolase suffers a poor specificity for neuroendocrine tumors, and, as such, it is not used as a sole determinant of neuroendocrine differentiation. An undifferentiated carcinoma may turn out to have an occult neuroendocrine differentiation, disclosed by immunostain. Although neuroendocrine markers are not usually included in the initial diagnostic panel for an undifferentiated tumor, detection of neuroendocrine differentiation is clinically significant, because this may imply prognosis and therapy similar to those for SmCC. 148,149 Because positive staining in a few tumor cells is frequent in any undifferentiated carcinoma, the diagnosis of neuroendocrine carcinoma should only be made if the stain is unequivocal and, in our experience, present in at least 20% of the tumor cells. In the lung, large cell neuroendocrine carcinoma must be differentiated from basaloid carcinoma. Because of their overlapping H&E morphology, the differential diagnosis is often difficult but can be facilitated by their specific immunoprofiles. Basaloid carcinoma is negative for neuroendocrine markers and TTF-1 and positive for HMW CK, whereas large cell neuroendocrine carcinoma is consistently positive for neuroendocrine markers, positive for TTF-1 in about 50% of cases, and often negative for HMW CK. 103,150,151 Thyroid Transcription Factor 1. TTF-1 is a nuclear transcription factor that promotes embryogenic pulmonary and thyroid differentiation and is expressed by most, but not all, lung or thyroid neoplasms. Although 80% to 100% of SmCCs and 96% to 100% of adenocarcinomas from lung express TTF-1 (Figure 11), pulmonary SCCs are negative in most cases ,150,152,153 Furthermore, TTF-1 expression tends to decrease in poorly differentiated (50% positive) compared with welldifferentiated (100% positive) adenocarcinomas, 153 diminishing the sensitivity of this marker for identification of the pulmonary origin of a poorly differentiated adenocar- 336 Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al

12 cinoma. Among thyroid carcinomas, undifferentiated anaplastic thyroid carcinomas are unfaithful in terms of TTF- 1 expression (positive in 5%). 154 TTF-1, as mentioned previously, may also be expressed in SmCCs arising from a variety of locations other than the lung 99,101,103,155 (see also Small Cell Carcinoma ). Thyroglobulin. Thyroglobulin is a very specific marker for thyroid follicular and papillary carcinomas but only rarely stains cells in undifferentiated anaplastic thyroid carcinoma. 154,156 Anaplastic thyroid carcinomas are generally positive for vimentin and CK 157,158 but are negative for CEA, 157 TTF-1, 154 and melanocytic, vascular, myogenous, and lymphoid markers. Hepatocyte Paraffin 1. Hepatocyte paraffin 1 (HepPar- 1) is a monoclonal antibody that stains a cellular antigen of unknown function of normal hepatocytes and is known to be a highly sensitive (positive in 90% of cases) and relatively specific marker for HCC HepPar-1 expression, however, decreases in HCC with higher nuclear grade. 164 HepPar-1 is occasionally observed in nonhepatic carcinomas, including those of gastrointestinal origin, in particular gastric signet ring cell carcinoma (47% 83%), and rarely in other tumors. 159, The distinction of HCC, especially its poorly differentiated forms, from metastatic adenocarcinoma and cholangiocarcinoma is commonly a diagnostic challenge. A panel that includes HepPar-1, MOC-31, pcea, and CD10, in addition to CK7 and CK20, is often helpful in making the accurate diagnosis. The immunoprofile of HCC includes CK7 /CK20, HepPar-1 positive, MOC-31 negative, sinusoidal cell CD34, and a canalicular pattern of positive immunostaining with both pcea and CD ,160,161,166 Metastatic adenocarcinoma and cholangiocarcinoma, on the other hand, are generally MOC-31 and CEA positive, the latter with a membrane/cytoplasmic staining pattern. The canalicular staining pattern with antibodies to CD10, positive in 68% of HCC, is distinct from the membrane or cytoplasmic staining seen in RCC. 166 CDX2. CDX2, an intestine-specific transcription factor, is a sensitive and specific marker for colorectal and duodenal adenocarcinomas in both primary and metastatic sites However, CDX2 expression tends to decline in the higher grade and stage of colorectal tumors (positive in only 56% of poorly differentiated tumors) 169 and is practically absent in an undifferentiated subset of large cell colonic carcinoma, usually associated with DNA mismatch repair defects. 170 CDX2 is variably expressed in other adenocarcinomas of the digestive tract, including gastric (55% 70%), esophageal (67%), pancreatic (32% 60%), and biliary (25% 60%). 163,167 CDX2 is also observed in a few extraintestinal carcinomas. For example, 47% to 100% of primary adenocarcinomas of the bladder 168,171 and 10.5% to 100% of ovarian carcinomas, particularly the mucinous type, are positive for CDX Because bladder adenocarcinoma also displays a urothelial profile (CK7, 65% positive; CK20, 53% positive; and thrombomodulin, 59% positive), 172 it may be differentiated from metastatic colorectal carcinoma by immunohistochemistry. Villin. Villin is a cytoskeletal protein associated with brush border microvilli of the intestine and proximal renal tubular epithelium. Villin is a sensitive marker of gastrointestinal adenocarcinomas, staining 82% to 100% of primary and metastatic colonic adenocarcinomas. 168,173,174 Villin expression does not seem to be associated with the state of tumor differentiation. 173 Villin, however, also stains a number of extragastrointestinal adenocarcinomas, including some adenocarcinomas of ovary, endometrium, kidney, and bladder. 171,173,175 Villin expression in lung adenocarcinoma correlates with the presence or absence of microvilli (positive in 67% and 10% of cases, respectively). 174 ER and PR. The role of ER and PR in determining the primary site in undifferentiated tumors is hampered by a wide spectrum of expression among a variety of tumors. Although ER and PR expression is expected to be associated with hormone-responsive organs and their neoplasms, such as breast, ovary, and endometrium, 176 there are frequent examples of unexpected ER or PR expression reported in a variety of other tumors, including those from lung, 98, thyroid, 180 stomach, 181 and some neuroendocrine tumors. 97 Furthermore, given that many highgrade carcinomas arising from hormone-responsive organs such as breast lack ER expression, we discourage sole reliance on ER and PR as determinants of the site of tumor origin, except in selected differential diagnoses and in combination with other immunomarkers. An example of the utility of ER in a diagnostic panel is its application combined with CEA 133 and vimentin in the distinction of an endometrial (vimentin /ER /CEA ) from an endocervical (vimentin /ER /CEA ) adenocarcinoma. Gross Cystic Disease Fluid Protein. Gross cystic disease fluid protein 15 (GCDFP-15), a 15-kd secretory glycoprotein of various body fluids, including saliva, milk, and seminal fluid, is considered a marker of apocrine differentiation 182,183 with high specificity for breast carcinomas In a study of 328 metastatic adenocarcinomas, Kaufmann et al 184 demonstrated that expression of GCDFP-15 and/or ER or PR had a sensitivity of 83%, a specificity of 93%, and a predictive accuracy of 92% for carcinomas of the breast against all other carcinomas excluding ovarian carcinomas. In another study, including 105 breast cancers and 585 nonmammary malignancies, GCDFP-15 was able to identify breast carcinomas with a sensitivity of 74% and a specificity of 95%. 185 Other tumor types with occasional GCDFP-15 expression include carcinomas of the salivary glands, sweat glands, and prostate. 185,187 Although a very specific marker, GCDFP-15 is not a particularly sensitive marker of breast carcinoma. 188,189 It is uncertain whether GCDFP-15 expression declines in poorly differentiated forms of mammary carcinoma. Mammaglobin. Mammaglobin, a mammary-specific member of the uteroglobin family, is overexpressed in human breast carcinoma. Mammaglobin expression has been observed in 48% to 84% of breast carcinoma and in 8% to 15% of carcinomas not from breast, including salivary gland tumors (55%) and endometrial carcinoma (13%) Although mammaglobin appears to be a more sensitive marker than GCDFP-15, it is not as specific as GCDFP-15 for breast carcinoma. 188 The predictive value of a combined mammaglobin and GCDFP-15 panel for mammary carcinomas in tumors of unknown origin needs to be investigated. RCC Marker. Renal cell carcinoma marker, a monoclonal antibody against a normal human proximal tubular brush border glycoprotein known as gp200, decorates conventional and papillary RCCs with an approximate sensitivity of 85% and more than 95%, respectively. 191,192 Among nonrenal carcinomas, a subset of breast (29%) and Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al 337

13 embryonal carcinoma (28%) may stain with RCC marker. 191 The sensitivity of RCC marker tends to decline from low-grade (92%) to high-grade (75%) conventional RCCs. 192 In addition, only 25% of sarcomatoid RCCs stain for this marker. 191 Although RCC marker remains highly specific (98%) for metastatic RCC, because of a rather low sensitivity in metastatic sites (positive in 67%), a negative result does not totally rule out metastatic RCC. 191 Negative vimentin and CD10, however, enhances the negative predictive value for conventional RCCs in an investigative panel for metastatic tumors. CD10, similar to vimentin, is a nonspecific marker for RCCs. It is, however, a relatively sensitive indicator for RCCs and stains approximately 90% of these tumors with a diffuse cytoplasmic or membranous pattern. 117 The distribution of CD10 appears to be independent of the grade or histologic type (conventional vs papillary) of the RCC. 192 PSA and PAP. Immunostain for the prostate-specific markers PSA and PAP, 2 glycoproteins produced almost exclusively by the prostatic glandular epithelium, is widely used for determination of the prostatic origin of metastatic tumors. Genega et al 193 demonstrated a sensitivity of 94% for intermediate- to high-grade prostate adenocarcinomas (Gleason score 8) with both PSA and PAP. Prostate-specific antigen expression has been rarely reported in some nonprostatic tissues and tumors, including salivary gland, breast, and gynecologic tumors Prostate-specific antigen and PAP expression tends to decrease in higher grade prostate adenocarcinomas. 198,199 In a study of 225 prostate adenocarcinomas by Goldstein, 200 all tumors with a Gleason score of 6 or 7 were reactive for PSA, whereas 13% of the adenocarcinomas with a Gleason score of 10 were nonreactive. Although some investigators found PAP slightly more sensitive than PSA in diagnosing poorly differentiated prostatic adenocarcinoma, 200,201 others could not confirm these findings. 199,202 Nevertheless, a combined immunostain for PAP and PSA would be expected to detect most prostatic adenocarcinomas in metastatic sites. 199,203 Parenthetically, -methylacyl-coa racemase (AMACR) encoded by the gene P504S, which is a highly specific and sensitive marker for prostatic carcinoma in prostatic specimens, 204 has limited value in detecting metastatic prostate cancer because it is also expressed in various normal tissues and nonprostatic tumors. 205 Thrombomodulin. Thrombomodulin, a cell surface glycoprotein involved in the regulation of intravascular coagulation, is expressed in 70% to 90% of primary or metastatic urothelial carcinomas. 107,206,207 Thrombomodulin, however, is also expressed by a variety of nonurothelial tumors, including SCC (majority) and endothelial vascular tumors. 207 Thrombomodulin is additionally known as a positive mesothelioma marker, although not as specific or sensitive as the other markers discussed later ,208 Uroplakin III. Uroplakin III, expressed by terminally differentiated superficial urothelial cells, is a highly specific marker for urothelial origin of tumors. 107,209 This marker, however, is not quite sensitive for urothelial carcinomas; thus, it is expressed in up to 60% of urothelial carcinoma in primary sites and slightly less frequently in metastases ( 50%). 107,209 The differential diagnosis between a poorly differentiated prostate adenocarcinoma involving the bladder and a high-grade urothelial carcinoma with prostatic extension can be very challenging. This challenge, which is usually solved by careful cytomorphologic evaluations (monotonous tumor cells, prominent nucleolus, and less mitoses for prostate cancers), may be facilitated by a panel that includes a number of discriminatory markers, in addition to CK profile, including PSA and PAP, markers of prostate adenocarcinoma, and HMW CK, p63, uroplakin III, and thrombomodulin, markers that are expected to be positive in urothelial carcinoma. 210,211 Inhibin. Inhibin is a peptide hormone produced by ovarian granulosa cells and testicular Sertoli cells. It serves as a sensitive and highly specific marker for ovarian and testicular sex cord stromal tumors Inhibin is also a sensitive marker for adrenal cortical neoplasms and reliably differentiates cortical from medullary adrenal tumors Melan-A. Melan-A, a product of MART-1 gene, is an antigen on melanoma cells that is recognized by the antibody A103. Although Melan-A is essentially used as a melanoma marker, 219 it is also a sensitive marker for adrenal cortical neoplasms 220 and, similar to inhibin and calretinin, a specific marker in differentiating cortical from medullary adrenal tumors. 216 Melan-A is additionally expressed by perivascular epithelioid cell tumors (PEComa). 219,221 Calretinin. Calretinin is a good marker for malignant mesothelioma with a sensitivity approaching 100%. 127,128,208,222 It is also quite specific for mesothelioma against adenocarcinomas, which are positive for it in only 8% to 11% of cases. 128,130,208,222 Calretinin decorates both mesothelial cells and malignant mesothelioma with both nuclear and cytoplasmic staining 223 (Figure 12). Calretinin additionally serves as a highly sensitive marker for sex cord stromal tumors. It is, however, not as specific as inhibin in this respect because it also labels a fraction of ovarian epithelial neoplasms (22%). 215,224,225 Like inhibin and Melan-A, calretinin also stains adrenal cortical neoplasms and discriminates them from adrenal medullary tumors. 216 Mesothelin. Mesothelin is a cell surface antigen that is strongly expressed in normal mesothelial cells, mesotheliomas, and a number of other carcinomas. 226 Although a highly sensitive marker for mesothelioma, mesothelin may also be present in approximately half of the lung adenocarcinomas 130,226 ; as such, it has limited value in discriminating between the 2 entities. Carcinomas with consistently strong exhibition for mesothelin include nonmucinous carcinomas of the ovary and adenocarcinomas of the pancreas and ampulla of Vater. 226 WT1. WT1, in addition to its diagnostic utility for SRCTs (see Small Round Cell Tumors ), is a sensitive marker for epithelioid mesothelioma, successfully discriminating it from adenocarcinoma. 128,227 Another epithelial tumor strongly positive for WT1 is ovarian serous carcinoma, which is positive in nearly all cases including the high-grade forms. 228 Because both peritoneal mesothelioma and ovarian serous carcinoma metastatic to the peritoneum express WT1, additional markers are needed for their differential diagnosis: A panel including calretinin, Ber-EP4, ER, and PR is helpful in differentiating mesothelioma (calretinin /Ber-EP4 /ER /PR ) from primary or metastatic serous ovarian carcinoma (calretinin /Ber- EP4 /ER /PR ). 229 Other Mesothelioma Markers. Immunohistochemistry has a crucial role in the differential diagnosis between 338 Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al

14 malignant epithelioid mesothelioma and adenocarcinoma metastatic to the serous membranes. A number of discriminatory markers are available to facilitate this recognition. It is generally recommended to include at least 2 positive and 2 negative markers in the differential panel for mesothelioma. Calretinin, WT1, and CK5/6 (discussed earlier) are established as highly reliable positive mesothelioma markers. 128 Other positive markers include mesothelin and thrombomodulin (discussed earlier). In addition, D2-40, 230 a lymphatic endothelial marker, and h-caldesmon, 231 a specific marker for smooth muscle tumors, have recently been shown to be valuable in discriminating mesothelioma from lung adenocarcinoma. On the other hand, CEA, MOC-31, Ber-EP4, BG-8, and B ,129 are accepted as reliable negative markers for discriminating epithelioid malignant mesothelioma from pulmonary adenocarcinoma. CD5. CD5 is a useful marker of primary thymic carcinomas, expressed in neoplastic epithelial cells of the thymic carcinoma but typically not in thymoma or other carcinomas involving the mediastinum Of the 2 used clones of anti-cd5 antibody, clone CD5/54/B4 identifies 30% to 67% of thymic carcinomas. 235,236 The other clone, NCL-CD5-4C7, although more sensitive for thymic carcinomas (45% 100% positive), also labels other neoplasms occasionally Markers of GCTs. Germ cell tumors sometimes present as undifferentiated metastatic carcinomas. Accurate recognition of these tumors is of utmost importance because of the available effective therapy. Placental alkaline phosphatase is consistently present in embryonal carcinoma and seminoma and variably in several other GCTs, including yolk sac tumor and choriocarcinoma. 237,238 Placental alkaline phosphatase immunoreactivity, however, is not completely specific to GCTs, as it has been seen in some soft tissue tumors with known myogenic differentiation. 239 OCT3/4, also known as POU5F1, is a transcription factor and a robust diagnostic marker for seminoma (Figure 13) and embryonal carcinoma in both primary and metastatic sites Seminoma also stains consistently with D2-40. Yolk sac tumor does not express OCT3/4 but is positive for -fetoprotein, albeit with a patchy staining pattern. Human chorionic gonadotropin is consistently expressed by syncytiotrophoblasts of choriocarcinomas. UNDIFFERENTIATED SARCOMATOUS OR SARCOMA-LIKE TUMORS In the approach to undifferentiated tumors with sarcomatous appearance, exclusion of nonmesenchymal neoplasms such as sarcomatoid carcinoma and sarcomatoid mesothelioma and other mimickers, for example, spindle cell melanoma or hematopoietic malignancies with sarcomatous feature, is essential. The distinction is usually attained by using the screening panel previously discussed in the introduction. Undifferentiated High-Grade Sarcomas Once the true sarcomatous nature of an undifferentiated tumor is established, investigation for a specific mode of differentiation, that is, neural, myogenous, lipomatous, or vascular lineage, should be implemented. Fletcher 243 demonstrated that among 159 neoplastic lesions initially diagnosed as pleomorphic sarcoma, 63% could be reclassified as specific types of sarcoma after implementing further studies, including combined immunohistochemistry and electron microscopy. Coindre et al 244 showed that among 25 tumors initially diagnosed as retroperitoneal malignant fibrous histiocytoma (MFH), 17 could be reclassified as dedifferentiated liposarcoma by extensive sampling, combined with immunohistochemistry and comparative genomic hybridization. These distinctions are important above the academic interest in view of their variable prognostic implications. 245 It is emphasized that ancillary tests do not replace proper tumor sampling, which often helps detect tumor foci with features suggestive of or diagnostic for a specific line of differentiation. According to the report of the International Chromosomes and Morphology (CHAMP) study group on 46 pleomorphic soft tissue sarcomas, it is unlikely that cytogenetic analysis, mainly because of the karyotype complexity of these tumors, can further improve their differential diagnostic subclassification. 246 With the help of immunohistochemistry in conjunction with generous tumor sampling, a high-grade undifferentiated sarcoma can often be classified into one specific category of pleomorphic sarcomas, including pleomorphic leiomyosarcoma, pleomorphic RMS, pleomorphic and dedifferentiated liposarcoma, osteosarcoma, pleomorphic malignant peripheral nerve sheath tumor (MPNST), and PDSS. The diagnosis of pleomorphic leiomyosarcoma requires demonstration of a positive reaction for smooth muscle markers, including smooth muscle actin, muscle-specific actin, desmin, calponin, and h-caldesmon, 246,247 in the presence of at least focal supporting morphologic characteristics (eosinophilic spindle cells with vesicular blunt-ended nuclei arranged in a fascicular pattern). The expression of myoid markers in the pleomorphic areas, compared with the leiomyosarcomatous foci, is usually significantly reduced. 247 Among myoid markers, h-caldesmon appears to be a promising reagent for specific smooth muscle differentiation that allows distinction of leiomyosarcoma from other tumors with smooth muscle like differentiation, including myofibroblastic tumors. 248,249 However, only 40% of pleomorphic leiomyosarcoma are labeled with this antibody. 247 The immunoprofile of pleomorphic RMS includes expression of muscle-related antigens, that is, desmin, myoglobin, and actin, 250 along with a diffuse reaction with at least one skeletal muscle specific marker including myogenin and Myo-D The staining pattern for skeletal muscle markers in pleomorphic RMS is typically diffuse, which should be distinguished from focal staining seen in a variety of sarcomas with limited areas of rhabdomyomatous differentiation. The diagnosis of liposarcomas, until a specific lipoblast marker is discovered, continues to be made essentially on the basis of the H&E light microscopy. Although normal fat cells are positive for S100, neoplastic adipocytes stain inconsistently. 252 S100 labels lipoblasts in up to half of pleomorphic liposarcomas, but nonlipogenic areas only rarely stain with S ,256 The ap2 gene product (ap2 protein) has been suggested as a relatively specific marker for lipoblasts in all types of liposarcoma. 257 This marker also stains brown fat cells but reportedly not benign adipocytes or cells of other mesenchymal or epithelial tumors. 257 Because of the paucity of pertinent studies, the diagnostic value of this marker remains to be deter- Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al 339

15 mined. Positive immunostainings for MDM2 and CDK4, which correlate with amplification of these genes in dedifferentiated liposarcomas, may help differentiate dedifferentiated liposarcomas from poorly differentiated sarcomas. 258 The diagnosis of osteosarcoma is essentially rendered at the H&E light microscopic level by demonstration of bone or lacelike osteoid associated with malignant cells. Osteocalcin, which seems to specifically highlight the osteoid and the cytoplasm of osteoblasts (90% 100% specific), 77,78 may be potentially helpful in the diagnosis of osteosarcoma in small biopsy material in the absence of recognizable osteoid. Notably, osteosarcomas can be immunoreactive for actin and rarely for epithelial markers. The diagnosis of pleomorphic MPNST is immunohistochemically supported by demonstration of nerve sheath differentiation by a number of neural markers including S100, Leu-7 (CD57), myelin basic protein, and protein gene product ,260 The coexpression of these antigens is more reassuring for the diagnosis because none of them in isolation is specific for nerve sheath tumors. 259 A focal staining for S100 is seen in most MPNSTs (50% 60%), 259,261 yet many high-grade MPNSTs display a decreased or negative reactivity for S100 and CD The diagnosis of high-grade spindle cell variant of PDSS is supported by demonstration of positive reaction for EMA, keratin and its subsets (CK7 and CK19), Bcl-2 antigen, and CD ,261 and negative staining for S100 and CD34. In questionable cases, molecular testing may be required for definitive diagnosis. Pleomorphic MFH or undifferentiated high-grade pleomorphic sarcoma is a group of pleomorphic sarcomas that do not demonstrate a definitive line of differentiation even with the application of immunohistochemistry. Malignant fibrous histiocytoma is therefore a diagnosis of exclusion, which is made in the absence of reaction with any lineageselective markers in a high-grade pleomorphic sarcoma. With current advances in diagnostic techniques, it is expected that the number of tumors diagnosed as MFH will be progressively smaller. Because a number of nonmesenchymal neoplasms may impart an MFH-like morphology, exclusion of these entities by immunohistochemistry is inevitable. Although keratin may stain a minor portion (up to 25%) of pleomorphic MFHs, the staining is often weak and focal. 55,263,264 The tumor cells may be focally positive for smooth muscle actin or muscle-specific actin, but they are generally negative for desmin and S100. Rare desminpositive cells in tumors with MFH-like morphology should not be regarded as evidence of myogenic differentiation. Sarcoma-like Tumors Sarcomatoid Carcinoma. Sarcomatoid (spindle cell) carcinomas are a group of poorly to undifferentiated carcinomas that contain a component of spindle cell differentiation with or without differentiated heterologous elements, such as malignant cartilage, bone, or skeletal muscle. 265,266 Some tumors are histologically biphasic with obvious sarcomatous and carcinomatous areas, whereas others may show no obvious epithelial areas despite generous sampling. 266,267 In such instances, the sarcomatoid foci are hardly distinguishable from true sarcomas at the light microscopic level; therefore, immunohistochemistry plays a pivotal role in delineation of epithelial differentiation. The tumor cells often coexpress CK (Figure 14) and vimentin. 266, However, because of the varied and unpredictable CK immunoreactivity in sarcomatoid carcinomas, multiple epithelial markers, including EMA and various CK subtypes, such as pancytokeratin, HMW CK (CK34 E12 or CK5/6), and CK7, may be necessary to demonstrate epithelial differentiation. 267,269,270 Evaluation of a number of alternative immunostains beyond the traditional epithelial markers (CKs and EMA) in the sarcomatoid carcinomas of the head and neck, lung, and urinary bladder showed some values in exposing the epithelial identity of tumors in that setting by adding p63 in the panel. 271 Sarcomatoid Mesothelioma. Immunohistochemistry has a limited role in the diagnosis of sarcomatoid mesothelioma and its distinction from sarcomatoid carcinomas and sarcomas. Sarcomatoid mesothelioma shows a marked decline in the expression of epithelial and mesothelial markers and has a wide immunophenotypic overlap with sarcomas and sarcomatoid carcinomas Only 57.8% of sarcomatoid mesotheliomas stain for calretinin, 39% for thrombomodulin, 25% for WT1, 19.6% for CK5/ 6, and 75% for keratin. 272 On the other hand, up to 60% of them may stain for actin. 273,274 It has been recently reported that a combination of calretinin and D2-40 improves the sensitivity for detecting mesothelioma in sarcomatoid areas to 66%. 275 Nevertheless, because of the lack of a specific marker, the diagnosis of sarcomatoid mesothelioma should be made after exclusion of alternative diagnostic entities and only with an integration of clinical, radiographic, gross, microscopic, and immunohistochemical findings. Spindle Cell MM. When dealing with a malignant spindle cell tumor at any site, the possibility of spindle cell melanoma should always be considered. The sensitivity of S100 protein in spindle cell MM appears to be more or less similar to conventional MM, 27 but HMB-45 expression is less frequent (positive in 80% compared with 90% 100% in the conventional type). 26 Of note, the immunohistologic features of desmoplastic MM, a morphologic subtype of spindle cell MM associated with pronounced desmoplasia, is substantially different from conventional melanoma and includes positive staining for S100 (in 94%) but lack of reactivity for HMB- 45 or other melanoma-specific markers. 27,276 TUMORS WITH OVERLAPPING HISTOLOGIC FEATURES Tumors with nondescript H&E histology that fail to fit into either a sarcoma or a carcinoma category often pose the greatest diagnostic challenge. The differential diagnosis is broad and includes melanoma, hematopoietic malignancies, neuroendocrine tumors, poorly differentiated carcinomas, and mesenchymal neoplasms with epithelioid appearance. Ancillary tests, including immunohistochemistry, play an essential role in the recognition of these tumors. Sarcomas With Epithelioid Appearance The screening panel can often successfully disclose the broad line of differentiation in tumors with overlapping histology (see Broad Lineage Determination ). The epithelioid morphology of sarcomas, which commonly correlates with their potential CK expression, however, further complicates the distinction of these tumors from epithelial malignancies. In a proper setting, a vimentin / 340 Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al

16 Figure 15. Algorithmic approach to undifferentiated tumors with overlapping histologic features. CKs indicate cytokeratins; SMA, smooth muscle actin; PDSS, poorly differentiated synovial sarcoma; MPNST, malignant peripheral nerve sheath tumor; and PEComa, perivascular epithelioid cell tumors. CK or a coordinate vimentin /CK in a tumor with overlapping histology should raise the possibility of sarcomas with epithelioid features and prompt performance of a battery of immunohistochemical stains for further characterization of these tumors (Figure 15). Sarcomas with epithelioid cells include epithelioid sarcoma, epithelioid angiosarcoma, clear cell sarcoma, epithelioid MPNST, and other rare sarcomas, such as sclerosing epithelioid fibrosarcoma, alveolar soft part sarcoma, and epithelioid leiomyosarcoma. The immunoprofile of epithelioid sarcoma includes positive staining for vimentin (Figure 16, a), LMW CKs, and EMA and variable staining for CD34 (positive in 50%) The latter finding, if present (Figure 16, b), helps to distinguish epithelioid sarcoma from carcinomas, which are rarely CD34 positive. Most epithelioid angiosarcomas are positive for both vimentin and CKs These tumors are recognized by expression of at least one of the endothelial markers, including CD31, CD34, and factor VIII FLI-1 protein has been recently shown to have equal or superior sensitivity and specificity compared with the traditional markers for vascular tumors 60,61 (Figure 17). Clear cell sarcoma has a similar immunohistochemical constituent to melanoma that includes expression of S100, HMB-45, and microphthalmia transcription factor in the majority of cases. 285,286 It is, however, genetically different from melanoma by its specific t(12;22) translocation. 287 Clear cell sarcomas are typically negative for CK and EMA. Epithelioid MPNST, a rare variant of MPNST, may be recognized by positive staining for S100 (in 80%) and NSE. 288 The epithelioid variant of pleomorphic liposarcomas in up to half of the cases may show reaction with S100 or epithelial markers, an important finding to be considered in the differential diagnosis of these tumors from solid carcinomas with clear cell feature. 253,255 The diagnosis of a number of rare sarcomas with epithelioid appearance, for example, sclerosing epithelioid fibrosarcoma and alveolar soft part sarcoma, is essentially made on the basis of their distinct light microscopic features. Miscellaneous Mesenchymal Tumors With Epithelioid Appearance Some mesenchymal neoplasms of borderline or uncertain malignant behavior may impart epithelioid appearance and be considered in the differential diagnosis of undifferentiated carcinomas; a few examples of which are herein given. Perivascular epithelioid cell tumors are mesenchymal neoplasms of perivascular epithelioid cells, 289 with a wide anatomic distribution, sometimes presenting as unusual clear cell tumors in various locations Immunohistochemically, these tumors are characterized by coexpression of melanocytic, including HMB-45 and Melan-A, and smooth muscle markers. 219,221,290 Sex cord stromal tumors are a heterogeneous group of neoplasms of the ovary and testis with various histologic patterns, not uncommonly confused as an undifferentiated carcinoma. Epithelial membrane antigen, which is nearly always negative, is a more reliable marker in distinction of these tumors from epithelial neoplasms because sex cord stromal tumors, in particular granulosa cell tumor, may variably stain for CKs (0% 64%). 214,225,293 Both inhibin and calretinin are useful markers for confirming the diagnosis. 212,214,215,224,225 Gastrointestinal stromal tumor, including the epithelioid subtype, is immunohistochemically characterized by expression of CD117 (c-kit) and CD34 in most cases, rare expression of smooth muscle actin and desmin, and negative staining for S Malignant Melanoma S100 is a sensitive, albeit not a specific, melanoma marker, decorating more than 95% of MMs of primary and metastatic sites. The diagnosis of MM requires confirmation with a melanocytic-specific marker, including HMB-45, Melan-A, microphthalmia transcription factor, and tyrosinase. HMB-45 is a specific monoclonal antibody against an antigen present in the cytoplasm of neoplastic melanocytic cells. It shows positive cytoplasmic staining in the majority of MMs ( 95% in ethanol-fixed tissues and slightly less in formalin-fixed tissues), with the exception of des- Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al 341

17 Figure 16. Photomicrograph of epithelioid sarcoma showing positive staining for vimentin (a) and CD34 (b) (original magnifications 20). Figure 17. Photomicrograph of epithelioid angiosarcoma showing positive nuclear staining for FLI-1 protein (original magnification 20). moplastic MM, which rarely demonstrates HMB-45 expression. 27,295 Melan-A/MART-1 is a newer melanocytic marker with sensitivity comparable to that of HMB-45 for conventional melanoma. Like HMB-45, it is negative in most desmoplastic MMs. 295 Although both Melan-A and HMB-45 are positive in more than 90% of conventional forms, their sensitivity declines in recurrent, spindle cell, or metastatic melanomas to 80%. 15,26 For metastatic melanomas, however, Melan-A seems to be more sensitive (positive in 82%) than HMB-45 (positive in 76%). 219,221 Both HMB-45 and Melan-A stain the PEComa family of neoplasms, 219,221 yet Melan-A also stains adrenal cortical neoplasms. 220 Malignant melanomas stain intensely for vimentin but are typically negative for epithelial markers, glial fibrillary acidic protein, CD45, and desmin. However, aberrant expression for a number of immunostains, including CK, EMA, pcea, or glial fibrillary acidic protein, has been rarely reported (also see Malignant Melanoma under Small Round Cell Tumors ). 15,16,26,296 Hematopoietic Malignancies The spectrum of hematolymphoid malignancies presenting as a mass of large atypical cells of uncertain origin is broad and includes various types of lymphoma, myeloid sarcoma, and plasma cell neoplasm, each with a diverse immunoprofile, the complexity of which is far beyond the scope of this manuscript. Some examples of the unexpected immunohistochemical expression in selected groups of hematopoietic tumors are herein provided. As mentioned previously, CD45 (LCA) is a valuable tool in the diagnostic separation of hematopoietic neoplasms, particularly of the lymphoid type, from poorly differentiated epithelial and mesenchymal neoplasms. Non-Hodgkin lymphomas of the B- and T-cell types are immunoreactive for LCA in 93% to 100%. 28,29 A negative LCA, however, does not absolutely preclude the diagnosis of lymphoma in a large cell undifferentiated tumor because LCA is rarely absent in some lymphomas of the T-cell type and some plasma cell neoplasms. The immunoprofile of anaplastic large cell lymphoma is highly variable and includes a positive reaction for LCA (60% 70% of cases), CD30 (nearly all), T-cell markers (54% 70%), ALK protein (60% 85%), and EMA ( 75%). 18, Hence, a potential CD45 /EMA immunoprofile in anaplastic large cell lymphoma may pose diagnostic confusion with an undifferentiated carcinoma. On the other hand, the typical CK /EMA immunoprofile in anaplastic large cell lymphoma may help to differentiate it from embryonal carcinoma (CK /EMA ), which is also reactive for CD30. Most but not all granulocytic sarcomas ( 75%) express LCA. 112 CD43 is a more sensitive marker for myeloid sarcomas, staining up to 100% of cases with an intense widespread staining pattern. 112 The diagnosis of myeloid tumor, however, requires demonstration of more specific markers, including myeloperoxidase and lysozyme. The immunoprofile complexity of neoplastic plasma cells (plasmacytoma or plasma cell myeloma), including variable expression for CD45, EMA, and CK, combined with commonly negative reaction for B-cell markers (CD19, CD20), may pose potential diagnostic pitfalls in their distinction from epithelial neoplasms. 10,33,34 A high index of suspicion should direct to a panel that includes CD38, CD138, and and light chains. Of note, although 342 Arch Pathol Lab Med Vol 132, March 2008 Undifferentiated Tumor, Immunohistochemistry Bahrami et al

18 CD138 is an excellent marker of plasmacytic differentiation within the hematopoietic system (positive in nearly all), it is also expressed in various nonhematopoietic neoplasms; hence, it is not considered a definitive marker for plasmacytic derivation, unless the hematolymphoid origin of tumor is established. 300 In summary, classification of a tumor beyond its apparent undifferentiated morphology is possible in the majority of cases. This not only is important for prognostication and therapy but should also provide further insights into the pathobiology of these tumors. The diagnostic pathway is started with recognizing a tumor as SRCT, carcinomatous tumor, sarcomatous (or sarcoma-like) tumor, or tumor with histologically overlapping features, followed by an immunohistochemical panel, which is judiciously constructed for each tumor. 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