Epithelioid trophoblastic tumor: Morphological and immunohistochemical study of three lung lesions

Epithelioid Trophoblastic Tumor: Morphological and Immunohistochemical Study of Three Lung Lesions SHUJI HAMAZAKI, MD, SHU NAKAMOTO, MD, TAKESHI OKINO, MD, CHOUTATSU TSUKAYAMA, MD, MASAHARU MORI, MD, KOHJI TAGUCHI, MD, AND SHIGERU OKADA, MD Epithelioid trophoblastic tumor (ETT) is a term proposed for an

gen was positive in rare multinucleate giant cells, and in 1 case, tumor

unusual variant of trophoblastic tumor that is closely related to choriocarcinoma but shows monomorphic growth of highly atypical

cells showed diffuse positivity for placental alkaline phosphatase. Because E T r has a remarkably epithelioid appearance in cytological and architectural features, differentiation from the epithelial malig-

trophoblastic cells instead of the typical dimorphic pattern of choriocarcinoma. We report here 3 cases of ETT, all of which were lung lesions probably originating from uterine trophoblastic disease. The antecedent pregnancies of the 3 cases were hydatidiform mole, invasive mole, and term pregnancy, respectively. The tumors were c o m p o s e d of highly atypical mononucleate cells, which mainly involved alveolar spaces, forming nests with central eosinophilic necrosis. Multinucleate giant cells were found within the nests, but they were fewer in number than in typical choriocarcinoma. The tumors were not associated with extensive hemorrhage or necrosis, except for 1 case, in which the ETT was combined with typical dimorphic choriocarcinoma. Immunohistochemically, multinucleate giant cells and occasional mononucleate tumor cells showed positivity for human chorionic gonadotropin. Staining for human placental lacto-

Gestational choriocarcinomas show a dimorphic plexiform pattern composed of clusters of cytotrophoblastic cells separated by streaming masses of syncytiotrophoblastic cells, recapitulating the pattern of trophoblastic growth in early placental development. 1,2 In 1982, Mazur et aP n o t e d an unusual lung t u m o r composed of m o n o m o r p h i c growth of atypical cells in autopsy material from patients who had died after intensive chemotherapy for gestational chorioearcinoma. 3 Mazur later analyzed 2 similar lung tumors resected from patients given multiple courses of c h e m o t h e r a p y for choriocarcinoma. 4 The cut surface of these tumors was white and devoid of extensive h e m o r r h a g e or necrosis. T h e tumors were composed of predominantly m o n o t o n o u s growth of atypical monocucleate cells, which infiltrated mainly alveolar spaces, forming solid nests and cords. T h e center of the tumoral nests often contained eosinophilic central necrotic debris, and few multinucleate syncytiotrophoblastic cells were intermingled with mononucleate t u m o r cells. Immunohistoehemical studies showed the production of h u m a n chorionic gonadotro-

From the Department of Pathology, Okayama University Hospital, Okayama; Department of Pathology, Tottofi Prefectural Hospital, Tottori; Department of Pathology, Kurashiki Central Hospital, Kurashiki; Department of Nursing, Faculty of Health and Welfare Science, Okayama Prefectural University, Sohja; and the Department of First Pathology, Okayama University Medical School, Okayama, Japan. Accepted for publication July 1, 1999. Address correspondence and reprint requests to Shuji Hamazaki, MD, Department of Pathology, Okayama University Hospital, 2-5-1 Shikata, Okayama 700-8558, Japan. Copyright © 1999 by W.B. Saunders Company 0046-8177/99/3011-0009510.00/0

nancies is problematic. Trophoblasfic markers are frequently expressed in nontrophoblastic tumors, and reactivity for those markers alone is not sufficient for exclusion of other tumors. Rather, evidence of ETT comes from a combination of morphological features, immunohistochemical study, and clinical history. HUM PATHOL30:13211327. Copyright © 1999 by W.B. Saunders Company Key words: epithelioid trophoblastic tumor, choriocarcinoma, immunohistochemistry. Abbreviations: ETT, epithelioid trophoblastic tumor; hCG, human chorionic gonadotropin; hPL, human placental !actogen; piAlp, placental alkaline phosphatase; SP1, pregnancy-specific beta-l-glycoprotein; CT, computed tomography; MGC, multinucleate giant cell.

pin (hCG) in the multinucleated syneytiotrophoblastic cells and some of the m o n o n u c l e a t e cells. Ultrastrueturally, the m o n o n u c l e a t e t u m o r cells possessed features intermediate between those of cytotrophoblasts and syncytiotrophoblasts, but different from those of the intermediate trophoblast of the placental site trophoblastic tumors. Based on these observations, Mazur et al coneluded that these tumors were metastatic gestational choriocarcinoma with an unusual m o n o m o r p h i c pattern, which presumably e m e r g e d because of the influence of chemotherapy. 4 Jones et al 5 r e p o r t e d identical m o n o m o r p h i c trophoblastic tumors in 6 cases of chemotherapy-resistant p u l m o n a r y metastases of gestational choriocarcinoma. Mazur and Kurman 1 recognized occurrence of similar tumors in the uterus, and proposed the term epithelioid trophoblastic tumor (ETT) for this monomorphic variant of gestational choriocarcinoma. Recently, Shih and Kurman 6 reported 14 additional cases of ETT, most of which were uterine tumors. In contrast to lung lesions, uterine ETT developed without a backg r o u n d of prior c h e m o t h e r a p y for choriocarcinoma, and has features ofchorion laeve type intermediate trophoblast. All of the reported cases of ETT were regarded as gestational in origin, but a testicular germ cell tumor showing m o n o m o r p h i c proliferation of trophoblasts similar to ETT has recently b e e n reported. 7 We describe 3 cases of ETT, all of which were lung lesions that presumably originated from intrauterine gestations.

MATERIALS AND METHODS All 3 cases were s e e n primarily by t h e authors. Medical r e c o r d s were reviewed for t h e clinical p r e s e n t a t i o n a n d

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clinical follow-up. Case 3 was previously included in the report of Shih and Kurman. 6 Tissue for light microscopy was fixed in 10% formalin and paraffin embedded in a standard manner. Routine sections were stained with hematoxylin and eosin, elastic van Gieson, and periodic acid-Schiff stains. Selected sections were immunostained with antibodies against cyt0keratin (AE1/AE3 and anti-cytokeratin 18), epithelial membrane antigen, carcinoembryonic antigen, vimentin, desmin, S100, hCG, human placental lactogen (hPL), placental alkaline phosphatase (plAIP), pregnancy-specific beta-l-glycoprotein (SP1), alpha-fetoprotein, alpha subunit of inhibin, leukocyte common antigen, and CD68 (Table 1). Antigen retrieval was performed by autoclaving in citrate buffer (10 mmol/L, pH 6.0), and sections were visualized using a streptavidin-biotin immunoperoxidase reagent kit (DAKO, Carpenteria, C~). Appropriate positive and negative controls were tested along with the tumors. For electron microscopy, small formalin: fixed tissues from case 1 were refixed in paraformaldehydeglutalaldehyde solutions and processed routinely.

RESULTS

'

Clinical Findings

Case 1. A 47-year-old J a p a n e s e w o m a n was referred to the hospital for an operation for breast cancer. In the course of preoperative evaluation, an a b n o r m a l shadow on the right u p p e r lung was p o i n t e d out. H e r medical history was significant for u n d e r g o i n g hysterectomy and several courses of c h e m o t h e r a p y for invasive mole at the age of 44. She u n d e r w e n t left mastectomy and lymph n o d e dissection for the breast cancer, and pathological examination indicated invasive ductal carcinoma. After the breast surgery, the size of the lung nodule gradually increased, a n d slight elevation of the s e r u m level of the beta subunit of h C G was d e m o n strated (0.70 n g / m L ) . Thoracoscopic resection of the right u p p e r lung t u m o r was p e r f o r m e d u n d e r a diagnosis of lung metastasis of breast cancer. T h e patient is alive and has no evidence of disease 2 years after the operation.

TABLE 1, The Immunohistochemical Antibodies Used Antibody

Source

Dilution

Anti-cytokeratin (AE1/AE3)

Lipshaw-Immunon (Pittsburgh, PA) DAKO(Carpinteria, CA) DAKO DAKO

1:50 1:25 1:50 1:500

DAKO DAKO DAKO

1:50 1:100 1:500

DAI~O

1:500

DAKO DAKO

1:500 1:500

DAKO DAKO Serotec(Oxford, UK) DAKO DAKO

1:100 1:500 1:250 1:100 1:100

Anti-cytokeratin 18 (DC10) Anti-EMA (E29) Anti-CEA (p01yclonal, rabbit) Anti-vimentin (V9) Anti-desmin (DE-R11) Anti-S100 (polyclonal, rabbit) Anti-hCG (polyclonal, rabbit) Anti-hPL (polyclonal,rabbit) Anti-plA1P (polyclonal, rabbit) Anti-SP1 (polyclonal,rabbit) Anti-AFP (polyclonal, rabbit) Anti-inhibin c~subunit (R1) Anti-LCA (2Bll -F PD7/26) Anti-CD68 (KP1)

Case 2. An a b n o r m a l lung shadow was p o i n t e d out in a 32-year-old J a p a n e s e w o m a n during a routine chest r a d i o g r a p h examination. She was gravida 3, para 1, and m o l a r pregnancies at the ages of 24 and 27 were evacuated by curettage. The patient had no symptoms or complaints, and all laboratory p a r a m e t e r s were normal. Chest r a d i o g r a p h and c o m p u t e d t o m o g r a p h y (CT) examinations showed a 3-cm mass in the right u p p e r lobe. She u n d e r w e n t right u p p e r lobectomy for the suspicion of lung cancer. T h e s e r u m h C G level was not evaluated before or after the operation. She has no evidence of r e c u r r e n t t u m o r after 3 years of follow-up. Case 3. A 42-year-old J a p a n e s e gravida 2, para 2 w o m a n presented with hemoptysis and cough. She was p r e m e n o p a u s a ! and had no history of trophoblastic disease or miscarriage. Chest radiograph and CT showed a 5-cm mass in the left u p p e r lobe. CT examinations disclosed small nodules in the right lung and the liver. Because of the gradual e n l a r g e m e n t of the mass, she u n d e r w e n t left u p p e r lobectomy and lymph n o d e dissection u n d e r a diagnosis of lung cancer. After the operation, an elevated s e r u m level of the beta subunit o f h C G (1,300 n g / m L ) was demonstrated. Pelvic examinations and a b d o m i n a l ultrasonography showed no abnormalities. After several courses of chemotherapy, the nodules of the right lung and the liver h a d disappeared, and the s e r u m level of h C G r e t u r n e d to normal. She had no evidence of disease 2 years after the operation. P a t h o l o g i c Findings

Gross Pathology. T h e tumors in cases 1 and 2 were well-circumscribed nodules of firm consistency with white-yellow cut surface. T h e m a x i m u m t u m o r diameter was 1.5 cm in case 1 and 2.5 cm in case 2. In b o t h casesl neither h e m o r r h a g e n o r necrosis was observed on gross inspection. T h e t u m o r in case 3 was an oval nodule of soft to firm consistency measuring 5 × 5 X 7 cm. On cut section, a reddish-brown h e m o r r h a g i c mass measuring 4 cm in d i a m e t e r was s u r r o u n d e d by a white-colored flattened lesion a b o u t 1 cm in thickness (Fig 1). Light Microscopy. T h e t u m o r histology c o m m o n to all cases was proliferation of atypical m o n o n u c l e a t e cells involving mainly alveolar spaces, which resulted in nests of t u m o r cells encircled by septal connective tissue (Figs 2 to 4). T h e central portion of the nests frequently contained dense eosinophilic necrotic debris and PASpositive hyaline material (Fig 2). A few d e g e n e r a t i n g t u m o r cells were mixed with the necrotic material. In o t h e r areas, the t u m o r cells f o r m e d solid cords and nests with scarce necrotic foci, and this solid growth pattern p r e d o m i n a t e d in cases 2 and 3 (Fig 3). Occasionally, the t u m o r infiltrated along bronchial mucosa, but vascular invasion was not seen. EVG staining showed preservation of septal elastic fibers within the tumor, confirming that the t u m o r cells grew mostly by filling the alveolar spaces. T h e p r e d o m i n a n t t u m o r cells had a m o d e r a t e a m o u n t of a m p h o p h i l i c cytoplasm, distinct cell borders, and large vesicular oval nuclei with p r o m i n e n t nucleoli

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FIGURE I . Gross specimen of the lung tumor in case 3, The tumor consisted of a white solid lesion encircling a hemorrhagic mass,

FIGURE 3. In case 2, solid cord and nests of the mononuclear cells predominated. (Original magnification x240,)

(Figs 3, 4). Mitotic figures were n u m e r o u s within these cells. T h e m o r p h o l o g y of the t u m o r cells and nested pattern gave the t u m o r an epithelioid appearance. In addition, a few multinucleate giant cells (MGCs) resembling syncytiotrophoblasts were intermingled with the m o n o n u c l e a t e t u m o r cells. They had pyknotic nuclei and dense eosinopholic cytoplasm and lacked vacuoles (Figs 3, 4). In cases 2 and 3, the MGCs were less frequent and had fewer nuclei than those of case l. Although most of the MGCs were mixed haphazardly with m o n o n u c l e a r cells, 2-cell layers consisting of mononucleate tumor cells and MGCs, reminiscent of trophoblastic villus, were observed focally along the thickened basement m e m b r a n e in cases 1 and 3 (Fig 5). Stromal m o n o n u c l e a r inflammation was more or less observed in all of the tumors and was most conspicuous in case 3. Hyalinization of the stroma a r o u n d the tumoral nests was observed focally in cases 2 and 3 (Fig 3). Neither diffuse h e m o r r h a g e n o r necrosis was f o u n d in the tumors, except for case 3. In case 3, the grossly hemorrhagic area of the tumor c o r r e s p o n d e d to choriocarcinoma with a typical dimorphic pattern (Fig 6), and

the choriocarcinomatous c o m p o n e n t m e r g e d with the epithelioid-appearing t u m o r described above at their boundary. No choriocarcinomatous c o m p o n e n t was f o u n d in cases 1 and 2. Regional lymph nodes were removed in cases 2 and 3, and no nodal metastasis was found. Immunohistochemistry. The results of the immunohistochemistry are summarized in Table 2. Generally, strongly positive staining for hCG was detected in some but not all of the MGCs in all cases (Fig 7A). In addition, few m o n o n u c l e a t e t u m o r cells also showed positive reactivity for hCG. T h e r e was a weakly positive reaction for hPL, SP1, and inhibin c~ in few MGCs in cases 1 and 3. In case 3, most of the t u m o r cells in the epithelioidappearing area showed positive m e m b r a n o u s staining for plA1P (Fig 7B), whereas the tumor cells in cases 1 and 2 were entirely negative for plAlE The typical choriocarcinomatous c o m p o n e n t in case 3 showed diffuse positive staining for hCG, SP1, and inhibin c~, and focal positive staining f o r hPL and plAlE Staining for cytokeratin AE1/AE3 and cytokeratin 18 showed diffuse positive reactivity in all tumors tested.

FIGURE 2. Nests of the tumor in case 1 contained a thin rim of tumor cells and central eosinophilic necrotic material, (Original magnification x 150.)

FIGURE 4. A few MGCs intermingled with mononuclear tumor ceils. (Case 3. Original magnification x360.)

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TABLE2. Immunohistochemical Features of ETTof Lung Case 3 Case 1

FIGURE 5.

Two-cell layers consisting of MGCs and mononucle-

ate tumor cells lined the alveolar septum. (Case 1; Original magnification x360,) Weakly positive staining of CEA and EMA was n o t e d in rare m o n o n u c l e a r t u m o r cells. M1 of the MGCs were negative for CD68 and LCA.

Electronmicroscopy Electron microscopic observation p e r f o r m e d in case 1 identified 2 populations o f t u m o r cells. The p r e d o m i n a n t cells had moderate amounts of cytoplasm and a single oval nucleus with conspicuous nucleolus and a b u n d a n t euchromatin (Fig 8A). The cytoplasm contained free ribosomes, glycogen granules, dilated endoplasmic reticulum, small vesicles, and bundles of intermediate filaments. These m o n o n u c l e a t e cells were closely packed or lined basement m e m b r a n e and were j o i n e d by multiple desmosomes. Cells situated at the periphery of the nests were focally invested by thick basement membrane, and rare cells had a tew short microvilli at the free surface. The second type of cell was the MGC, characterized by increase in electron density of the cytoplasm (Fig 8B). The nuclei of the MGCs were p l e o m o r p h i c and had a b u n d a n t h e t e r o c h r o m a t i n and inconspicuous nucleoli. The cytoplasm of MGC con-

FIGURE 6. In case 3, typical choriocarcinoma was found adjacent to ETT.(Original magnification x 160.)

Case 2

MTC

MGC

MTC

Cytokeratin AE1/AE3 Cytokerati n 18 EMA

++ ++ p+

++ p+ -

++ ND p+

CEA Vimentin Desmin S100 HCG

p+ . . . p+

HPL

-

PIA1P

.

sP1

-

AFp Inhibin ct LCA CD68

. . .

-

p+

. . .

. . .

p+ p+ .

p+ . -

. p+ .

. . .

.

. p+ ND . . . . . .

ETT

MGC MTC

MGC

CT

ST

++ p+ -

++ p+ -

++ + -

-

-

p+ p+ p+ -

++ p+ p+ +

p+

+

++ ND -

++ ++ p+

. . . p+ -

p+ . . . . . . p+ + . . . . . .

. ND . .

CC

. . . p+ p+ + p+ . p+ . .

NOTE. In case 3, results of E T T a n d choriocarcinqmatous c o m p o n e n t were separately evaluated. Scores: + + , positive staining in m o r e t h a n 80% of t u m o r cells; +, positive staining in 10% to 80% o f t u m o r cells; p + positive staining u p to 10% of t u m o r cells; - , n o staining. Abbreviations: ETT, epithelioid trophoblastic tumor; CC, choriocarcinoma; MTC, m o n o n u c l e a t e t u m o r ceils; MGC, multinucleate giant cells; CT, cytotrophoblast; ST, syncytiotrophoblast; ND, n o t done.

tained a b u n d a n t cytoplasmic organeUa and vesicles. Where the MGCs faced an open space, a b u n d a n t microvilli were found. Most of the MGCs were mixed with the m o n o n u c l e a t e t u m o r cells, and few desmosomes were f o r m e d between the 2 types of t u m o r cells. Focally, 2-cell layers of the MGCs and m o n o n u c l e a t e t u m o r cells were n o t e d along the basement membranes, which recapitulated villous trophoblastic layers (Fig 8A).

DISCUSSION The tumors described in this report showed lightmicroscopic, immunohistochemical, and ultrastructural features similar to those of previously reported p u l m o n a r y lesions of ETT. 1,3-5Whereas most of the lung lesions of ETT were e n c o u n t e r e d in the patients with persistent metastatic tumors after intensive chemotherapy for choriocarcinoma, all o f the present tumors developed as lung nodules without apparent intrauterine lesions of choriocarcinoma. Gestadonal choriocarcinoma may be associated with any form of pregnancy, and most of the lesions are preceded by abnormal gestations such as molar pregnancies or spontaneous abortion. 1,2,s Development of choriocarcinoma in extrauterine locations is a not uncomm o n event after these abnormal pregnancies and has been described as heterotopic choriocarcinoma by Hertig and Manse!l. s In these cases, it is speculated that the choriocarcinoma in the uterus u n d e r w e n t regression after metastasizing to distant sites, or the tumors

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FIGURE 7. (A) Some of the MGCs in ETT stained positively for hCG. (Case 1. Original magnification x360.) (B) In case 3, immunoreactMty for plALP is observed in most of mononucleate tumor cells and MGCs. (Original magnification x240,)

arose f r o m d e p o r t a t i o n of a benign trophoblast that had subsequently dedifferentiated. L2 In the c u r r e n t cases, a n t e c e d e n t m o l a r p r e g n a n c y had b e e n n o t e d in cases 1 and 2, a n d these histories provide s u p p o r t that the tumors were of trophoblastic origin. In case 3, history of m o l a r p r e g n a n c y or miscarriage was lacking, but a m o n o m o r p h i c t u m o r similar to those of cases 1 and 2 s u r r o u n d e d a typical d i m o r p h i c choriocarcinoma, suggesting that E T T e m e r g e d f r o m the choriocarcinomatous c o m p o n e n t . Rarely, extrauterine choriocarcinoma develops without history of a b n o r m a l pregnancy, and has b e e n i n t e r p r e t e d as a p r i m a r y somatic tumor. However, these tumors arising in w o m e n of reproductive age are rather r e g a r d e d as heterotopic gestational choriocarcinomas derived f r o m a n t e c e d e n t t e r m pregnancies or u n n o t i c e d miscarriages t h r o u g h abovem e n t i o n e d mechanism. 1 Thus, d i m o r p h i c choriocarcin o m a and E T T in case 3 can be r e g a r d e d as gestational

FIGURE 8. (A) Mononucieate tumor cells and MGCs form 2 cell layers. Mononucleate tumor cells have undifferentiated appearance with fewer cytoplasmic organella. (Case 1; original magnification x3,200.) (B) MGC has complex cytoplasm and microvilli, (Case 1; Original magnification x5,000.)

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VoLume30, No. 11 (November 1999)

in its origin, despite the apparent lack of history of abnormal pregnancy. Although dimorphic growth of the cytotrophoblastic and syncytiotrophoblastic cells is the hallmark of the choriocarcinoma, focal overgrowth of either of the 2 components is encountered in some tumors. 1 In this regard, ETT might be interpreted as choriocarcinoma that shows predominant growth of cytotrophoblastic cells. However, the mononuclear tumor cells seen in the ETT have distinctive immunohistochemical and ultrastructural features as compared with nonneoplastic or neoplastic cytotrophoblasts. In normal villi, cytotrophoblasts are proliferating stem cells with primitive morphological features, and possess virtually no specific immunohistochemical markers. 9,1° The syncytiotrophoblasts have differentiated morphological and functional features, such as complex cytoplasmic architecture, formation of microvilli, and production of hGG and hPL. Expression of membranous plAlP is also limited to syncytiotrophoblasts. Because the syncytiotrophoblasts are terminally differentiated syncytia with no proliferative ability, their growth and regeneration depend on syncytial fusion of the cytotrophoblasts. Fractions of villous cytotrophoblasts undergo maturation and finally incorporate with the outer syncytial layer.9,1°Cytotrophoblasts that have encroached deeply in the decidua lose the ability to form syncytiotrophoblasts and enter another pathway of differentiation. Those extravillous trophoblasts with increased intermediate filaments, nuclear pleomorphism, and negative hCG and positive hPL immunophenotype, are called intermediate trophoblast or extravillous cytotrophoblast. 9,1° Considering occasional expression of hCG and differentiated cytoplasmic ultrastructures, some of the multinucleate giant cells in the ETT are presumed to have the phenotype of differentiated syncytiotrophoblasts. The mon0nucleate tumor cells of ETT show occasional:expression of hCG, and have rather complex q)toplasmic ultrastructural architectures as compared with normal cytotrophoblasts. Based on these features, Mazur ~,4 concluded that mononucleate tumor cells correspond to trophoblastic cells with partially differentiated features intermediate between those of cytotrophoblasts and syncytiotrophoblasts, but different from those of intermediate trophoblasts of implantation site2 ,4 Immunohistochemical and electronmicroscopic observations of the current cases concurred with Mazur's results, and diffuse positive staining of cytokeratin 18 observed in mononuclear tumor cells further supports their differentiated nature. Recently, Shih and Kurman 6 analyzed 14 cases of ETT and showed that the neoplastic cells of ETT are closely related to chorionic-type intermediate trophoblast of chorion laeve. 6 Although our study could not verify their hypothesis directly, some morphological features, such as 2 cell layers of mononuclear cells and MGCs, rather suggest villous trophoblastic differentiation in the neoplastic cells. This discrepancy can be interpreted as the result of the diverse phenotypes the tumor cells represent. Alternatively, the difference in the site of the tumor development might induce pheno-

typi c alteration s, because most of the ETT Shih an{t Kurman analyzed w e r e w i m a r y uterine lesi0ns. 6 The relationshi p between pulmonary ETT and uterine ETT n e e d s further elucidation. Our current contention is that ETT is a dedifferentiated variant of choriocarcinoma, which has lost n0t 0nly structural organization of the 2 trophoblastic Components, but also the regulation of the trophoblastic differentiation. Since the first report of pulmonary ETT as a variant form of choriocarcinoma, only a few cases have been documented in the literature. 3-5 Probably the tumor is confused with other types of carcinomas because of its epithelioid growth pattern and cytologic features. 4 The differentiation of ETT from other epithelial tumors is not a straightforward task, particularly in the cases of pulmonary lesions. Although the presence of MGCs producing hCG is prerequisite for the diagnosis of ETT, the extent of hCG expression is variable among the cases, and reactivity for other trophoblastic markers is also variable. Conversely, hCG and other trophoblastic markers are frequently expressed in a variety of nontrophoblastic tumors. 11,12 In particular cases, carcinomas contain giant cells with positive staining for hCG, suggesting focal syncytiotrophoblastic differentiation. Moreover, most of the epithelial markers are commonly expressed in both epithelial and trophoblastic tumors. Thus, immunohistochemistry helps little in the differential diagnosis of the ETT. Although ETT has some resemblance to squamous cell carcinoma due to nested morphology and eosinophilic material within the nest, careful observation shows several differences from ordinary carcinomas. First, the mononuclear tumor cells do not show the cytoplasmic eosinophilia or intercellular bridges frequently observed in differentiated squamous cell carcinoma. Moreover, infiltration of alveolar spaces by highly atypical tumor cells and preservation of the alveolar septa are not common features of invasive carcinoma. In this context, positive immunostaining for cytokeratin 18 in the tumor cells will support the diagnosis of ETT, because squamous cell carcinomas are generally negative for cytokeratin 18. 6 Meanwhile, some electronmicroscopic features of ETT, such as microvilli and polarity of tumor cells, suggest a diagnosis of adenocarcinoma. These features, however, are also compatible with the diagnosis of trophoblastic tumor, because villous trophoblastic ultrastructures are fairly comparable to those of epithelial glandular cells. Rather, the consistent expression of these differentiated features in MGCs and the primitive phenotype of the mononucleate cells indicate trophoblastic nature of the neoplastic cells. Moreover, the characteristic light-microscopic appearance of the ETT would easily dismiss the diagnosis of ordinary adenocarcinoma. Other pulmonary tumors, such as large cell carcin o m a with MGCs and bronchial gland tumors, would be also differentiated from ETT on morphological grounds. In summary, the morphological characteristics, as well as hCG-p0sitive MGCs, and careful review of the clinical history, provide the evidence of ETT.

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Achnowledgment. T h e authors thank Dr RJ. K u r m a n ( D e p a r t m e n t of Gynecology-Obstetrics and Pathology, School of M e d i c i n e , J o h n s Hopkins University) for his valuable advice r e g a r d i n g the diagnosis of case 3. REFERENCES 1. Mazur MT, Kurman RJ: Gestational trophoblastic disease, in Kurman RJ (ed): Blaustein's Pathology of the Female Genital Tract. NewYork, NY, Springer-Verlag, 1994, pp 1049-1096 2. Benirschke K, Kaufmann P: Pathology of the Human Placenta. NewYork, NY, Springer-Verlag, 1990, chap 28 3. Mazur MT, LurainJR, BrewerJI: Fatal gestational choriocarcinoma: Clinicopathologic study of patients treated at a trophoblastic disease center. Cancer 50:1833-1846, 1982 4. Mazur MY: Metastatic gestational choriocarcinoma: Unusual pathologic variant following therapy. Cancer 63:1370-1377, 1989 5. Jones WB, Romain K, Erlandson RA, et ah Thoracotomy in the management of gestational choriocarcinoma: A clinicopathologic study. Cancer 72:2175-2181, 1993

6. Shih IM, Kurman RJ: Epithelioid trophoblastic tumor: A neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. AmJ Surg Patho122:1393-1403, 1998 7. Ulbright TM, Young RH, Scully RE: Trophoblastic tumors of testis other than classic choriocarcinoma: "Monophasic" choriocarcinoma and placental site trophoblastic tumor: A report of two cases. AmJ Surg Patho121:282-288, 1997 8. Hertig AT, Mansell H: Tumors of the female Sex Organs. Part 1. Hydatidform mole and choriocarcinoma, in Atlas of Tumor Pathology, Fascicle 33, Washington DC, Armed Forces Institute of Pathology, 1956 9. Gersell DJ, IO'aus FT: Diseases of the placenta, in Kurman RJ (ed): Blaustein's Pathology of the Female Genital Tract. New York, NY, Springer-Verlag, 1994, pp 975-1048 10. Benirschke K, Kaufmann P: Pathology of the Human Placenta. NewYork, NY, Springer-Verlag, 1990, chaps 3 and 9 11. Boucher LD, Yoneda K: The expression of trophohlastic cell markers by lung carcinomas. HuM PA'rI~OL26:1201-1206, 1995 12. Moch H, Oberholzer M, Dalquen P, et ah Diagnostic tools for differentiating between pleural mesothelioma and lung adenocareinoma in paraffin embedded tissue. Part I: Immunohistochemical findings. Virchows Arch A 423:19-27, 1993

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