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Germ cell tumor-like neoplasms occurring outside the anatomic midline
Germ Cell Tumor-like Neoplasms Occurring Outside the Anatomic Midline J. Carlos Manivel, MD, and Stefan Pambuccian, MD ● Most germ cell tumors occur in the gonads or in extragonadal sites in the anatomic midline; this article reviews tumors with similar or identical histologic features that arise in other topographic locations. Such lesions often represent the presence of “germ cell-like” or “germinal” components in what is otherwise recognized as a somatic neoplasm; however, they may also occur in pure form. The morphologic and immunohistochemical features of these proliferations are reviewed, according to the types of germ cell tumors that they recapitulate. © 2003 Elsevier Inc. All rights reserved. INDEX WORDS: Germ cells; germ cell-like; extragonadal germinal tumors
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HE TOPIC of this issue of Seminars in Diagnostic Pathology—that is, the recognition of familiar pathologic lesions in unfamiliar settings–requires 2 sequential steps. First, one must look at microscopic sections with no bias as to the anatomic location from which they were taken; second, once the site is taken into consideration, and the observer has recovered from his or her astonishment, one must establish an adequate differential diagnosis by using the morphologic findings, historical data, and a carefully crafted group of adjunctive studies. The latter statement is predicated in part on an anecdote which has been ascribed to Dr. Arthur Purdy Stout by some of our mentors. He apparently used to say “If I saw my grandmother in China, I would be quite surprised, but I would recognize her without a doubt.” Nonetheless, many times microscopic examination does not allow for immediate diagnostic certainty in and of itself (except, perhaps, for Dr. Stout). In such instances one may use a technique that has proved very useful to us; if a diagnosis is not certain, or correlation with location or history do not appear to make much sense, the following question should be posed “what would this be if I saw it in another anatomic site?” Most germ cell tumors occur in the gonads. OtherFrom the Division of Surgical Pathology, Department of Laboratory Medicine Medicine & Pathology, University of Minnesota School of Medicine, Minneapolis, MN. Address reprint requests to J. Carlos Manivel, MD, Division of Surgical Pathology, Department of Laboratory Medicine & Pathology, University of Minnesota School of Medicine, C446 Mayo Bldg., MMC 76, FUMC, 420 Delaware St SE, Minneapolis, MN 55455; e-mail: [email protected]. © 2003 Elsevier Inc. All rights reserved. 0740-2570/03/2004-0003$30.00/0 doi:10.1053/j.semdp.2003.08.001 260
wise, midline sites such as the sacrococcygeal region, anterior mediastinum, and central nervous system are the preferred locations for these lesions. The differential diagnosis of germ cell tumors and their morphologic simulators can be viewed from 2 diametrical perspectives. First, one can consider true germ cell tumors, in both gonadal and extragonadal sites, that may be mistaken for nongerminal neoplasms; second, one must be able to recognize nongerm cell (somatic) neoplasms that may imitate germ cell tumors. This review deals predominantly with the second of those scenarios; however, differential diagnostic criteria applying to mimics of germ cell tumors are equally helpful in identifying true germ cell neoplasms. As will become apparent in the subsequent discussion, this issue is actually more complex; definitions of “germcell differentiation” and “germ-cell-like differentiation” are imprecise, contentious, or heterogeneously applied. As one of our mentors asked, “is an albino man born in a black African family a white man or a black man?” The answer depends on the criteria used to make the definition; namely, skin pigmentation only, other phenotypic features, or genetic factors. Similarly, it is obvious that criteria used for the definition of germ cell tumors may encompass different determinants, and, in order to make some sense of them, one must carefully delineate the criteria being used. This is not always easy, because the criteria may not be well established and those that exist may not be as specific as we would like. For example, most observers would agree that a somatic adenocarcinoma producing alpha-fetoprotein, as sometimes seen in the ovaries, should not be regarded as a true yolk-sac tumor; similarly, a gastric adenocarcinoma comprising beta-human chorionic gonadotrophin (bHCG)-secreting multinucleated giant cells should not be classified as a choriocarcinoma. However, one may encounter tumors in these sites that
Seminars in Diagnostic Pathology, VOL 20, NO 4 (NOVEMBER), 2003: pp 260-271
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contain areas which are histologically-indistinguishable from true yolk sac tumor or choriocarcinoma, in addition to others that clearly represent somatic carcinoma. Indeed, only the germ-cell (or germ-cell-like) component is identified in some instances, and the possibility that another somatic component was “overrun” by the former constituent cannot be excluded. Metastasis to the viscera from a germ cell tumor in a “conventional” site must also be considered. It would be desirable to have an absolute genetic “fingerprint” of germ cell origin that would aid in these assessments. In fact, however, even though an isochromosome of the short arm of chromosome 12 has been thought to represent such a marker, it has also been identified by fluorescence in-situ hybridization (FISH) in a primary tumor (called “choriocarcinoma”) of the bladder.1 With both comparative genomic hybridization (CGH) and FISH, other investigators have found that secondary acquisition of chromosome 12 abnormalities correlated with development of a germ cell (choriocarcinomatous) phenotype in renal pelvic transitional cell carcinoma2 and gastric adenocarcinoma.3 Both of the components in these 2 “hybrid” tumors also had cytogenetic abnormalities that were characteristic of urothelial carcinoma (losses of chromosome 9 and 17p)2 and gastric adenocarcinoma (gains in 1p34-36, 18p and 20 and loss on 18q), respectively.3 Thus, it would appear that chromosome 12 aberrations may appear secondarily in somatic neoplasms, and therefore are not specific for “pure” germ cell tumors. Almost 100 years after the first descriptions of neoplasms that were histological simulators of true germ cell tumors, but in “unusual” somatic sites,4 uncertainty still exists regarding their histogenesis. They could potentially be explained by aberrant migration of pluri(or toti-) potential germ cells; secondary germ-cell differentiation (“retrodifferentiation” or “dedifferentiation”) in a somatic neoplasm; or metastasis from a clinically-occult bona-fide primary germ cell tumor. Finally, the possibility must also be entertained that the neoplasm in question has nothing to do with germ cells at a basic level and simply possesses one or more features that suggest a germinal nature. It is interesting to note that all of these hypotheses were considered in 1904 by Djewitzki to explain the occurrence of pure “choriocarcinoma” in the urinary bladder of a 75year-old woman. Similar premises were advanced by Davidsohn in 1905 in reference to a composite “choriocarcinoma”-adenocarcinoma in the stomach of a 44-year-old man, and by Risel in 1907 regarding
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“choriocarcinomatous” lymph node metastases in 2 women with gastric adenocarcinomas. It is apparent that any one of these hypotheses may be operative in an individual case, bolstered by experimental and clinical evidence. Although it is important to try to establish genetic markers and genetic “definitions” for human neoplasms, we believe that morphological examination continues to represent the cornerstone of diagnosis in clinical medicine. Therefore, only when strict histologic criteria are fulfilled should a neoplasm be accepted as exhibiting germ cell features. Advances in the treatment of germ cell tumors over the past 25 years have considerably improved the outlook for patients with such lesions, even in the face of metastatic disease. Thus, the importance of their accurate recognition cannot be overemphasized. This discussion will address extragonadal neoplasms which, because of their histologic features, may imitate classical germ cell tumors. In doing so, the World Health Organization (WHO) classification of germ cell tumors and related lesions will be used, as follows: 1. Tumors that may simulate choriocarcinoma 2. Tumors that may simulate teratoma 3. Tumors that may simulate yolk sac tumor 4. Tumors that may simulate embryonal carcinoma 5. Tumors that may simulate seminoma/dysgerminoma These lesions are hereafter grouped primarily according to the foregoing designations, with secondary consideration of anatomic locations, to better assist the reader in their differential diagnosis. Analysis of the virtues of various hypotheses on causation, as enumerated above, is beyond the scope of this review (and its authors). Suffice it to say that bona-fide germ cell tumors may indeed arise in unusual sites and must be distinguished from metastatic germinal neoplasms and somatic malignancies alike. We shall exclude from consideration germ cell tumors of the gonads, retroperitoneum, mediastinum, and the midline central nervous system, because these represent the “familiar” or “usual” sites for such proliferations. TUMORS WITH CHORIOCARCINOMATOUS FEATURES & SIMULANTS OF CHORIOCARCINOMA Regardless of whether they are of germ cell origin or gestational in nature, choriocarcinomas show alternating areas of cytotrophoblastic and syncytiotrophoblastic differentiation with a plexiform pattern. In general, a distinction should be made between poorly differentiated somatic carcinomas that contain isolated bHCG-
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producing multinucleated giant cells from other neoplasms that display all of the expected morphologic features of choriocarcinoma. Urinary Tract Rarely, poorly differentiated urothelial carcinomas of the urinary bladder contain areas that have been interpreted as “choriocarcinomatous” or “resembling choriocarcinoma.”1,5-7 Moreover, bHCG may be demonstrated immunohistochemically in up to one third of otherwise ordinary high-grade transitional-cell bladder carcinomas.8 It has been suggested that trophoblastic differentiation in urothelial neoplasms results from heterogeneity of epithelial differentiation and a metaplastic potential of the urothelium. Furthermore, some have concluded that all primary bladder tumors with trophoblastic components basically represent transitional cell carcinomas with trophoblastic differentiation (TCTD), instead of neoplasms of true germinal origin. The latter assertion is supported by clinical similarities between TCTD and conventional transitional cell carcinomas, including patient age and sex distribution (mean 62 years; 3:1 male-to-female ratio) and a location in or near the trigone.6 Pathologically, TCTDs have shown the presence of an overt transitional cell component in all but the most advanced cases (as seen at autopsy), in which the choriocarcinomatous elements may have outgrown the urothelial carcinoma. In some instances, a diagnosis of “choriocarcinoma” was preceded by biopsies of the same tumor showing transitional-cell or poorly-differentiated somatic carcinoma.6 These findings suggest that when trophoblastic differentiation is extensive, thorough sampling is essential to document the presence of an urothelial component. One case of pure “choriocarcinoma”9 and 2 cases of mixed “choriocarcinoma”- transitional cell carcinoma of the renal pelvis have also been described,2,10 in addition to another of renal “choriocarcinoma.”11 Despite the fact that classical choriocarcinomas are very chemosensitive tumors that usually respond to single-agent therapy with methotrexate or actinomycinD12, results with chemotherapy for “choriocarcinomas” of the urinary tract has been disappointing. Most patients have succumbed within 1 year6 and the longest reported survival in that group was 33 months.7
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cells (Fig 1). The latter were immunoreactive for bHCG, potentially causing elevation of that marker in the serum. Uterine “carcinosarcomas” (sarcomatoid carcinomas; malignant mixed mullerian tumors) with a “choriocarcinomatous” component have also been documented.15,16 Similarly, “choriocarcinomas” or choriocarcinoma-like neoplasms have been reported in the breast; some were associated with areas of conventional infiltrating ductal carcinoma17; others were manifest in lymph node metastases of a “mucoid” carcinoma,18 or they were associated with ductal carcinoma in situ.19 Lung Rare cases have been described of presumed primary pulmonary choriocarcinoma20,21 and an example of choriocarcinoma that putatively arose from the pulmonary artery.22 However, as in other anatomic sites, other cases of malignancies in the lung with germ-cell features are thought to represent divergent trophoblastic differentiation in conventional large cell carcinomas, adenocarcinomas, or small-cell carcinomas, and the latter components can be recognized with appropriate sampling. Some of these tumors have shown immunoreactivity for thyroid transcription factor-1 (TTF-1), a marker of pulmonary differentiation, making some authors doubt the existence of “pure” primary pulmonary choriocarcinoma23 and instead favoring the diagnosis of “pleomorphic carcinoma with choriocarcinoma-like features.” On the other hand, tumors lacking an adenocarcinomatous, large-cell-, or small-cell carcinoma component have been felt to derive from the abnormal migration of primordial germ cells into the lungs during fetal development.24 Before making a diagnosis of pri-
Gynecologic Tract & Breast Rarely, poorly differentiated endometrial13 and endocervical14 adenocarcinomas have shown choriocarcinoma-like or “trophoblastic differentiation,” characterized by the presence of syncytiotrophoblastic-like giant
Fig 1. Potential mimic of choriocarcinoma: poorly differentiated endometrial adenocarcinoma with syncytial giant cells.
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mary choriocarcinoma of the lung, serious consideration should be given to metastasis from an occult gestational or gonadal primary tumor and these possibilities should be addressed clinically. In this context, it must be acknowledged that the possibility of a “burnedout” (regressed) gonadal choriocarcinoma25 cannot be entirely excluded, even with an extensive radiographic evaluation. Liver & Pancreatobiliary System An uncommon presentation of hepatoblastoma in boys is that of isosexual precocity, characterized by a deepening of the voice, penile enlargement, and growth of pubic hair. These children have elevated serum and urinary levels of human chorionic gonadotropin, and that hormone can be detected in the hepatoblastoma cells immunohistochemically.26 Rare examples of primary “pure” choriocarcinoma of the liver,27 one of which occurred in a neonate,28 have also been described. Another unusual location for choriocarcinoma is the gallbladder, where 2 examples were documented,29,30 in addition to another case that was included in a series of “unusual types of gallbladder carcinoma.”31 One example of pancreatic choriocarcinoma arose in the body of that organ and presented in a manner simulating an inflammatory pseudocyst.32 Gastrointestinal Tract Although they are rare, choriocarcinomas of the gastrointestinal tract are the most well-represented of trophoblastic tumors in “unusual” sites; 67 gastric “choriocarcinomas” had been reported through 1996 in the English literature,33 with an additional 79 cases in Japanese publications.34 Five examples of “choriocarcinoma” also have occurred in the esophagus.35,36 “Choriocarcinomas” of the alimentary tract are frequently admixed with adenocarcinomas (in 75% of cases) or, in esophageal sites, with squamous cell carcinoma.35,36 Because of these associations, such lesions are thought to derive from trophoblastic differentiation (“retrodifferentiation”) of somatic epithelial tumor cells. In tumors with no adenocarcinomatous components, it is thought to be probable that the growth of the germ-cell tumor-like element obliterated the adenocarcinoma through preferential overgrowth. The average age of patients with these neoplasms is similar to that of individuals with ordinary esophagogastric malignancies. Most patients with tumors in the stomach are elderly men (with a gender preference of 2:1), and their prognosis is dismal. Production of bHCG
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by these neoplasms can be documented by examination of serum, and it may become manifest clinically with the development of gynecomastia in males or menstrual irregularities (eg, postmenopausal vaginal bleeding) in women. Grossly, one sees extensive necrosis and hemorrhage in choriocarcinoma-like gastrointestinal lesions. The stomach appears to be a good paradigm for the analysis of extragonadal trophoblastic differentiation, because normal antral-neck cells, metaplastic epithelium in atrophic gastritis, and the cells of 25% to 50% of ordinary gastric adenocarcinomas exhibit bHCGreactivity immunohistochemically.37 The next most common member of the “spectrum” of extragonadal germ cell proliferations would be mixed somatic adenocarcinoma-choriocarcinoma, followed by “pure” choriocarcinoma. By convention, the unqualified term of “choriocarcinoma” is reserved for those tumors which fulfill all morphologic and biochemical criteria for that diagnosis. There is a tendency for choriocarcinomatous components of mixed malignancies to metastasize hematogenously to the liver and lung, whereas the somatic adenocarcinomatous elements spread lymphatically to regional lymph nodes. Insufficient information is available to determine if the prognosis of gastric “choriocarcinoma” is worse than that of ordinary adenocarcinoma. Intestinal adenocarcinomas with trophoblastic differentiation are characterized by the presence of multinucleated giant cells that are immunoreactive for bHCG; occasionally, these tumors also may contain both cytotrophoblastic and syncytiotrophoblastic components. They tend to occur in the cecum or rectosigmoid colon in relatively young adults, who have elevated serum levels of bHCG. The prognosis of this tumor variant is poor.38 “Choriocarcinomas” of the small bowel39 usually represent divergent trophoblastic differentiation in conventional adenocarcinomas that display both cytotrophoblastic and syncytiotrophoblastic elements. TUMORS THAT MAY SIMULATE TERATOMAS Teratomas are defined as “neoplasms that originate in pluripotential cells, comprising a wide diversity of tissues that are foreign to the organ or anatomic site in which they arise.”40 Indeed, teratomas represent a grotesque caricature of embryogenesis; as such, they are typified by a mixture of tissues. These frequently, but not necessarily, include 2 or 3 germ layers. These usually exhibit recognizable organization; in other words, one does not simply recognize a nondescript mass of mesodermal tissue adjacent to a similar aggre-
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gation of epithelial cells. Instead, the mesenchymal tissue is frequently structured as lamina propria or stroma, and overall organization of the lesion may be sufficiently advanced to allow for recognition of such elements as skin, bronchi, intestinal segments, or teeth. The purpose of this brief introduction is to allow for the conclusion that tumors that simulate teratomas are those that contain different cell types (usually although “aberrant or “heterologous” differentiation), and these are associated with one another in a variably organoid fashion. Teratomas arising in “familiar” anatomic sites–such as the gonads or along the midline in the central nervous system, mediastinum, retroperitoneum, and sacrococcygeal region– generally do not pose serious diagnostic difficulties. However, lesions with comparable histological images may also occur in “unfamiliar” settings, and, in fact, practically every organ and anatomic site can be so affected. Indeed, an entire fascicle of the Armed Forces Institute of Pathology Atlas of Tumor Pathology (Fascicle 18, Series 2) was dedicated to a discussion of extragonadal teratomas. In keeping with the preceding approach of this review, true teratomas in familiar locations will not be addressed further; rather, the main focus is on somatic tumors that are potentially confused with them. Teratoid Neoplasms “Teratoid” tumors are pediatric neoplasms that morphologically recapitulate the development of the organ in which they arise. As such, they are termed “dysembryogenic.” Examples of hepatoblastoma and nephroblastoma belong to this group. In addition to their usual components, they may contain cells that are foreign to the organ of origin. In “conventional” nephroblastomas (Wilms’ tumors), epithelial tumor cells may show several levels of differentiation, and the stromal component usually comprises spindle shaped, fibroblast-like elements. Together with blastematous components, the epithelial and stromal tissues produce a typically “triphasic” appearance in classical nephroblastomas. However, the stromal component may also pursue differentiation along adipocytic, smooth muscle-, or rhabdomyogenic lines. When the last of those is prominent, it may virtually efface all other components; this is true in so-called “rhabdomyomatous” Wilms tumor, not to be confused with the much more aggressive rhabdoid tumor of the kidney or with rhabdomyosarcoma. Nephroblastomas with stromal differentiation into fat or myogenous tissues are still classified as “conven-
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tional;” the term “teratoid nephroblastoma” has been applied to those that include ciliated-, mucinous-, squamous- or transitional- epithelium; endocrine cells of different types; renin-producing cells; neuroepithelial or neuroblastic tissues; and mature ganglion cells.41,42 Conventional hepatoblastomas are composed of uniform populations of “fetal” or “embryonal” hepatocytes in purely epithelial tumor variants, or combinations thereof with mesenchymal cells in mixed hepatoblastomas. The mesenchymal component often focally resembles osteoid, although the tumor cells embedded in the material resembling bone matrix have ultrastructural and immunohistochemical properties of epithelium43 The designation of “teratoid hepatoblastoma” (or hepatoblastoma with teratoid features) is applied to those lesions that contain melanocytes, ganglion cells, squamous epithelium, or cysts lined by cuboidal and goblet-cell epithelium (resembling respiratory or intestinal mucosa), in addition to areas of “classical” hepatoblastoma44 (Fig 2). The term “atypical teratoid/rhabdoid tumor” has been used in reference to highly malignant nervous system tumors that are seen supratentorially or in the posterior fossa or brainstem of young children.45 Microscopically, they contain medium-sized to large cells with prominent nucleoli, arranged in sheets that are separated by fibrovascular septa. Fascicular and trabecular patterns of growth also may be seen. A small-cell component reminiscent of medulloblastoma may be present in some instances. The modifier “teratoid” is intended to reflect the presence of morphologic and immunohistochemical heterogeneity in this group of lesions, but does not have the same connotation as in reference to blastomas of the liver and kidney. Some cells in rhabdoid tumor have abundant eosinophilic cytoplasm, yielding a cytological image which is similar to that seen in rhabdoid tumors of the kidney and soft tissues. Immunohistologic studies show positivity for vimentin and frequently also for glial fibrillary acidic protein, epithelial membrane antigen, and cytokeratin. Reactivity for synaptophysin and chromogranin is occasionally present as well, but labeling for neurofilament proteins is uncommon. Although some cells may stain for actin and desmin, those with a “rhabdoid” appearance are consistently negative for myogenic markers. Most atypical teratoid rhabdoid tumors demonstrate karyotypic monosomy 22 or deletions of the chromosomal band 22q11, with alterations of the hSNF5/INI1 gene.46,47 The relationship between these lesions and the rhabdoid tumors of the kidney and soft tissues may be more than morphological. Neuraxial
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heterologous mesenchymal components, including striated muscle, bone, cartilage, and adipose tissue.51 Ovary Sertoli-Leydig cell tumors (androblastomas) can contain heterologous components; in 18% of such cases, these are represented by cysts and glands lined by gastric- or intestinal-type epithelium, including goblet cells, argentaffinic elements, and, rarely, Paneth cells. Five percent of cases show mesenchymal differentiation, with skeletal muscle- or cartilaginous components. Such “teratoid androblastomas” can be confused with teratomas; nonetheless, it must be remembered that Sertoli and Leydig cells are not seen in ovarian teratomas. Malignant mixed mesodermal tumors of ovarian (and uterine) origin comprise malignant epithelial and stromal components that are mesodermally-derived. Heterologous differentiation, in the form of rhabdomyosarcomatous, osteosarcomatous and chondrosarcomatous components, is not rare, but neuroectodermal components are exceptional. These lesions also lack the variety of differentiated tissues that is seen in teratomas. Furthermore, the epithelial and mesenchymal elements in malignant mixed mullerian tumors are malignant cytologically, and those lesions occur at a much later age than that associated with teratomas. Lung & Pleura Fig 2. Teratoid hepatoblastoma showing areas of (A) melanocytic and (B) squamous differentiation, in addition to osteoid formation.
rhabdoid tumors, like their extracranial counterparts, may harbor a chromosomal translocation or monosomy involving chromosome 22, and be part of the “rhabdoid predisposition syndrome (RPS)” that is characterized by germline mutations of the hSNF5/INI1 tumor suppressor gene.48 These neoplasms are aggressive and are characterized by common local recurrence and meningeal spread. Medulloblastomas also sometimes contain foci of neoplastic glial cells (“medulloblastoma with mixed differentiation”); in addition, heterologous or “aberrant” differentiation may manifest itself in the form of skeletal muscle (“medullomyoblastoma”), foci of pigmented epithelioid cells (“melanotic medulloblastoma”)49 or a combination of those tissues (“teratoid medulloblastoma”)50 Similarly, in addition to typical neuroepithelial structures resembling primitive neural tubes, medulloepitheliomas may show astrocytic and
Pleuropulmonary blastomas (PPBs) may display heterologous differentiation toward cell types that are not normally present in the lung or its coverings; moreover, they have an embryonic microscopic appearance. These features may lead to confusion with teratomatous tumors arising in the thorax or metastasizing to it.52 PPBs are seen almost exclusively in children and adolescents. They contain immature mesenchymal tissue with a blastomatous appearance; focally, myxoid areas, anaplastic-pleomorphic foci, and areas of rhabdomyosarcomatous or chondrosarcomatous differentiation may be seen. None of the tumor cells is epithelial in nature, but the lesional constituents are interspersed with glands, ducts, and cysts lined by benign entrapped cells of bronchial or mesothelial derivation (Fig 3). Accordingly, only sarcomatous elements are identified in metastatic deposits. PPB is a highly aggressive tumor, but long-term survival is better for younger patients with predominantly-cystic intrapulmonary tumors (50% at 5 years) than it is for patients with large, solid, pleuralbased and unresectable tumors (25% at 5 years).53 For the sake of clarity, a few words on 2 other
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TUMORS THAT MIMIC YOLK-SAC CARCINOMA Tumors with areas that reproduce the appearance of yolk sac carcinoma (YSC; endodermal sinus tumor) to variable degrees have been described in several sites (Fig 5); 2 such cases were variants of pulmonary blastoma.56 Another 2 examples were transitional (“Schneiderian”) carcinomas that arose in the nasopharynx and paranasal sinuses, and contained areas that imitated yolk sac carcinomas histologically and immunohistochemically.57 True endodermal sinus tumors of the upper aerodigestive tract have also been described in children, including examples in the nasopharynx, oropharynx, and oral cavity.58 Two additional cases were documented in the ear in young children.59 YSC-like components have rarely been described in
Fig 3. Pleuropulmonary blastoma showing areas of (A) skeletal muscle differentiation and (B) cartilaginous differentiation, in addition to blastematous components. Note the cystic structure lined by entrapped benign epithelium (A).
pulmonary neoplasms are included here. Well-differentiated “fetal” adenocarcinoma of the lung (also known as “pulmonary endodermal tumor” and “pure epithelial blastoma” of the lung) and biphasic pulmonary blastoma are 2 neoplasms that are entirely distinct from PPB, and which themselves may constitute a separate spectrum of lesions.54 Fetal-type adenocarcinoma comprises glands with an endometrioid appearance that simulate the pseudoglandular tubular stage of lung development. Scattered squamoid morules are also a typical part of that tumor (Fig 4A). Biphasic pulmonary blastomas are composed of malignant glands with a fetal-endometrioid appearance, admixed with malignant mesenchymal elements that are primitive in appearance (Fig 4B). Finally, pulmonary “carcinosarcomas” (sarcomatoid carcinomas) represent a mixture of carcinoma and sarcoma-like components, both of which have “adult” phenotypes.55
Fig 4. Pulmonary blastoma. (A) “Monophasic” pulmonary blastoma (“well-differentiated adenocarcinoma of fetal type”), showing crowded “secretory-phase endometrioid-like” glands and morulae. (B). “Biphasic” pulmonary blastoma showing “endometrioid-like” glands and frankly malignant stroma.
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Fig 5. Potential mimics of yolk sac tumor: (A) Epithelioid mesothelioma with papillary structures resembling Schiller-Duval bodies. (B). Epithelioid gastrointestinal stromal tumor with clear cell change mimicking the microcystic pattern of yolk sac tumor.
gastric adenocarcinomas, including one example that also contained choriocarcinoma-like elements.60,61 One case of composite YSC-conventional gastric adenocarcinoma demonstrated the same p53 mutations in both of those components, likely indicating evolution from the same cellular clone.62 Another example showed immunoreactivity for gastrin in the yolk sac-like elements.63 Cases of allegedly primary “pure” YSCs probably represent lesions in which a somatic adenocarcinoma has been overrun by an endodermal sinus tumor-like component. It should be mentioned that reactivity for alphafetoprotein (a common marker for YSC) has been observed immunohistochemically in 50% of typical gastric adenocarcinomas. However, the positive cells in those lesions had an obviously adenocarcinomatous or “hepatoid” appearance and did not resemble yolk sac tumor elements.64
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Anecdotal examples of “pure” YSC in the liver65 have been described; other similar hepatic tumors have included examples of hepatocellular carcinoma66 or hepatoblastoma67 that contained yolk sac elements. One example of YSC originated in the gallbladder of a 36-year-old woman in a background of cholelithiasis.68 Cases of YSC in the urinary bladder69 and urachus70 have been described. After rhabdomyosarcoma and clear cell adenocarcinoma, YSC is the third most common vaginal tumor in pediatric patients; rare cases also occur in the vulva. Most patients with vulvovaginal lesions are ⬍2 years old at diagnosis and the majority are infants. The histologic and immunohistochemical features of those neoplasms are identical to those observed in more “familiar” sites, and they are not admixed with other tumor types.71 Successful treatment with chemotherapy and surgery leads to normalization of previously elevated alpha-fetoprotein levels in serum. Although the prognosis for these patients used to be grim, current treatment has produced 2-year diseasefree survival in up to 95% of cases.72 Primary YSCs have also been described in the endometrium, as “pure” lesions73 and as partners with endometrial adenocarcinoma74 or malignant mixed mullerian tumor.75 An unusual case of YSC in association with colonic endometriosis has also been reported.76 One example of YSC was seen in the penis of a 17-month-old patient,77 and a few additional examples likewise have been described in the prostate,78 including some in patients with Klinefelter’s syndrome.79,80 Finally, it should be remembered that myxoid and cystic changes in other neoplasms may focally simulate the appearance of YSC. We have observed similar changes in testicular sex cord-stromal tumors in pediatric patients, which were initially misinterpreted as yolk sac tumors. Proper tissue sampling and immunophenotyping should obviate these problems.81 TUMORS THAT MAY SIMULATE SEMINOMA/ DYSGERMINOMA One might think it difficult to find a tumor that would recapitulate the appearance of classical seminoma adequately enough to be legitimately confused with it (Fig 6). However, seminomas-dysgerminomas may exhibit secondary changes that complicate their diagnosis and distinction from other tumor types. Such alterations include an unusually prominent lymphoid infiltrate or granulomatous reaction, as well as fibrosis. Furthermore, mediastinal germinomas (seminomas) may be associated with prominent reactive follicular lymphoid hyperplasia or marked internal cystification. Therefore,
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TUMORS THAT CAN IMITATE EMBRYONAL CARCINOMA Undifferentiated large cell carcinomas and poorly differentiated adenocarcinomas of virtually any organ may simulate the microscopic image of embryonal carcinoma (Fig 7). This problem is the most troublesome in reference to metastatic tumors of unknown origin, and its importance is underscored by the significant differences in prognosis in this group of tumors if proper therapy is given. In general, the clinical setting (usually involving a patient under the age of 45 years old) may provide some information that assists in differential diagnosis; however, a high level of suspicion, vis-a`-vis the possibility of a germinal tumor, is paramount in that regard. It should be remembered that except for choriocarcinoma and epithelial elements in teratomas, germ cell tumors are negative for epithelial membrane antigen and immunoreactive for either CD117 (seminoma) or CD30 (embryonal carcinoma). On the other hand, except for CD117 reactivity in some
Fig 6. Potential mimics of seminoma: The large clear cells and collagenous septae with lymphoid infiltrate of infiltrating ductal carcinoma of the breast with (A) medullary features and (B) pheochromocytoma may mimic seminoma/dysgerminoma.
all mediastinal cysts containing lymphoid elements must be thoroughly evaluated to address the possibility of a germinoma. Anaplastic large cell lymphoma and metastatic melanoma represent other tumors that may occasionally be confused with metastatic seminoma. They are readily separable with sufficient clinical information, thorough sampling, and adjunctive pathologic studies, but obviously those data cannot be accrued if the differential diagnosis is too narrow. Sertolicell tumors likewise may simulate the uncommon tubular variant of seminoma; in contrast to the latter lesion, however, stromal neoplasms of the gonads are immunoreactive for inhibin and negative for placental alkaline phosphatase (PLAP) and CD117. Viewing this topic conversely, one must also remember that bona fide “pure” seminomas have also arisen rarely in unusual midline extragonadal locations. These include the prostate82 and the urinary bladder.83
Fig 7. Potential mimics of embryonal carcinoma: (A) Poorly differentiated adenocarcinoma of the lung. (B) Large cell neuroendocrine carcinoma of the lung.
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neuroendocrine carcinomas, somatic tumors typically lack both of the latter markers. IMMUNOPHENOTYPES OF GERM-CELL NEOPLASMS Because immunohistology is so crucial to differential diagnosis in this context, it seems appropriate to reiterate the phenotypic characteristics of the tumors under discussion. Choriocarcinoma is always reactive for cytokeratin (seen best with the reagent CAM 5.2) and for bHCG, and it shows variable staining for epithelial membrane antigen (in 50% of cases) and PLAP. That lesion may also demonstrate labeling for carcinoembryonic antigen and is positive for inhibin in its syncytiotrophoblastic component. Thus, choriocarcinoma is, perhaps, the most difficult of the germinal neoplasms to separate from somatic malignancies. Seminoma (germinoma, dysgerminoma) is virtually always positive (⬎95% of cases) for PLAP, as well as CD117 (c-kit protein), both of which have a cell-membrane-based pattern of immunoreactivity.84 Although roughly 30% of cases contain scattered cells that label for various cytokeratins (as seen with antibodies to CK7, CAM 5.2, AE1/AE3, and “wide-spectrum” keratin),85,86 diffuse strong staining with those reagents essentially excludes a diagnosis of pure seminoma. Seminomas consistently lack immunoreactivity for epithelial membrane antigen, alpha-fetoprotein, and CD30, although individual tumor cells may occasionally stain for the last of those markers.85 Yolk sac tumors are always reactive for PLAP and cytokeratin (with CAM 5.2). They are also positive for alpha-fetoprotein, although reactivity for that determinant may be focal. YSC lacks CD3085 and is negative for epithelial membrane antigen. Embryonal carcinoma is always positive for cytokeratin (using CAM 5.2), PLAP, and CD30 (Ki-1 antigen; recognized by the monoclonal antibody Ber-H2), but is usually negative for epithelial membrane antigen.86 Scattered cells may label for alpha-fetoprotein and bHCG, but that is unusual. Teratomas express epithelial markers (cytokeratins and epithelial membrane antigen) in their epithelial components, which are also positive for carcinoembryonic antigen in many cases. Mesenchymal elements are positive for vimentin and may also express more specific lineage-related markers (eg, desmin, S100 protein), depending on the particular morphological constituents of the lesion. Neuroectodermal differentiation is reflected by the presence of positivity for neuron-
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specific enolase, synaptophysin, CD56, and neurofilament proteins. Again, it is emphasized that although PLAP may be present in some somatic carcinomas (10%-15% of cases); the latter lesions are also positive for epithelial membrane antigen.87-89 That combination of results generally militates against a diagnosis of germ cell tumor, with the possible exception of choriocarcinoma. REFERENCES 1. Hanna NH, Ulbright TM, Einhorn LH: Primary choriocarcinoma of the bladder with the detection of isochromosome 12p. J Urol 167:178, 2002 2. Zettl A, Konrad MA, Polzin S, et al: Urothelial carcinoma of the renal pelvis with choriocarcinomatous features: Genetic evidence of clonal evolution. Hum Pathol 33:1234-1237, 2002 3. Liu AY, Chan WY, Ng E, et al: Gastric choriocarcinoma shows characteristics of adenocarcinoma and gestational choriocarcinoma: A comparative genomic hybridization and fluorescence in situ hybridization study. Diagn Mol Pathol 10:161-165, 2001 4. Djewitzki WS: Uber einen Fall von Chorionepithelioma der Harnblase. Virchows Arch 178:451-464, 1904 5. Young RH, Eble JN: Unusual forms of carcinoma of the urinary bladder. Hum Pathol 22:948-965, 1991 6. Campbell PA, McKendrick J: Choriocarcinoma of the urinary bladder. Aust N Z J Surg 69:533-537, 1999 7. Sievert K, Weber EA, Herwig R, et al: Pure primary choriocarcinoma of the urinary bladder with long-term survival. Urology 56:856, 2000 8. Martin JE, Jenkins BJ, Zuk RJ, et al: Human chorionic gonadotrophin expression and histological findings as predictors of response to radiotherapy in carcinoma of the bladder. Virchows Arch A Pathol Anat Histopathol 414:273-277, 1989 9. Vahlensieck W Jr, Riede U, Wimmer B, et al: Beta-human chorionic gonadotropin-positive extragonadal germ cell neoplasia of the renal pelvis. Cancer 67:3146-3149, 1991 10. Grammatico D, Grignon DJ, Eberwein P, et al: Transitional cell carcinoma of the renal pelvis with choriocarcinomatous differentiation. Immunohistochemical and immunoelectron microscopic assessment of human chorionic gonadotropin production by transitional cell carcinoma of the urinary bladder. Cancer 71:1835-1841, 1993 11. Mihatsch MJ, Bleisch A, Six P, et al: Primary choriocarcinoma of the kidney in a 49-year-old woman. J Urol 108:537-539, 1972 12. Lurain JR: Treatment of gestational trophoblastic tumors. Curr Treat Options Oncol 3:113-124, 2002 13. Bradley CS, Benjamin I, Wheeler JE, et al: Endometrial adenocarcinoma with trophoblastic differentiation. Gynecol Oncol 69: 74-77, 1998 14. Shintaku M, Kariya M, Shime H, et al: Adenocarcinoma of the uterine cervix with choriocarcinomatous and hepatoid differentiation: report of a case. Int J Gynecol Pathol 19:174-178, 2000 15. Nguyen CP, Levi AW, Montz FJ, et al: Coexistent choriocarcinoma and malignant mixed mesodermal tumor of the uterus. Gynecol Oncol 79:499-503, 2000 16. Khuu HM, Crisco CP, Kilgore L, et al: Carcinosarcoma of the uterus associated with a nongestational choriocarcinoma. South Med J l 93:226-228, 2000
270 17. Saigo PE, Rosen PP: Mammary carcinoma with “choriocarcinomatous” features. Am J Surg Pathol 5:773-778, 1981 18. Green DM: Mucoid carcinoma of the breast with choriocarcinoma in its metastases. Histopathology 16:504-506, 1990 19. Erhan Y, Ozdemir N, Zekioglu O, et al: Breast carcinomas with choriocarcinomatous features: Case reports and review of the literature. Breast J 8:244-248, 2002 20. Chen F, Tatsumi A, Numoto S: Combined choriocarcinoma and adenocarcinoma of the lung occurring in a man: Case report and review of the literature. Cancer 91:123-129, 2001 21. Arslanian A, Pischedda F, Filosso PL, et al: Primary choriocarcinoma of the lung. J Thor Cardiovasc Surg 125:193-196, 2003 22. Watanabe S, Shimokawa S, Sakasegawa K, et al: Choriocarcinoma in the pulmonary artery treated with emergency pulmonary embolectomy. Chest 121:654-656, 2002 23. Rossi G, Valli R, Rivasi F, et al: Does primary pulmonary choriocarcinoma really exist? Chest 123:313, 2003 24. Pushchak MJ, Farhi DC: Primary choriocarcinoma of the lung. Arch Pathol Lab Med 111:477-479, 1987 25. Burt ME, Javadpour N: Germ-cell tumors in patients with apparently normal testes. Cancer 47:1911-1915, 1981 26. Heimann A, White PF, Riely CA, et al: Hepatoblastoma presenting as isosexual precocity. The clinical importance of histologic and serologic parameters. J Clin Gastroenterol 9:105-110, 1987 27. Arai M, Oka K, Nihei T, et al: Primary hepatic choriocarcinoma–A case report. Hepatogastroenterology 48:424-426, 2001 28. Kim SN, Chi JG, Kim YW, et al: Neonatal choriocarcinoma of liver. Pediatr Pathol 13:723-730, 1993 29. Abu-Farsakh H, Fraire AE: Adenocarcinoma and (extragonadal) choriocarcinoma of the gallbladder in a young woman. Hum Pathol 22:614-615, 1991 30. Wang JC, Angeles S, Chak P, et al: Choriocarcinoma of the gallbladder: Treated with cisplatin-based chemotherapy. Med Oncol 18:165-169, 2001 31. Albores-Saavedra J, Cruz-Ortiz H, Alcantara-Vazques A, et al: Unusual types of gallbladder carcinoma. A report of 16 cases. Arch Pathol Lab Med 105:287-293, 1981 32. Childs CC, Korsten MA, Choi HS, et al: Pancreatic choriocarcinoma presenting as inflammatory pseudocyst. Gastroenterology 89:426-431, 1985 33. Tokisue M, Yasutake K, Oya M, et al: Coexistence of choriocarcinoma and adenocarcinoma in the rectum: Molecular aspects. J Gastroenterol 31:431-436, 1996 34. Imai Y, Kawabe T, Takahashi M, et al: A case of primary gastric choriocarcinoma and a review of the Japanese literature. J Gastroenterol 29:642-646, 1994 35. Merimsky O, Jossiphov J, Asna N, et al: Choriocarcinoma arising in a squamous cell carcinoma of the esophagus. Am J Clin Oncol 23:203-206, 2000 36. Ishihara A, Mori T, Koono M: Diffuse pagetoid squamous cell carcinoma of the esophagus combined with choriocarcinoma and mucoepidermoid carcinoma: An autopsy case report. Pathol Int 52: 147-152, 2002 37. Yakeishi Y, Mori M, Enjoji M: Distribution of beta-human chorionic gonadotropin-positive cells in noncancerous gastric mucosa and in malignant gastric tumors. Cancer 66:695-701, 1990 38. Le DT, Austin RC, Payne SN, et al: Choriocarcinoma of the colon: Report of a case and review of the literature. Dis Colon Rectum 46:264-266, 2003 39. Chan GS, Ng WK, Chua DT, et al: Raised serum hCG in a
MANIVEL AND PAMBUCCIAN male patient caused by primary jejunal choriocarcinoma. J Clin Pathol 51:413-415, 1998 40. Gonzalez-Crussi F: Extragonadal teratomas, in Atlas of Tumor Pathology, Series 2, Fascicle 18. Washington, DC, Armed Forces Institute of Pathology, 1984 41. Variend S, Spicer RD, Mackinnon AE: Teratoid Wilms’ tumor. Cancer 53:1936-1942, 1984 42. Pawel BR, de Chadarevian JP, Smergel EM, et al: Teratoid Wilms tumor arising as a botryoid growth within a supernumerary ectopic ureteropelvic structure. Arch Pathol Lab Med 122:925-928, 1998 43. Abenoza P, Manivel JC, Wick MR, et al: Hepatoblastoma: An immunohistochemical and ultrastructural study. Hum Pathol 18: 1025-1035, 1987 44. Manivel C, Wick MR, Abenoza P, et al: Teratoid hepatoblastoma. The nosologic dilemma of solid embryonic neoplasms of childhood. Cancer 57:2168-2174, 1986 45. Burger PC, Yu IT, Tihan T, et al: Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: A Pediatric Oncology Group study. Am J Surg Pathol 22:1083-1092, 1998 46. Packer RJ, Biegel JA, Blaney S, et al: Atypical teratoid/ rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 24:337-342, 2002 47. Uno K, Takita J, Yokomori K, et al: Aberrations of the hSNF5/INI1 gene are restricted to malignant rhabdoid tumors or atypical teratoid/rhabdoid tumors in pediatric solid tumors. Genes Chromosomes Cancer 34:33-41, 2002 48. Lee HY, Yoon CS, Sevenet N, et al: Rhabdoid tumor of the kidney is a component of the rhabdoid predisposition syndrome. Pediatr Dev Pathol 5:395-399, 2002 49. Boesel CP, Suhan JP, Sayers MP: Melanotic medulloblastoma. Report of a case with ultrastructural findings. J Neuropathol Exp Neurol 37:531-543, 1978 50. Duinkerke SJ, Slooff JL, Gabreels FJ, et al: Melanotic rhabdomyomedulloblastoma or teratoid tumour of the cerebellar vermis. Clin Neurol Neurosurg 83:29-33, 1981 51. Auer RN, Becker LE: Cerebral medulloepithelioma with bone, cartilage, and striated muscle. Light microscopic and immunohistochemical study. J Neuropathol Exp Neurol 42:256-267, 1983 52. Manivel JC, Priest JR, Watterson J, et al: Pleuropulmonary blastoma. The so-called pulmonary blastoma of childhood. Cancer 62:1516-1526, 1988 53. Priest JR, McDermott MB, Bhatia S, et al: Pleuropulmonary blastoma: A clinicopathologic study of 50 cases. Cancer 80:147-161, 1997 54. Koss MN, Hochholzer L, O’Leary T: Pulmonary blastomas. Cancer 67:2368-2381, 1991 55. Koss MN, Hochholzer L, Frommelt RA: Carcinosarcomas of the lung: A clinicopathologic study of 66 patients. Am J Surg Pathol 23:1514-1526, 1999 56. Siegel RJ, Bueso-Ramos C, Cohen C, et al: Pulmonary blastoma with germ cell (yolk sac) differentiation: Report of two cases. Mod Pathol 4:566-570, 1991 57. Manivel C, Wick MR, Dehner LP: Transitional (cylindric) cell carcinoma with endodermal sinus tumor-like features of the nasopharynx and paranasal sinuses. Clinicopathologic and immunohistochemical study of two cases. Arch Pathol Lab Med 110:198-202, 1986 58. Devaney KO, Ferlito A: Yolk sac tumors (endodermal sinus
GERM CELL TUMOR-LIKE NEOPLASMS tumors) of the extracranial head and neck regions. Ann Otol Rhinol Laryngol 106:254-260, 1997 59. Fukunaga M, Miyazawa Y, Harada T, et al: Yolk sac tumour of the ear. Histopathology 27:563-567, 1995 60. Motoyama T, Saito K, Iwafuchi M, et al: Endodermal sinus tumor of the stomach. Acta Pathol Jpn 35:497-505, 1985 61. Garcia RL, Ghali VS: Gastric choriocarcinoma and yolk sac tumor in a man: Observations about its possible origin. Hum Pathol 16:955-958, 1985 62. Puglisi F, Damante G, Pizzolitto S, et al: Combined yolk sac tumor and adenocarcinoma in a gastric stump: Molecular evidence of clonality. Cancer 85:1910-1916, 1999 63. Zamecnik M, Patrikova J, Gomolcak P: Yolk sac carcinoma of the stomach with gastrin positivity. Hum Pathol 24:927-928, 1993 64. Kodama T, Kameya T, Hirota T, et al: Production of alphafetoprotein, normal serum proteins, and human chorionic gonadotropin in stomach cancer: histologic and immunohistochemical analyses of 35 cases. Cancer 48:1647-1655, 1981 65. Gunawardena SA, Siriwardana HP, Wickramasinghe SY, et al: Primary endodermal sinus (yolk sac) tumour of the liver. Eur J Surg Oncol 28:90-91, 2002 66. Morinaga S, Nishiya H, Inafuku T: Yolk sac tumor of the liver combined with hepatocellular carcinoma. Arch Pathol Lab Med 120: 687-690, 1996 67. Cross SS, Variend S: Combined hepatoblastoma and yolk sac tumor of the liver. Cancer 69:1323-1326, 1992 68. Albores-Saavedra J, Henson DE, Klimstra DE: Miscellaneous malignant tumors, in Tumors of the Gallbladder, Extrahepatic Bile ducts and Ampulla of Vater (Atlas of Tumor Pathology, Series 3, Fascicle 27). Washington, DCp 138, Armed Forces Institute of Pathology, 2000 69. Taylor G, Jordan M, Churchill B, et al: Yolk sac tumor of the bladder. J Urol 129:591-594, 1983 70. D’Alessio A, Verdelli G, Bernardi M, et al: Endodermal sinus (yolk sac) tumor of the urachus. Eur J Ped Surg 4:180-181, 1994 71. Young RH, Scully RE: Endodermal sinus tumor of the vagina: A report of nine cases and review of the literature. Gynecol Oncol 18:380-392, 1984 72. Handel LN, Scott SM, Giller RH, et al: New perspectives on therapy for vaginal endodermal sinus tumors. J Urol 168:687-690, 2002 73. Spatz A, Bouron D, Pautier P, et al: Primary yolk sac tumor of the endometrium: A case report and review of the literature. Gynecol Oncol 70:285-288, 1998 74. Patsner B: Primary endodermal sinus tumor of the endome-
271 trium presenting as “recurrent” endometrial adenocarcinoma. Gynecol Oncol 80:93-95, 2001 75. Shokeir MO, Noel SM, Clement PB: Malignant mullerian mixed tumor of the uterus with a prominent alpha-fetoprotein-producing component of yolk sac tumor. Mod Pathol 9:647-651, 1996 76. Lankerani MR, Aubrey RW, Reid JD: Endometriosis of the colon with mixed “germ cell” tumor. Am J Clin Pathol 78:555-559, 1982 77. Kennedy R, Lacson A: Congenital endodermal sinus tumor of the penis. J Pediatr Surg 22:791-792, 1987 78. Benson RC Jr, Segura JW, Carney JA: Primary yolk-sac (endodermal sinus) tumor of the prostate. Cancer 41:1395-398, 1978 79. Tay HP, Bidair M, Shabaik A, et al: Primary yolk sac tumor of the prostate in a patient with Klinefelter’s syndrome. J Urol 153: 1066-1069, 1995 80. Namiki K, Tsuchiya A, Noda K, et al: Extragonadal germ cell tumor of the prostate associated with Klinefelter’s syndrome. Int J Urol 6:158-161, 1999 81. Goswitz JJ, Pettinato G, Manivel JC: Testicular sex cordstromal tumors in children: Clinicopathologic study of sixteen children with review of the literature. Pediatr Pathol Lab Med 16:451470, 1996 82. Hayman R, Patel A, Fisher C, et al: Primary seminoma of the prostate. Br J Urol 76:273-274, 1995 83. Khandekar JD, Holland JM, Rochester D, et al: Extragonadal seminoma involving urinary bladder and arising in the prostate. Cancer 71:3972-3974, 1993 84. Arber DA, Tamayo R, Weiss LM: Paraffin section detection of the c-kit gene product (CD117) in human tissues: Value in the diagnosis of mast cell disorders. Hum Pathol 29:498-504, 1998 85. Suster S, Moran CA, Dominguez-Malagon H, et al: Germ cell tumors of the mediastinum and testis: A comparative immunohistochemical study of 120 cases. Hum Pathol 29:737-742, 1998 86. Cheville JC, Rao S, Iczkowski KA, et al: Cytokeratin expression in seminoma of the human testis. Am J Clin Pathol 113:583-588, 2000 87. Manivel JC, Jessurun J, Wick MR, et al: Placental alkaline phosphatase immunoreactivity in testicular germ-cell neoplasms. Am J Surg Pathol 11:21-29, 1987 88. Wick MR, Swanson PE, Manivel JC: Placental-like alkaline phosphatase reactivity in human tumors: An immunohistochemical study of 520 cases. Hum Pathol 18:946-954, 1987 89. Niehans GA, Manivel JC, Copland GT, et al: Immunohistochemistry of germ cell and trophoblastic neoplasms. Cancer 62:11131123, 1988
T
HE TOPIC of this issue of Seminars in Diagnostic Pathology—that is, the recognition of familiar pathologic lesions in unfamiliar settings–requires 2 sequential steps. First, one must look at microscopic sections with no bias as to the anatomic location from which they were taken; second, once the site is taken into consideration, and the observer has recovered from his or her astonishment, one must establish an adequate differential diagnosis by using the morphologic findings, historical data, and a carefully crafted group of adjunctive studies. The latter statement is predicated in part on an anecdote which has been ascribed to Dr. Arthur Purdy Stout by some of our mentors. He apparently used to say “If I saw my grandmother in China, I would be quite surprised, but I would recognize her without a doubt.” Nonetheless, many times microscopic examination does not allow for immediate diagnostic certainty in and of itself (except, perhaps, for Dr. Stout). In such instances one may use a technique that has proved very useful to us; if a diagnosis is not certain, or correlation with location or history do not appear to make much sense, the following question should be posed “what would this be if I saw it in another anatomic site?” Most germ cell tumors occur in the gonads. OtherFrom the Division of Surgical Pathology, Department of Laboratory Medicine Medicine & Pathology, University of Minnesota School of Medicine, Minneapolis, MN. Address reprint requests to J. Carlos Manivel, MD, Division of Surgical Pathology, Department of Laboratory Medicine & Pathology, University of Minnesota School of Medicine, C446 Mayo Bldg., MMC 76, FUMC, 420 Delaware St SE, Minneapolis, MN 55455; e-mail: [email protected]. © 2003 Elsevier Inc. All rights reserved. 0740-2570/03/2004-0003$30.00/0 doi:10.1053/j.semdp.2003.08.001 260
wise, midline sites such as the sacrococcygeal region, anterior mediastinum, and central nervous system are the preferred locations for these lesions. The differential diagnosis of germ cell tumors and their morphologic simulators can be viewed from 2 diametrical perspectives. First, one can consider true germ cell tumors, in both gonadal and extragonadal sites, that may be mistaken for nongerminal neoplasms; second, one must be able to recognize nongerm cell (somatic) neoplasms that may imitate germ cell tumors. This review deals predominantly with the second of those scenarios; however, differential diagnostic criteria applying to mimics of germ cell tumors are equally helpful in identifying true germ cell neoplasms. As will become apparent in the subsequent discussion, this issue is actually more complex; definitions of “germcell differentiation” and “germ-cell-like differentiation” are imprecise, contentious, or heterogeneously applied. As one of our mentors asked, “is an albino man born in a black African family a white man or a black man?” The answer depends on the criteria used to make the definition; namely, skin pigmentation only, other phenotypic features, or genetic factors. Similarly, it is obvious that criteria used for the definition of germ cell tumors may encompass different determinants, and, in order to make some sense of them, one must carefully delineate the criteria being used. This is not always easy, because the criteria may not be well established and those that exist may not be as specific as we would like. For example, most observers would agree that a somatic adenocarcinoma producing alpha-fetoprotein, as sometimes seen in the ovaries, should not be regarded as a true yolk-sac tumor; similarly, a gastric adenocarcinoma comprising beta-human chorionic gonadotrophin (bHCG)-secreting multinucleated giant cells should not be classified as a choriocarcinoma. However, one may encounter tumors in these sites that
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contain areas which are histologically-indistinguishable from true yolk sac tumor or choriocarcinoma, in addition to others that clearly represent somatic carcinoma. Indeed, only the germ-cell (or germ-cell-like) component is identified in some instances, and the possibility that another somatic component was “overrun” by the former constituent cannot be excluded. Metastasis to the viscera from a germ cell tumor in a “conventional” site must also be considered. It would be desirable to have an absolute genetic “fingerprint” of germ cell origin that would aid in these assessments. In fact, however, even though an isochromosome of the short arm of chromosome 12 has been thought to represent such a marker, it has also been identified by fluorescence in-situ hybridization (FISH) in a primary tumor (called “choriocarcinoma”) of the bladder.1 With both comparative genomic hybridization (CGH) and FISH, other investigators have found that secondary acquisition of chromosome 12 abnormalities correlated with development of a germ cell (choriocarcinomatous) phenotype in renal pelvic transitional cell carcinoma2 and gastric adenocarcinoma.3 Both of the components in these 2 “hybrid” tumors also had cytogenetic abnormalities that were characteristic of urothelial carcinoma (losses of chromosome 9 and 17p)2 and gastric adenocarcinoma (gains in 1p34-36, 18p and 20 and loss on 18q), respectively.3 Thus, it would appear that chromosome 12 aberrations may appear secondarily in somatic neoplasms, and therefore are not specific for “pure” germ cell tumors. Almost 100 years after the first descriptions of neoplasms that were histological simulators of true germ cell tumors, but in “unusual” somatic sites,4 uncertainty still exists regarding their histogenesis. They could potentially be explained by aberrant migration of pluri(or toti-) potential germ cells; secondary germ-cell differentiation (“retrodifferentiation” or “dedifferentiation”) in a somatic neoplasm; or metastasis from a clinically-occult bona-fide primary germ cell tumor. Finally, the possibility must also be entertained that the neoplasm in question has nothing to do with germ cells at a basic level and simply possesses one or more features that suggest a germinal nature. It is interesting to note that all of these hypotheses were considered in 1904 by Djewitzki to explain the occurrence of pure “choriocarcinoma” in the urinary bladder of a 75year-old woman. Similar premises were advanced by Davidsohn in 1905 in reference to a composite “choriocarcinoma”-adenocarcinoma in the stomach of a 44-year-old man, and by Risel in 1907 regarding
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“choriocarcinomatous” lymph node metastases in 2 women with gastric adenocarcinomas. It is apparent that any one of these hypotheses may be operative in an individual case, bolstered by experimental and clinical evidence. Although it is important to try to establish genetic markers and genetic “definitions” for human neoplasms, we believe that morphological examination continues to represent the cornerstone of diagnosis in clinical medicine. Therefore, only when strict histologic criteria are fulfilled should a neoplasm be accepted as exhibiting germ cell features. Advances in the treatment of germ cell tumors over the past 25 years have considerably improved the outlook for patients with such lesions, even in the face of metastatic disease. Thus, the importance of their accurate recognition cannot be overemphasized. This discussion will address extragonadal neoplasms which, because of their histologic features, may imitate classical germ cell tumors. In doing so, the World Health Organization (WHO) classification of germ cell tumors and related lesions will be used, as follows: 1. Tumors that may simulate choriocarcinoma 2. Tumors that may simulate teratoma 3. Tumors that may simulate yolk sac tumor 4. Tumors that may simulate embryonal carcinoma 5. Tumors that may simulate seminoma/dysgerminoma These lesions are hereafter grouped primarily according to the foregoing designations, with secondary consideration of anatomic locations, to better assist the reader in their differential diagnosis. Analysis of the virtues of various hypotheses on causation, as enumerated above, is beyond the scope of this review (and its authors). Suffice it to say that bona-fide germ cell tumors may indeed arise in unusual sites and must be distinguished from metastatic germinal neoplasms and somatic malignancies alike. We shall exclude from consideration germ cell tumors of the gonads, retroperitoneum, mediastinum, and the midline central nervous system, because these represent the “familiar” or “usual” sites for such proliferations. TUMORS WITH CHORIOCARCINOMATOUS FEATURES & SIMULANTS OF CHORIOCARCINOMA Regardless of whether they are of germ cell origin or gestational in nature, choriocarcinomas show alternating areas of cytotrophoblastic and syncytiotrophoblastic differentiation with a plexiform pattern. In general, a distinction should be made between poorly differentiated somatic carcinomas that contain isolated bHCG-
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producing multinucleated giant cells from other neoplasms that display all of the expected morphologic features of choriocarcinoma. Urinary Tract Rarely, poorly differentiated urothelial carcinomas of the urinary bladder contain areas that have been interpreted as “choriocarcinomatous” or “resembling choriocarcinoma.”1,5-7 Moreover, bHCG may be demonstrated immunohistochemically in up to one third of otherwise ordinary high-grade transitional-cell bladder carcinomas.8 It has been suggested that trophoblastic differentiation in urothelial neoplasms results from heterogeneity of epithelial differentiation and a metaplastic potential of the urothelium. Furthermore, some have concluded that all primary bladder tumors with trophoblastic components basically represent transitional cell carcinomas with trophoblastic differentiation (TCTD), instead of neoplasms of true germinal origin. The latter assertion is supported by clinical similarities between TCTD and conventional transitional cell carcinomas, including patient age and sex distribution (mean 62 years; 3:1 male-to-female ratio) and a location in or near the trigone.6 Pathologically, TCTDs have shown the presence of an overt transitional cell component in all but the most advanced cases (as seen at autopsy), in which the choriocarcinomatous elements may have outgrown the urothelial carcinoma. In some instances, a diagnosis of “choriocarcinoma” was preceded by biopsies of the same tumor showing transitional-cell or poorly-differentiated somatic carcinoma.6 These findings suggest that when trophoblastic differentiation is extensive, thorough sampling is essential to document the presence of an urothelial component. One case of pure “choriocarcinoma”9 and 2 cases of mixed “choriocarcinoma”- transitional cell carcinoma of the renal pelvis have also been described,2,10 in addition to another of renal “choriocarcinoma.”11 Despite the fact that classical choriocarcinomas are very chemosensitive tumors that usually respond to single-agent therapy with methotrexate or actinomycinD12, results with chemotherapy for “choriocarcinomas” of the urinary tract has been disappointing. Most patients have succumbed within 1 year6 and the longest reported survival in that group was 33 months.7
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cells (Fig 1). The latter were immunoreactive for bHCG, potentially causing elevation of that marker in the serum. Uterine “carcinosarcomas” (sarcomatoid carcinomas; malignant mixed mullerian tumors) with a “choriocarcinomatous” component have also been documented.15,16 Similarly, “choriocarcinomas” or choriocarcinoma-like neoplasms have been reported in the breast; some were associated with areas of conventional infiltrating ductal carcinoma17; others were manifest in lymph node metastases of a “mucoid” carcinoma,18 or they were associated with ductal carcinoma in situ.19 Lung Rare cases have been described of presumed primary pulmonary choriocarcinoma20,21 and an example of choriocarcinoma that putatively arose from the pulmonary artery.22 However, as in other anatomic sites, other cases of malignancies in the lung with germ-cell features are thought to represent divergent trophoblastic differentiation in conventional large cell carcinomas, adenocarcinomas, or small-cell carcinomas, and the latter components can be recognized with appropriate sampling. Some of these tumors have shown immunoreactivity for thyroid transcription factor-1 (TTF-1), a marker of pulmonary differentiation, making some authors doubt the existence of “pure” primary pulmonary choriocarcinoma23 and instead favoring the diagnosis of “pleomorphic carcinoma with choriocarcinoma-like features.” On the other hand, tumors lacking an adenocarcinomatous, large-cell-, or small-cell carcinoma component have been felt to derive from the abnormal migration of primordial germ cells into the lungs during fetal development.24 Before making a diagnosis of pri-
Gynecologic Tract & Breast Rarely, poorly differentiated endometrial13 and endocervical14 adenocarcinomas have shown choriocarcinoma-like or “trophoblastic differentiation,” characterized by the presence of syncytiotrophoblastic-like giant
Fig 1. Potential mimic of choriocarcinoma: poorly differentiated endometrial adenocarcinoma with syncytial giant cells.
GERM CELL TUMOR-LIKE NEOPLASMS
mary choriocarcinoma of the lung, serious consideration should be given to metastasis from an occult gestational or gonadal primary tumor and these possibilities should be addressed clinically. In this context, it must be acknowledged that the possibility of a “burnedout” (regressed) gonadal choriocarcinoma25 cannot be entirely excluded, even with an extensive radiographic evaluation. Liver & Pancreatobiliary System An uncommon presentation of hepatoblastoma in boys is that of isosexual precocity, characterized by a deepening of the voice, penile enlargement, and growth of pubic hair. These children have elevated serum and urinary levels of human chorionic gonadotropin, and that hormone can be detected in the hepatoblastoma cells immunohistochemically.26 Rare examples of primary “pure” choriocarcinoma of the liver,27 one of which occurred in a neonate,28 have also been described. Another unusual location for choriocarcinoma is the gallbladder, where 2 examples were documented,29,30 in addition to another case that was included in a series of “unusual types of gallbladder carcinoma.”31 One example of pancreatic choriocarcinoma arose in the body of that organ and presented in a manner simulating an inflammatory pseudocyst.32 Gastrointestinal Tract Although they are rare, choriocarcinomas of the gastrointestinal tract are the most well-represented of trophoblastic tumors in “unusual” sites; 67 gastric “choriocarcinomas” had been reported through 1996 in the English literature,33 with an additional 79 cases in Japanese publications.34 Five examples of “choriocarcinoma” also have occurred in the esophagus.35,36 “Choriocarcinomas” of the alimentary tract are frequently admixed with adenocarcinomas (in 75% of cases) or, in esophageal sites, with squamous cell carcinoma.35,36 Because of these associations, such lesions are thought to derive from trophoblastic differentiation (“retrodifferentiation”) of somatic epithelial tumor cells. In tumors with no adenocarcinomatous components, it is thought to be probable that the growth of the germ-cell tumor-like element obliterated the adenocarcinoma through preferential overgrowth. The average age of patients with these neoplasms is similar to that of individuals with ordinary esophagogastric malignancies. Most patients with tumors in the stomach are elderly men (with a gender preference of 2:1), and their prognosis is dismal. Production of bHCG
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by these neoplasms can be documented by examination of serum, and it may become manifest clinically with the development of gynecomastia in males or menstrual irregularities (eg, postmenopausal vaginal bleeding) in women. Grossly, one sees extensive necrosis and hemorrhage in choriocarcinoma-like gastrointestinal lesions. The stomach appears to be a good paradigm for the analysis of extragonadal trophoblastic differentiation, because normal antral-neck cells, metaplastic epithelium in atrophic gastritis, and the cells of 25% to 50% of ordinary gastric adenocarcinomas exhibit bHCGreactivity immunohistochemically.37 The next most common member of the “spectrum” of extragonadal germ cell proliferations would be mixed somatic adenocarcinoma-choriocarcinoma, followed by “pure” choriocarcinoma. By convention, the unqualified term of “choriocarcinoma” is reserved for those tumors which fulfill all morphologic and biochemical criteria for that diagnosis. There is a tendency for choriocarcinomatous components of mixed malignancies to metastasize hematogenously to the liver and lung, whereas the somatic adenocarcinomatous elements spread lymphatically to regional lymph nodes. Insufficient information is available to determine if the prognosis of gastric “choriocarcinoma” is worse than that of ordinary adenocarcinoma. Intestinal adenocarcinomas with trophoblastic differentiation are characterized by the presence of multinucleated giant cells that are immunoreactive for bHCG; occasionally, these tumors also may contain both cytotrophoblastic and syncytiotrophoblastic components. They tend to occur in the cecum or rectosigmoid colon in relatively young adults, who have elevated serum levels of bHCG. The prognosis of this tumor variant is poor.38 “Choriocarcinomas” of the small bowel39 usually represent divergent trophoblastic differentiation in conventional adenocarcinomas that display both cytotrophoblastic and syncytiotrophoblastic elements. TUMORS THAT MAY SIMULATE TERATOMAS Teratomas are defined as “neoplasms that originate in pluripotential cells, comprising a wide diversity of tissues that are foreign to the organ or anatomic site in which they arise.”40 Indeed, teratomas represent a grotesque caricature of embryogenesis; as such, they are typified by a mixture of tissues. These frequently, but not necessarily, include 2 or 3 germ layers. These usually exhibit recognizable organization; in other words, one does not simply recognize a nondescript mass of mesodermal tissue adjacent to a similar aggre-
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gation of epithelial cells. Instead, the mesenchymal tissue is frequently structured as lamina propria or stroma, and overall organization of the lesion may be sufficiently advanced to allow for recognition of such elements as skin, bronchi, intestinal segments, or teeth. The purpose of this brief introduction is to allow for the conclusion that tumors that simulate teratomas are those that contain different cell types (usually although “aberrant or “heterologous” differentiation), and these are associated with one another in a variably organoid fashion. Teratomas arising in “familiar” anatomic sites–such as the gonads or along the midline in the central nervous system, mediastinum, retroperitoneum, and sacrococcygeal region– generally do not pose serious diagnostic difficulties. However, lesions with comparable histological images may also occur in “unfamiliar” settings, and, in fact, practically every organ and anatomic site can be so affected. Indeed, an entire fascicle of the Armed Forces Institute of Pathology Atlas of Tumor Pathology (Fascicle 18, Series 2) was dedicated to a discussion of extragonadal teratomas. In keeping with the preceding approach of this review, true teratomas in familiar locations will not be addressed further; rather, the main focus is on somatic tumors that are potentially confused with them. Teratoid Neoplasms “Teratoid” tumors are pediatric neoplasms that morphologically recapitulate the development of the organ in which they arise. As such, they are termed “dysembryogenic.” Examples of hepatoblastoma and nephroblastoma belong to this group. In addition to their usual components, they may contain cells that are foreign to the organ of origin. In “conventional” nephroblastomas (Wilms’ tumors), epithelial tumor cells may show several levels of differentiation, and the stromal component usually comprises spindle shaped, fibroblast-like elements. Together with blastematous components, the epithelial and stromal tissues produce a typically “triphasic” appearance in classical nephroblastomas. However, the stromal component may also pursue differentiation along adipocytic, smooth muscle-, or rhabdomyogenic lines. When the last of those is prominent, it may virtually efface all other components; this is true in so-called “rhabdomyomatous” Wilms tumor, not to be confused with the much more aggressive rhabdoid tumor of the kidney or with rhabdomyosarcoma. Nephroblastomas with stromal differentiation into fat or myogenous tissues are still classified as “conven-
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tional;” the term “teratoid nephroblastoma” has been applied to those that include ciliated-, mucinous-, squamous- or transitional- epithelium; endocrine cells of different types; renin-producing cells; neuroepithelial or neuroblastic tissues; and mature ganglion cells.41,42 Conventional hepatoblastomas are composed of uniform populations of “fetal” or “embryonal” hepatocytes in purely epithelial tumor variants, or combinations thereof with mesenchymal cells in mixed hepatoblastomas. The mesenchymal component often focally resembles osteoid, although the tumor cells embedded in the material resembling bone matrix have ultrastructural and immunohistochemical properties of epithelium43 The designation of “teratoid hepatoblastoma” (or hepatoblastoma with teratoid features) is applied to those lesions that contain melanocytes, ganglion cells, squamous epithelium, or cysts lined by cuboidal and goblet-cell epithelium (resembling respiratory or intestinal mucosa), in addition to areas of “classical” hepatoblastoma44 (Fig 2). The term “atypical teratoid/rhabdoid tumor” has been used in reference to highly malignant nervous system tumors that are seen supratentorially or in the posterior fossa or brainstem of young children.45 Microscopically, they contain medium-sized to large cells with prominent nucleoli, arranged in sheets that are separated by fibrovascular septa. Fascicular and trabecular patterns of growth also may be seen. A small-cell component reminiscent of medulloblastoma may be present in some instances. The modifier “teratoid” is intended to reflect the presence of morphologic and immunohistochemical heterogeneity in this group of lesions, but does not have the same connotation as in reference to blastomas of the liver and kidney. Some cells in rhabdoid tumor have abundant eosinophilic cytoplasm, yielding a cytological image which is similar to that seen in rhabdoid tumors of the kidney and soft tissues. Immunohistologic studies show positivity for vimentin and frequently also for glial fibrillary acidic protein, epithelial membrane antigen, and cytokeratin. Reactivity for synaptophysin and chromogranin is occasionally present as well, but labeling for neurofilament proteins is uncommon. Although some cells may stain for actin and desmin, those with a “rhabdoid” appearance are consistently negative for myogenic markers. Most atypical teratoid rhabdoid tumors demonstrate karyotypic monosomy 22 or deletions of the chromosomal band 22q11, with alterations of the hSNF5/INI1 gene.46,47 The relationship between these lesions and the rhabdoid tumors of the kidney and soft tissues may be more than morphological. Neuraxial
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heterologous mesenchymal components, including striated muscle, bone, cartilage, and adipose tissue.51 Ovary Sertoli-Leydig cell tumors (androblastomas) can contain heterologous components; in 18% of such cases, these are represented by cysts and glands lined by gastric- or intestinal-type epithelium, including goblet cells, argentaffinic elements, and, rarely, Paneth cells. Five percent of cases show mesenchymal differentiation, with skeletal muscle- or cartilaginous components. Such “teratoid androblastomas” can be confused with teratomas; nonetheless, it must be remembered that Sertoli and Leydig cells are not seen in ovarian teratomas. Malignant mixed mesodermal tumors of ovarian (and uterine) origin comprise malignant epithelial and stromal components that are mesodermally-derived. Heterologous differentiation, in the form of rhabdomyosarcomatous, osteosarcomatous and chondrosarcomatous components, is not rare, but neuroectodermal components are exceptional. These lesions also lack the variety of differentiated tissues that is seen in teratomas. Furthermore, the epithelial and mesenchymal elements in malignant mixed mullerian tumors are malignant cytologically, and those lesions occur at a much later age than that associated with teratomas. Lung & Pleura Fig 2. Teratoid hepatoblastoma showing areas of (A) melanocytic and (B) squamous differentiation, in addition to osteoid formation.
rhabdoid tumors, like their extracranial counterparts, may harbor a chromosomal translocation or monosomy involving chromosome 22, and be part of the “rhabdoid predisposition syndrome (RPS)” that is characterized by germline mutations of the hSNF5/INI1 tumor suppressor gene.48 These neoplasms are aggressive and are characterized by common local recurrence and meningeal spread. Medulloblastomas also sometimes contain foci of neoplastic glial cells (“medulloblastoma with mixed differentiation”); in addition, heterologous or “aberrant” differentiation may manifest itself in the form of skeletal muscle (“medullomyoblastoma”), foci of pigmented epithelioid cells (“melanotic medulloblastoma”)49 or a combination of those tissues (“teratoid medulloblastoma”)50 Similarly, in addition to typical neuroepithelial structures resembling primitive neural tubes, medulloepitheliomas may show astrocytic and
Pleuropulmonary blastomas (PPBs) may display heterologous differentiation toward cell types that are not normally present in the lung or its coverings; moreover, they have an embryonic microscopic appearance. These features may lead to confusion with teratomatous tumors arising in the thorax or metastasizing to it.52 PPBs are seen almost exclusively in children and adolescents. They contain immature mesenchymal tissue with a blastomatous appearance; focally, myxoid areas, anaplastic-pleomorphic foci, and areas of rhabdomyosarcomatous or chondrosarcomatous differentiation may be seen. None of the tumor cells is epithelial in nature, but the lesional constituents are interspersed with glands, ducts, and cysts lined by benign entrapped cells of bronchial or mesothelial derivation (Fig 3). Accordingly, only sarcomatous elements are identified in metastatic deposits. PPB is a highly aggressive tumor, but long-term survival is better for younger patients with predominantly-cystic intrapulmonary tumors (50% at 5 years) than it is for patients with large, solid, pleuralbased and unresectable tumors (25% at 5 years).53 For the sake of clarity, a few words on 2 other
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TUMORS THAT MIMIC YOLK-SAC CARCINOMA Tumors with areas that reproduce the appearance of yolk sac carcinoma (YSC; endodermal sinus tumor) to variable degrees have been described in several sites (Fig 5); 2 such cases were variants of pulmonary blastoma.56 Another 2 examples were transitional (“Schneiderian”) carcinomas that arose in the nasopharynx and paranasal sinuses, and contained areas that imitated yolk sac carcinomas histologically and immunohistochemically.57 True endodermal sinus tumors of the upper aerodigestive tract have also been described in children, including examples in the nasopharynx, oropharynx, and oral cavity.58 Two additional cases were documented in the ear in young children.59 YSC-like components have rarely been described in
Fig 3. Pleuropulmonary blastoma showing areas of (A) skeletal muscle differentiation and (B) cartilaginous differentiation, in addition to blastematous components. Note the cystic structure lined by entrapped benign epithelium (A).
pulmonary neoplasms are included here. Well-differentiated “fetal” adenocarcinoma of the lung (also known as “pulmonary endodermal tumor” and “pure epithelial blastoma” of the lung) and biphasic pulmonary blastoma are 2 neoplasms that are entirely distinct from PPB, and which themselves may constitute a separate spectrum of lesions.54 Fetal-type adenocarcinoma comprises glands with an endometrioid appearance that simulate the pseudoglandular tubular stage of lung development. Scattered squamoid morules are also a typical part of that tumor (Fig 4A). Biphasic pulmonary blastomas are composed of malignant glands with a fetal-endometrioid appearance, admixed with malignant mesenchymal elements that are primitive in appearance (Fig 4B). Finally, pulmonary “carcinosarcomas” (sarcomatoid carcinomas) represent a mixture of carcinoma and sarcoma-like components, both of which have “adult” phenotypes.55
Fig 4. Pulmonary blastoma. (A) “Monophasic” pulmonary blastoma (“well-differentiated adenocarcinoma of fetal type”), showing crowded “secretory-phase endometrioid-like” glands and morulae. (B). “Biphasic” pulmonary blastoma showing “endometrioid-like” glands and frankly malignant stroma.
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Fig 5. Potential mimics of yolk sac tumor: (A) Epithelioid mesothelioma with papillary structures resembling Schiller-Duval bodies. (B). Epithelioid gastrointestinal stromal tumor with clear cell change mimicking the microcystic pattern of yolk sac tumor.
gastric adenocarcinomas, including one example that also contained choriocarcinoma-like elements.60,61 One case of composite YSC-conventional gastric adenocarcinoma demonstrated the same p53 mutations in both of those components, likely indicating evolution from the same cellular clone.62 Another example showed immunoreactivity for gastrin in the yolk sac-like elements.63 Cases of allegedly primary “pure” YSCs probably represent lesions in which a somatic adenocarcinoma has been overrun by an endodermal sinus tumor-like component. It should be mentioned that reactivity for alphafetoprotein (a common marker for YSC) has been observed immunohistochemically in 50% of typical gastric adenocarcinomas. However, the positive cells in those lesions had an obviously adenocarcinomatous or “hepatoid” appearance and did not resemble yolk sac tumor elements.64
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Anecdotal examples of “pure” YSC in the liver65 have been described; other similar hepatic tumors have included examples of hepatocellular carcinoma66 or hepatoblastoma67 that contained yolk sac elements. One example of YSC originated in the gallbladder of a 36-year-old woman in a background of cholelithiasis.68 Cases of YSC in the urinary bladder69 and urachus70 have been described. After rhabdomyosarcoma and clear cell adenocarcinoma, YSC is the third most common vaginal tumor in pediatric patients; rare cases also occur in the vulva. Most patients with vulvovaginal lesions are ⬍2 years old at diagnosis and the majority are infants. The histologic and immunohistochemical features of those neoplasms are identical to those observed in more “familiar” sites, and they are not admixed with other tumor types.71 Successful treatment with chemotherapy and surgery leads to normalization of previously elevated alpha-fetoprotein levels in serum. Although the prognosis for these patients used to be grim, current treatment has produced 2-year diseasefree survival in up to 95% of cases.72 Primary YSCs have also been described in the endometrium, as “pure” lesions73 and as partners with endometrial adenocarcinoma74 or malignant mixed mullerian tumor.75 An unusual case of YSC in association with colonic endometriosis has also been reported.76 One example of YSC was seen in the penis of a 17-month-old patient,77 and a few additional examples likewise have been described in the prostate,78 including some in patients with Klinefelter’s syndrome.79,80 Finally, it should be remembered that myxoid and cystic changes in other neoplasms may focally simulate the appearance of YSC. We have observed similar changes in testicular sex cord-stromal tumors in pediatric patients, which were initially misinterpreted as yolk sac tumors. Proper tissue sampling and immunophenotyping should obviate these problems.81 TUMORS THAT MAY SIMULATE SEMINOMA/ DYSGERMINOMA One might think it difficult to find a tumor that would recapitulate the appearance of classical seminoma adequately enough to be legitimately confused with it (Fig 6). However, seminomas-dysgerminomas may exhibit secondary changes that complicate their diagnosis and distinction from other tumor types. Such alterations include an unusually prominent lymphoid infiltrate or granulomatous reaction, as well as fibrosis. Furthermore, mediastinal germinomas (seminomas) may be associated with prominent reactive follicular lymphoid hyperplasia or marked internal cystification. Therefore,
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TUMORS THAT CAN IMITATE EMBRYONAL CARCINOMA Undifferentiated large cell carcinomas and poorly differentiated adenocarcinomas of virtually any organ may simulate the microscopic image of embryonal carcinoma (Fig 7). This problem is the most troublesome in reference to metastatic tumors of unknown origin, and its importance is underscored by the significant differences in prognosis in this group of tumors if proper therapy is given. In general, the clinical setting (usually involving a patient under the age of 45 years old) may provide some information that assists in differential diagnosis; however, a high level of suspicion, vis-a`-vis the possibility of a germinal tumor, is paramount in that regard. It should be remembered that except for choriocarcinoma and epithelial elements in teratomas, germ cell tumors are negative for epithelial membrane antigen and immunoreactive for either CD117 (seminoma) or CD30 (embryonal carcinoma). On the other hand, except for CD117 reactivity in some
Fig 6. Potential mimics of seminoma: The large clear cells and collagenous septae with lymphoid infiltrate of infiltrating ductal carcinoma of the breast with (A) medullary features and (B) pheochromocytoma may mimic seminoma/dysgerminoma.
all mediastinal cysts containing lymphoid elements must be thoroughly evaluated to address the possibility of a germinoma. Anaplastic large cell lymphoma and metastatic melanoma represent other tumors that may occasionally be confused with metastatic seminoma. They are readily separable with sufficient clinical information, thorough sampling, and adjunctive pathologic studies, but obviously those data cannot be accrued if the differential diagnosis is too narrow. Sertolicell tumors likewise may simulate the uncommon tubular variant of seminoma; in contrast to the latter lesion, however, stromal neoplasms of the gonads are immunoreactive for inhibin and negative for placental alkaline phosphatase (PLAP) and CD117. Viewing this topic conversely, one must also remember that bona fide “pure” seminomas have also arisen rarely in unusual midline extragonadal locations. These include the prostate82 and the urinary bladder.83
Fig 7. Potential mimics of embryonal carcinoma: (A) Poorly differentiated adenocarcinoma of the lung. (B) Large cell neuroendocrine carcinoma of the lung.
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neuroendocrine carcinomas, somatic tumors typically lack both of the latter markers. IMMUNOPHENOTYPES OF GERM-CELL NEOPLASMS Because immunohistology is so crucial to differential diagnosis in this context, it seems appropriate to reiterate the phenotypic characteristics of the tumors under discussion. Choriocarcinoma is always reactive for cytokeratin (seen best with the reagent CAM 5.2) and for bHCG, and it shows variable staining for epithelial membrane antigen (in 50% of cases) and PLAP. That lesion may also demonstrate labeling for carcinoembryonic antigen and is positive for inhibin in its syncytiotrophoblastic component. Thus, choriocarcinoma is, perhaps, the most difficult of the germinal neoplasms to separate from somatic malignancies. Seminoma (germinoma, dysgerminoma) is virtually always positive (⬎95% of cases) for PLAP, as well as CD117 (c-kit protein), both of which have a cell-membrane-based pattern of immunoreactivity.84 Although roughly 30% of cases contain scattered cells that label for various cytokeratins (as seen with antibodies to CK7, CAM 5.2, AE1/AE3, and “wide-spectrum” keratin),85,86 diffuse strong staining with those reagents essentially excludes a diagnosis of pure seminoma. Seminomas consistently lack immunoreactivity for epithelial membrane antigen, alpha-fetoprotein, and CD30, although individual tumor cells may occasionally stain for the last of those markers.85 Yolk sac tumors are always reactive for PLAP and cytokeratin (with CAM 5.2). They are also positive for alpha-fetoprotein, although reactivity for that determinant may be focal. YSC lacks CD3085 and is negative for epithelial membrane antigen. Embryonal carcinoma is always positive for cytokeratin (using CAM 5.2), PLAP, and CD30 (Ki-1 antigen; recognized by the monoclonal antibody Ber-H2), but is usually negative for epithelial membrane antigen.86 Scattered cells may label for alpha-fetoprotein and bHCG, but that is unusual. Teratomas express epithelial markers (cytokeratins and epithelial membrane antigen) in their epithelial components, which are also positive for carcinoembryonic antigen in many cases. Mesenchymal elements are positive for vimentin and may also express more specific lineage-related markers (eg, desmin, S100 protein), depending on the particular morphological constituents of the lesion. Neuroectodermal differentiation is reflected by the presence of positivity for neuron-
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specific enolase, synaptophysin, CD56, and neurofilament proteins. Again, it is emphasized that although PLAP may be present in some somatic carcinomas (10%-15% of cases); the latter lesions are also positive for epithelial membrane antigen.87-89 That combination of results generally militates against a diagnosis of germ cell tumor, with the possible exception of choriocarcinoma. REFERENCES 1. Hanna NH, Ulbright TM, Einhorn LH: Primary choriocarcinoma of the bladder with the detection of isochromosome 12p. J Urol 167:178, 2002 2. Zettl A, Konrad MA, Polzin S, et al: Urothelial carcinoma of the renal pelvis with choriocarcinomatous features: Genetic evidence of clonal evolution. Hum Pathol 33:1234-1237, 2002 3. Liu AY, Chan WY, Ng E, et al: Gastric choriocarcinoma shows characteristics of adenocarcinoma and gestational choriocarcinoma: A comparative genomic hybridization and fluorescence in situ hybridization study. Diagn Mol Pathol 10:161-165, 2001 4. Djewitzki WS: Uber einen Fall von Chorionepithelioma der Harnblase. Virchows Arch 178:451-464, 1904 5. Young RH, Eble JN: Unusual forms of carcinoma of the urinary bladder. Hum Pathol 22:948-965, 1991 6. Campbell PA, McKendrick J: Choriocarcinoma of the urinary bladder. Aust N Z J Surg 69:533-537, 1999 7. Sievert K, Weber EA, Herwig R, et al: Pure primary choriocarcinoma of the urinary bladder with long-term survival. Urology 56:856, 2000 8. Martin JE, Jenkins BJ, Zuk RJ, et al: Human chorionic gonadotrophin expression and histological findings as predictors of response to radiotherapy in carcinoma of the bladder. Virchows Arch A Pathol Anat Histopathol 414:273-277, 1989 9. Vahlensieck W Jr, Riede U, Wimmer B, et al: Beta-human chorionic gonadotropin-positive extragonadal germ cell neoplasia of the renal pelvis. Cancer 67:3146-3149, 1991 10. Grammatico D, Grignon DJ, Eberwein P, et al: Transitional cell carcinoma of the renal pelvis with choriocarcinomatous differentiation. Immunohistochemical and immunoelectron microscopic assessment of human chorionic gonadotropin production by transitional cell carcinoma of the urinary bladder. Cancer 71:1835-1841, 1993 11. Mihatsch MJ, Bleisch A, Six P, et al: Primary choriocarcinoma of the kidney in a 49-year-old woman. J Urol 108:537-539, 1972 12. Lurain JR: Treatment of gestational trophoblastic tumors. Curr Treat Options Oncol 3:113-124, 2002 13. Bradley CS, Benjamin I, Wheeler JE, et al: Endometrial adenocarcinoma with trophoblastic differentiation. Gynecol Oncol 69: 74-77, 1998 14. Shintaku M, Kariya M, Shime H, et al: Adenocarcinoma of the uterine cervix with choriocarcinomatous and hepatoid differentiation: report of a case. Int J Gynecol Pathol 19:174-178, 2000 15. Nguyen CP, Levi AW, Montz FJ, et al: Coexistent choriocarcinoma and malignant mixed mesodermal tumor of the uterus. Gynecol Oncol 79:499-503, 2000 16. Khuu HM, Crisco CP, Kilgore L, et al: Carcinosarcoma of the uterus associated with a nongestational choriocarcinoma. South Med J l 93:226-228, 2000
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