Primary pulmonary α-fetoprotein-producing malignant germ cell tumor

Case Studies PRIMARY PULMONARY a-FETOPROTEIN-PRODUCING

MALIGNANT GERM CELL TUMOR

STEPHEN HUNTER, MD, KARLENE HEWAN-LOWE, MD. AND MICHAELJ. COSTA, MD

We are reporting the clinical and pathologic features oJ a primary, pulmonary, malignant germ ~11 tumor associated with a marked elevation of serum cy-fetoprotein (38.427 nglmL) and lactate dehydrogenase activity (756 UIL). in a 26year-old female. This controversial_ rare neoplasm has not been extensively discussed in the pathology literature. We emphasize the clinical jmportance of establishing this diagnosis in view of the favorable response to chemotherapy shown by malignant germ cell tumors. Hrar PAT~IOI. 21:1074-1076. 0 1990 by W.B. Saunders Company.

Extragonadal germ cell tumors are uncommon (2% to 3%’ of all germ cell tumors). They occur in the anterior mediastinum, retroperitoneum, pineal gland, and the presacral region primarily before the sixth decade of life.‘,’ A few cases have been reported to originate in the lung. Kuhn and Weissbach’ reported a 42-year-old male with a mixed mature and immature teratoma with embrvonal carcinoma and components of yolk sac tumor. His serum a-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactate dehydrogenase activity (LDH) were normal. Feun et al” presented another case of mixed seminoma and embryonal carcinoma in a 41-year-old male who underwent an orchiectomy which showed no neoplasm. Their case also failed to show elevated serum AFP levels. Jamieson and McGowan3 reported an endobronchial teratoma which showed no immature elements or malignant germ cell elements in a 22-year-old female who apparently had chest x-ray findings of this same tumor 17 years previously. She did well following complete excision. Their review of the literature uncovered three previously reported cases with identical pathologic findings3 We describe a primary pulmonary AFP-producing malignant germ cell tumor composed predominantly of embryonal carcinoma with a minor component of yolk sac tumor. REPORT

OF A CASE

A 26year-old previously healthy woman presented to the emergency room with fever and an acute abdomen. Emergency exploratory surgery revealed a left tuboovarian abscess with bilateral acute salpingitis which led to a total abdominal hysterectomy with bilateral salpingooophorectomy. Pathologic evaluation of the specimen, including complete histologic evaluation of both ovaries, confirmed the clinical diagnosis and showed no neoplasm. The patient’s preoperative chest x-ray showed a rounded right middle lobe density which did not resolve postoperatively with antibiotic treatment. Computed tomo-

Received October 3 1, 1989 from the Department of Anatomic Pathology, Emory University School of Medicine, Atlanta, GA. Accepted for publication January 10, 1990. Key words: Malignant germ cell tumor, embryonal carcinoma, yolk sac tumor, primary lung carcinoma, a-fetoprotein Address correspondence and reprint requests to Michael J. Costa, MD, Department of Anatomic Pathology, Grady Memorial Hospital, 80 Butler St, SE, Atlanta, CA 30335-3801. 0 1990 by W.B. Saunders Company. 0046~8177/90/21 lo-0013$5,00/O

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graphic scan and magnetic resonance imaging of the chest showed a 5-cm soft-tissue mass in the right minor fissure which extended into the left atrium through the right pulmonary vein. The mediastinum was otherwise unremarkable. Computed tomographic scan-directed fine needle aspiration biopsy with preparation of a cell block showed a malignant glandular neoplasm with histologic and immunohistochemical features of an embryonal carcinoma with areas of volk sac differentiation. The’patient underwent thoractomy through a median sternotomy incision which showed a large right lung tumor with extension into the left atrium. The anterior mediastinum was not involved. Following cardiopulmonary bypass, the surgeon performed a right pneumonectomy along with partial resection en bloc of the left atria1 tumor and a small attached portion of the left atria1 wall. The procedure was complicated by a left-sided cerebral infarct in the distribution of the middle cerebral artery. The preoperative serum level of AFP, 38,427 ng/mL (O-15). fell to 1,962 ng/mL postoperatively. Preoperative serum LDH, 756 U/L (112-220), fell to 322 U/L postoperatively. One month following surgery, the patient was started on a chemotherapy protocol active against extragonadal germ cell tumors (cisplatin and etoposide). Nine months following surgery the patient was doing well, and her postoperative AFP level of 1,962 ng/mL (presumably due to the residual left atria1 tumor) has fallen to 25.0 ng/mL with chemotherapy. PATHOLOGIC

FINDINGS

We received a right pneumonectomy specimen showing a single &cm friable tumor involving the lower portion of the upper lobe and the upper portion of the lower and middle lobes. The tumor extended through the right pulmonary vein and was firmly attached to the submitted 0.5cm segment of left atria1 wall. Microscopic sections suggested an origin from the left main bronchus (Fig 1A) and demonstrated invasion into the pulmonary vein and the endocardial surface of the left atrium. Histologically. the tumor showed features of a mixed germ cell tumor demonstrating predominantly embryonal carcinoma with foci of yolk sac differentiation. The areas of embryonal carcinoma showed epithelial cells arranged in solid sheets (Fig lA, inset) alternating with cleftlike and primitive glandular spaces (Fig 1B). The cells had clear cytoplasm, indistinct cell borders, and enlarged nuclei with multiple prominent nucleoli. Scattered larger cells, necrosis, and many mitotic figures also characterized this area. The areas of yolk sac differentiation showed papillary structures with vascular or hyalinized cores and complex glandular spaces (Fig IC). The cells showed less necrosis and mitotic activity. Intracellular and extracellular periodic acid-Schiff (PAS)-positive diastase-resistant globules were easily identified in these papillary areas. The tumor extended to the left atria1 margin. The bronchial margins, peribronchial, and mediastinal lymph nodes were free from tumor. We performed immunohistochemical stains on paraf-

CASE STUDIES

FIGURE 2. Electron-dense intracytoplasmic secretions and associated lysosome. (Original magnification x 9,200.) (Inset) a-Fetoprotein globule (arrow) and diffuse cytoplasmic staining. (Immunohistochemical PAP stain for AFP; magnification x 400.)

FIGURE 1. (A) Endobronchial tumor replacing normal bronchial mucosa (arrow). (Hematoxylin-eosin stain; magnification x 40.) (Inset) Solid growth pattern in an area of embryonal carcinoma differentiation (Hematoxylin-eosin stain; magnification x 250.) (B) Primitive glandular structures in an area of emblyonal carcinoma differentlotion (resembles endometrioid-like yolk sac tumor]. (Hematoxylin-eosin stain; magnification x 160.) [C] Complex glandular spaces and papillary structures in an area of yolk sac differentiation (Hematoxylin-eosin stain; magnification x 160.)

persed, small clumps of heterochromatin. one to two compact nucleoli, and shallow indentations of the nuclear membrane. The morphologic appearance of cells in areas of the tumor with a papillary growth pattern was :similar to that of cells in the solid areas. The apical surface of several cells which formed acini and which lined the papillary cores exhibited sparse. stubby microvilli. Electron-dense, globular secretory material was present in the cytoplasm of some cells (Fig 2). in the lumen of acini. and in extracellulal spaces which were rimmed by a basal lamina.

Our review of the recent literature showed at least five single case reports of primary lung carcinoma which produced AFP (serum levels at presentation ranged from 280 to 19,700 ng/mL).l-X The clinical and pathologic features of these cases were very similar. The patients were all in their seventh decade or older. The ,4FP production was associated with another oncofetal marker or hormone production (CEA in two cases,‘,’ HC(; in one case,” and CEA and HCG in another case”) and the serum level of AFP correlated with tumor burden. All the patients except for one’ died within 18 months of diagnosis. The tumors histologically were characteristic lung carcinomas: three adenocarcinomas,“-x one atypical carcinoid with adenocarcinoma differentiation,’ and one large-cell carcinoma.i Intracytoplasmic location of AFP was demonstrated immunohistologically in all cases and biochemically in two cases. ‘-’ These five cases appear to be typical lung carcinomas in which AFP production was identified. Our case differed from these cases in patient age (third versus seventh decade), higher serum level of AFP at presentation, and most importantly, in pathologic features.+’ Histologically-. ultrastructurally. and immunohistochemicallp our case was identical to an ovarian or testicular malignant germ cell tumor showing a major component of embryonal carcinoma (Fig 1A, inset, and Fig 1B) with a minor component of yolk sac tumor (Fig lC).” This minor com-

lin blocks (Ising the peroxidase antiperoxidase (PAP) techclique with the following antibodies: AFP, carcinoembryonic antigen (CE.4). HCG, epithelial membrane antigen, 1)lacental alkaline phosphatase (Dakopatts, Copenhagen, Denmark); cytokeritin, chromgranin (Hybritech, San Dirgo. CA): S-100 protein (Chemicon, Temecula. CA); and 1372.3 (Biomed Tech, Stroughton, MA). The majority of the tumor showed diffuse cytoplasmic staining for AFP with focal intense globular staining in the yolk sac areas (Fig 2, inset). Cytokeratin showed strong cliffuse cytoplasmic staining. I‘he remainder of the antibodies essentially did not stain the tumor. The portion of the tumor sampled for transmission electron microscopy consisted predominantly of papillary .u-eas with a small sample of the solid area. The solid areas demonstrated large, poorly differentiated tumor cells. Intracytoplasmic organelles consisted of sparse profiles of rough endoplasmic reticulum, inconspicuous golgi bodies, ,md a few mitochondria. Tiumerous polyribosomes were also present. Acinar spaces, some of which were lined by basement membrane material, were present between some tumor cells. ‘The closely apposed cell membranes were joined by scattered desmosomes, and apical tight junctions were prenent around acinar spaces. The nuclei showed dis1075

HUMAN PATHOLOGY

Volume 21, No. 10 (October 1990)

ponent of yolk sac tumor differentiation showed a papillary pattern (Fig 1C) with globules of PAS-positive intracellular and extracellular materiaLg Intense globular immunohistochemical staining for AFP (Fig 2, inset) corresponded to these PAS-positive globules histologically, and to electron dense material ultrastructurally (Fig 2).‘,‘” Positive cytokeratin staining in the absence of epithelial membrane antigen and CEA staining supported germ cell differentiation, and would be unusual in AFP-producing pulmonary carcinoma,4-8 in which staining for all of these markers would be expected. In addition, our case lacked neuroendocrine differentiation both ultrastructurally and immunohistochemically, which was observed in many cases of fetal adenocarcinoma;“~” this was our main differential consideration in view of the many primitive glandular structures seen histologically (Fig 1B). The pathologic findings in our case could be explained by a solitary pulmonary metastasis from a primary gonadal germ cell tumor. However, complete histologic examination of this patient’s ovaries showed no germ cell tumor, and computed tomographic scan from cranium to pelvis did not disclose another primary lesion. In addition, inspection of the anterior mediastinum during the median sternotomy procedure showed no tumor. For these reasons, we felt our case was a primary pulmonary tumor rather than a metastatic lesion or extension from a mediastinal germ cell tumor. Richardson et al’s reported 12 patients with advanced malignancy who received an initial pathologic diagnosis of poorly differentiated carcinoma. These investigators felt that, clinically, the neoplasms were really extragonadal teratomas. In four of the cases, retrospective pathologic review with additional clinical information and appropriate immunohistochemical studies led to a revised diagnosis of extragonadal germ cell tumor. More importantly, seven of 12 patients responded well to chemotherapy, a completely unexpected result for non-germ cell carcinoma. Detailed pathologic description is not present in this paper. However, our case resembled the clinical features (young age and pulmonary involvement) and revised pathologic diagnosis of a few of the cases discussed in this

paper. ls In view of the response to chemotherapy shown by malignant germ cell tumors, this diagnosis should be considered when presented with a malignant pulmonary neoplasm with the appropriate clinical and pathologic features. Oncofetal tumor markers such as AFP may assist in establishing the diagnosis. The authors would like to thank Ed Jackson Acknowledgmenh. for expert photographic assistance: and Anthony Gal. MD, and Ayten Someren, MD for their review of the case. REFERENCES 1. Kuhn MW, Weissbach L: Localization. incidence, diagnosis and treatment of extratesticular germ cell tumors. Ural lnt 40: 166.172. 1985 2. Few LG, Samson MK. Stephens RL: Vinblastine (VLB). Bleomycin (BLEO). Cis-Diamminedichloroplatinum (DDP) in disseminated extragonadal germ cell tumors. A southwest oncology group study. Cancer 45:25432549, 1980 3. Jam&on MPG. McGowan AR: Endobronchial teratoma. Thorax 37:157-159. 1982 4. Ohtsuki H, Midorikawa 0. Okada H. et al: Pulmonary atypical carcinoid tumor with marked alpha-fetoprotein production and features of an adenocarcinoma differentiation. Pathol Res Pratt 1984:86-94, 1989 5. Yoshimoto T, Higashino K,HadaT,et al: A primary lung carcinoma producing alpha-fetoprotein, carcinoembryonic antigen, and human chorionic gonadotropin. lmmunohistochemical and biochemical studies. Cancer 60:2744-2750, 1987 6. Miyake M, lto M, Mitsuoka A, et al: Alpha-fetoprotein and human charionic gonadotropin producing lung cancer. Cancer 59:227-232, 1987 7. Yasunami R, Hashimoto 2. Ogura T, et al: Primary lung cancer producing alpha-fetoprotein: A case report. Cancer 47:926-929, 1981 8. Saka H, Sakai S, Kondo N. et al: Successful resection of alphafetoprotein-producing lung cancer. Chest 94:879-880. 1988 9. Nogales-Fernander F. Silverberg SG, Bloustein PA, et al: Yolk sx carcinoma (endodermal sinus tumor). Ultrastructure and histogenesis of gonadal and extragonadal tumors in comparison to normal human yolk sac. Cancer 39:1462-1474. 1977 10. Niehans GA, Manivel C, Copland GT. et al: lmmunohistochemistry of germ cell and trophoblastic neoplasms. Cancer 62: 1113-l 123, 1988 11. Manning JT, Ordonez NG. Rosenberg HS, et al: Pulmonary endodermal tumor resembling fetal lung. Report of a case with immunohistochemical studies. Arch Pathol Lab Med 109:48-50, 1985 12. Muller-Hermelink HK, Kaiserling E: Pulmonary adenocarcinoma of the fetal type: Alternating differentiation argues in favor of a common endodermal stem cell. Virchows Arch (A) 409:195-210. 1986 13. Richardson RL, Shoumacher RA. Fer MF, et al: The unrecognized extragonadal germ cell cancer syndrome. Ann Intern Med 94: 181-186. 1981

LORAR ATROPHY WITH PONTINE NEURONAL CHROMATOLYSIS CAROL

F. LIPPA,

MD,

THOMAS

W.

SMITH,

MD,

(“RALLOONED”

NEURONS)

AND UMBERTO DEGIROLAMI, MD

A 64.year-old man developed progressive dementia over a period of 11 years. Postmortem examination showed severe atrophy of the temporal lobes of the brain with extensive neuronal loss and a remarkable alteration of the neuronal perikaryon-the “ballooned” neuron-restricted to the nuclei of the basis pontis. No neuritic plaques, neurofibrillary tangles, or Pick bodies were seen. HUM PATHOL 21:1076-1079 0 1990 by W.B. Saunders Company. Received August 3 1, 1989 from the Departments of Pathology (Neuropathology) and Neurology, University of Massachusetts Medical Center, Worcester, MA. Accepted for publication lanuarv 29, 1990. Key words: dementia, lobar atrophy, Pick’s disease, basis pontis, chromatolysis. Address correspondence and reprint requests to Carol F.

Lippa, MD, Department of Pathology (Neuropathology), University of Massachusetts Medical Center, 55 Lake Ave N, Worcester, MA 01655. 0 1990 by W.B. Saunders Company. 0046-8177/90/21 lo-0014$5.00/O

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Lobar atrophy is a condition characterized clinically by progressive dementia, and pathologically by marked reduction in the size of the temporal (and frontal) lobes associated with microscopic evidence of neuronal loss and gliosis.’ In some patients with lobar atrophy, Pick bodies and greatly enlarged chromatolytic (“ballooned”) neurons may be found in the cortex and subcortical grey matter.2,Y We report a unique case of lobar atrophy without Pick bodies in which “ballooned” neurons were restricted to the nuclei of the basis pontis. REPORT

OF A CASE

A 53-year-old man initially presented with memory loss and difficulty naming objects. Two years later he was described as hyperactive, with abnormalities in both receptive and expressive language function. He subsequently developed global memory loss and cognitive dysfunction with inability to recall recent events, recognize family members,