609
0 1990
The Japanese Society of Pathology
Atypical Carcinoid Tumor of the Lung, Associated with Giant-cell Transformation in Bone Metastasis
Yutaka Tsutsumi', Koji Yazaki1V2,and Koichiro Yoshioka'J A case of neuroendocrine lung tumor located beneath the pleura in a 71-year-old woman is reported. At autopsy, the tumor was found to have metastasized to the bones and liver without involving the hilar lymph nodes. Histologically, the tumor cells at the primary site and in the liver metastasis exhibited a carcinoid-like organoid structure, whereas pleomorphic giant cells were noted in the bone metastasis. The argyrophilic tumor cells were immunoreactive for neuron-specific enolase, chromogranin A, serotonin, calcitonin, calcitonin gene-related peptide, gastrin-releasing peptide, neuropeptide Y, gastrin, pancreatic polypeptide, glicentin, the alpha-subunit of human chorionic gonadotropin, keratin, epithelial membrane antigen, Leu M1 and carcinoembryonic antigen. Electron microscopy revealed abundant neurosecretory granules in the cytoplasm. This was considered t o be a rare case of neuroendocrine lung tumor showing carcinoid-like histology at the primary site and large-cell transformation in bone metastasis. Acta Pathol Jpn 40: 609-615, 1990. Key words : Atypical bronchial carcinoid, Peripheral small cell lung carcinoma resembling carcinoid tumor, Neuroendo-
crine lung tumor
INTRODUCTION Pulmonary neuroendocrine tumors show a spectrum of histologic variations ranging from classic carcinoid tumors to small cell carcinomas (1-5). Occasionally, tumors with intermediate histologic characteristics are encountered. These have been called atypical carcinoid (4-6), well differentiated neuroendocrine carcinoma (3, 7) and peripheral small cell lung carcinoma resembling carcinoid tumor (8). Large-cell variants of neuroendocrine lung carcinomas have also been reported (9-12). ____
Received March 26, 1990. Accepted for publication May 17, 1990. Departments of 'Pathology and 21nternal Medicine, Tokai University School of Medicine, Isehara. Mailing address: Yutaka Tsutsumi, M.D. Department of Pathology, Tokai University School of Medicine, Bohseidai, lsehara, Kanagawa 259-1 1, Japan.
(tz z),
In the present paper, we describe an autopsy case of peripheral neuroendocrine lung tumor showing a carcinoid-like organoid arrangement at the primary site and in liver metastasis, and anaplastic giant-cell change in generalized bone metastasis. No lymph nodal involvement was observed. Multiple hormone production by the tumor cells was revealed immunohistochemically.
CLINICAL SUMMARY A 71-year-old woman noticed progressive back pain in September, 1986. She visited a local hospital in October, and received analgesics for 3 months. The pain continued and necessitated admission to hospital in December. By myelography, metastatic tumors to the vertebrae a t Th 2, 4 and 7 were found. She was therefore referred to Tokai University Hospital, Isehara, on March 3, 1987. Gallium bone scintigraphy showed multiple hot lesions in the skull, vertebrae and long bones. Despite detailed examinations, the primary focus was not identified. Shortly after admission, she developed paraplegia below Th 7, due to compression of the spinal cord by a metastatic tumor mass. Radiation therapy, total 2 0 Gy for 5 days, was given to the vertebra at Th 7. On March 27, massive vomiting occurred, and abdominal roentgenography revealed marked dilatation of bowel loops (ileus). Her general condition deteriorated progressively and was complicated a t the terminal stage by septicemia. She died of acute renal failure on April 4, 1987. No chemotherapy was given throughout the clinical course. No clinical signs or symptoms indicating overproduction of hormones were noted. Serum levels of alpha-fetoprotein (AFP; less than 12 ng/ml), carcinoembryonic antigen (CEA, 2.5 ng/ml) and CA19-9 (6 U/ml) were all within the normal ranges.
AUTOPSY FINDINGS At autopsy performed 2 h after death, massive metastatic deposits were observed throughout the bone tis-
610
Neuroendocrine Lung Cancer with Giant Cells (Tsutsumi et a/.)
Figure 1. Gross appearance of thoracic spine and the spinal cord at the corresponding level. Massive metastasis to the spine has caused compression of the spinal cord at Th 7 (arrows).
Figure2. Macroscopic view of the primary focus in the right lung (S1 segment). The tumor, white in color with ill-defined margins, is located just beneath the pleura, and measures 1 3 x 12 x 9 mm. Arrows indicate disseminated small abscesses.
sue, including the vertebrae, skull, scapulae, ribs, pelvic bones and left femoral head. The Th 7 vertebra bore a tumor 7 cm in diameter, protruding into both the retromediastinum and the vertebral canal, compressing the spinal cord at this level (Fig. 1). The bone metastasis showed pronounced necrosis. In the liver, there were a few small, necrotic metastatic nodules up to 1 cm in size in both lobes. The primary focus, measuring 1 3 x l 2 x 9 m m , was found in the S1 segment of the right lung, just beneath the pleura (Fig. 2). The lung
generally showed disseminated multiple small abscesses in association with marked congestion and edema. Neither intrapulmonary metastasis nor hilar lymph nodal involvement was noted. Histologically, the primary lung lesion consisted of relatively uniform round or polygonal cells. The neoplastic cells showed an organoid structure arranged mainly in solid nests or in a ribbon-like pattern, and contained eosinophilic granular cytoplasm and a centrally located nucleus with finely dispersed chromatin, a
Figure 3. Carcinoid-like organoid structure seen in the primary lung lesion. Hematoxylin and eosin (HE) (a,b). The presence of nuclear atypia, focal necrosis and mitotic figures indicates the malignant nature of this tumor. Venous involvement is focally observed (inset).
611
Acta Pathologica Japonica 40 (8) : 1990
Figure 4. Highly pleomorphic cellular features in bone metastasis (lumbar spine). HE (a, b). A large number of giant tumor cells are seen in association with frequent mitosis and necrosis of the tumor cells.
distinct nuclear rim and inconspicuous nucleoli (Fig. 3a). Nuclear pleomorphism, patchy necrosis, mitosis and venous invasion were observed occasionally (Fig. 3b). The liver metastasis also showed similar carcinoid-like histologic features with massive central necrosis. By contrast, it was characteristic that the tumor cells metastasized to the bone were highly pleomorphic and frequently associated with giant-cell formation (Fig. 4). The carcinoid-like arrangement was focal and incomplete. Tumor necrosis was conspicuous in the bone, and
fable 1. Final Anatomical Diagnoses 1. Atypical carcinoid tumor of the lung (right S1 segment, peripheral type, 1 3 X 1 2 X 9 mm) A) Metastasis: a) Bones (vertebrae, skull, scapulae, ribs, pelvic bones, left femora I head)* * Numbers of pleomorphic tumor giant cells seen b) Liver (bilateral lobes, up to 1 c m in size, 1,400 g) B) Treatment: Irradiation (spine Th 7, 2 0 Gy) 2. Multiple lung abscesses (bilateral, left 300 g : right 580 g) a) Bacterial culture : Pseudomonas aeruginosa and Escherichia coli 3. Septicemia (blood culture : Pseudomonas aeruginosa) a) Acute splenitis (130 g) 4. Acute tubular necrosis of the kidneys (210 g : 2 1 0 g) 5. Ischemic colitis (terminal ileum through sigmoid colon) a) Ulcer formation (marked at the splenic flexure) b) Dilatation of the colon 6. Compression myelopathy (Th 7) 7. Chronic duodenal ulcer (bulb, UI 4) 8. Systemic congestion 2 ml 9. HVDerDlaStiC DOIVDof the gallbladder ( 4 ~ 4 x m 10. Post-hysterectomy status-due to hydatidiform mole
mitotic figures were frequently noted. Such anaplastic transformation was seen in all of the metastatic foci in the bone (vertebrae Th 4, Th 7, Th 9, Th 12, L 3, rib and left femoral head were examined microscopically). This ruled out the possibility that these morphologic changes had been induced by the irradiation therapy applied only a t the Th 7 level. The final anatomical diagnoses are shown in Table 1. lleus was caused by ischemic colitis. Septicemia due to Pseudomonas aeruginosa resulted in multiple lung abscesses, acute splenitis and acute tubular necrosis of the kidneys. Secondary degeneration of the long tracts of the spinal cord was confirmed histologically.
HISTOCHEMICAL FINDINGS Grimelius silver staining showed abundant argyrophilic granules in the cytoplasm of a number of tumor cells in both the primary and metastatic foci (Fig. 5). FontanaMasson silver staining for argentaffin cells was negative. Periodic acid-Schiff (PAS) staining after diastase digestion, and alcian blue staining, showed mucin-positive intracytoplasmic lumina formed by the anaplastic tumor cells in the bone (Fig. 5, inset). Such mucin production was seen only in the bone metastases. lmmunohistochemical findings demonstrated by the indirect immunoperoxidase technique with methyl green counterstaining are summarized in Table 2. The specificities of the polyclonal and monoclonal antibodies used have been described previously (13). The tumor cells were immunoreactive for neuron-specific enolase
612
Neuroendocrine Lung Cancer with Giant Cells (Tsutsumi et d.)
Figure 5. Argyrophilic tumor cells at the primary focus (a) and in bone metastasis (b). Grimelius silver. Many tumor cells, including giant cells in the bone, contain abundant argyrophilic granules in the cytoplasm. Inset : PAS-positive intracytoplasmic lumina formed in tumor cells that have metastasized to the bone. PAS staining after diastase digest ion.
(NSE), chromogranin A, serotonin, calcitonin, calcitonin gene- related peptide (CGR P), gastrin- releasing peptide (GRP), neuropeptide Y (NPY), gastiin, pancreatic poly peptide (PP), glicentin and the alpha-subunit of human chorionic gonadotropin (HCGa) (Fig. 6). Among these hormones, serotonin and calcitonin were most frequently demonstrated. NSE, chromogranin A, serotonin and calcitonin were found as frequently in bone metastases as in the primary lesion. Expression of these neuroendocrine substances was less frequent in the liver tumor. GRP, PP and glicentin were expressed in the primary focus but not in the bone, whereas NPY was demonstrat-
ed only in bone metastases. Adrenocorticotropic hormone (ACTH), methionine-enkephalin, insulin and somatostatin were negative. In addition, epithelial antigens such as keratin, epithelial membrane antigen (EMA), Leu M1 and CEA were detected in the tumor cells. lmmunostaining for vimentin, secretory component (SC), S-100 protein, AFP, CA125 and CA19-9 was negative.
ELECTRON MICROSCOPIC FINDINGS Electron microscopic studies were performed using formalin-fixed autopsy material. Although fine-struc-
Table 2. Summary of Histochemical Staining Staining/Marker Grimelius Fo nta na - Mas o n NSE Chromogranin A Serotonin Calcitonin CGRP GRP Neuropeptide Y Met-enkephalin Gastrin Glicentin PP Somatostatin Insulin ACTH HCG. a-subunit
Primary Lung 9
Metastasis Liver Bone it 9
Staining/Marker EMi1 Keratin Vimentin CEA Leu M1 S-100 protein
Primary Lung
+
Metastasis Liver Bone it
sc
CA125 CA19-9 Diastase-PAS Alcian blue
-
-
+
itit : Most tumor cells positive, 9 : More than half of tumor cells positive, it : A modest number of tumor cells positive, A few tumor cells positive, - : Negative.
+:
613
Acta Pathologica Japonica 40 (8) : 1990
Figure 6. l m m u n o r e a c t i v e chrornogranin A (a), serotonin (b), calcitonin gene-related p e ptide (CGRP) (c), and keratin (d) demonstrated in bone metastasis. Indirect immunoperoxidase staining. A considerable number of pleomorphic tumor cells are positive immunohistochemically for chromogranin A and serotonin. A few CGRP-immunoreactive cells can be identified. Keratin, revealed by a monoclonal antibody KL1, is expressed in almost all of the tumor cells.
Figure 7. Electron micrographs of two different pleomorphic tumor cells in the bone fixed in 10% formalin ~ 3 5 , 0 0 0(a) and ~ 3 1 , 0 0 0(b). The cytoplasm is rich in dense cored neurosecretory type granules, which have a mean diameter of 270 nm. Bar indicates 500 nm
614
Neuroendocrine Lung Cancer with Giant Cells (Tsutsumi et a/.)
tural preservation was poor, the presence of dense-cored neurosecretory granules was confirmed in the cytoplasm of the tumor cells in both the primary lesion and bone metastases (Fig. 7). The size of the neurosecretory granules was similar at both sites, ranging from 130 t o 360 nm (mean : 270 nm).
DISCUSSION Pulmonary neuroendocrine tumors occur occasionally in the peripheral region of the lung. Eighteen percent of bronchial carcinoids are seen at the periphery (14, 15), whereas the frequency of small cell carcinomas of the peripheral type has been reported to range from 19% to 39% (16-18). In 1985, Mark and Ramirez proposed a subtype of neuroendocrine lung neoplasm termed “peripheral small cell carcinoma of the lung resembling carcinoid tumor”. The histologic and clinicopathologic features of this subtype are intermediate between classic carcinoid tumor and usual small cell carcinoma (8). The tumor in the present case was categorized under this subtype in view of its malignant nature, its site in the lung and the histology of the primary tumor and liver metastasis. This subtype also corresponds to tumors reported as “well differentiated neuroendocrine carcinoma of the lung”(3, 7) and “Kulchitzky cell carcinoma, grade 11” (4) when located at the periphery of the lung. On the other hand, the occurrence and/or predominance of large-sized tumor cells in neuroendocrine lung carcinomas has also been reported(1, 2, 9-12); the names “atypical endocrine tumor of the lung” (lo), “large cell neuroendocrine tumor of the lung” (12), and “mixed small and large cell bronchogenic carcinoma” (11) have been given to such large-cell variants. The bone metastasis in the present case evidently belongs to this large-cell category of neuroendocrine carcinoma. So far, large-cell transformation of small cell carcinomas has been shown to occur as a result of chemotherapy (19) or heterotransplantation into nude mice (20). Such secondary iatrogenic modification of the tumor morphology can be ruled out in the present case, since the giantcell features were observed in all of the bone lesions examined. By contrast, the presence of undifferentiated lung carcinomas of the small cell type without accompanying neuroendocrine differentiation has been pointed out by a Japanese group(l8). To our knowledge, there has been no detailed report describing neuroendocrine lung tumors associated with the simultaneous occurrence of a carcinoid-like histology in the primary lesion and large-cell transformation in metastatic foci. The lack of any hilar lymph nodal involvement is a feature quite distinct from common-
type small cell lung carcinomas(1, 2, 16, 17). The pattern of metastasis indicates purely hematogenous tumor cell spread. Ultrastructural demonstration of abundant neurosecretory granules and immunohistochemical detection of a variety of neuroendocrine substances are common in bronchial carcinoids, but in small cell carcinomas neurosecretory granules are usually sparse and immunoreactive substances show more limited variety (3,7, 13, 21). In this sense, the neoplasm in the present case can be regarded as the “malignant” form of bronchial carcinoid tumor.
REFER ENC ES 1. Yesner R. Small cell tumors of the lung. Am J Surg Pathol 7 : 775-785, 1983. 2. Carter DC. Small-cell carcinoma of the lung. Am J Surg Pathol 7 : 787-795, 1983. 3. Gould VE, Linnoila RI, Memoli VA, and Warren WH. Neuroendocrine cells and neuroendocrine neoplasms of the lung. Pathol Annu 18 (Part I): 287-330, 1983. 4. Eggleston JC. Bronchial carcinoids and their relationship to other pulmonary tumors with endocrine features. In Becker KL and Gazdar AF, eds. The endocrine lung in health and disease. W.B. Saunders, Philadelphia, 1984: 389-405. 5. Paladugu RR, Benfield JR, Pak HY, Ross RK, and Teplitz RL. Bronchopulmonary Kulchitzky cell carcinomas. A new classification scheme for typical and atypical carcinoids. Cancer 55: 1303-1311, 1985. 6. Mills SE, Walker AN, Cooper PH, and Kron IL. Atypical carcinoid tumor of the lung. A clinicopathologic study of 17 cases. Am J Surg Pathol 6 : 643654, 1982. 7. Warren WH, Memoli VA, and Gould VE. Immunohistochemical and ultrastructural analysis of bronchopulmonary neuroendocrine neoplasms. II. Welldifferentiated neuroendocrine carcinomas. Ultrastr Pathol 7 : 185-199, 1984. 8. Mark EJ and Ramirez JF. Peripheral small-cell carcinoma of the lung resembling carcinoid tumor. A clinical and pathologic study of 14 cases. Arch Pathol Lab Med 109: 263-269, 1985. 9. Gould VE and Chejfec G. Ultrastructural and biochemical analysis of “undifferentiated” pulmonary carcinomas. Hum Pathol 9 : 377-384, 1978. 10. McDowell EM, Wilson TS, and Trump BF. Atypical endocrine tumors of the lung. Arch Pathol Lab Med 105: 20-28, 1981. 11. Radice PA, Mattews MJ, lhde DC, et a/. The clinical behavior of “mixed” small cell/large cell bronchogenic carcinoma compared to “pure” small cell subtypes. Cancer 50 : 2894-2902, 1982. 12. Hammond ME and Sause WT. Large cell neuroendocrine tumors of the lung. Clinical significance and histopathologic definition. Cancer 56: 1624-1629, 1985. 13. Tsutsumi Y. lmmunohistochemical analysis of neuroendocrine substances in nonneoplastic lung and in neuroendocrine lung tumors. In Lechago J and Kameya T, eds. Endocrine pathology update, vol. 1.
Acta Pathologica Japonica 40 (8): 1990
14. 15.
16. 17.
18.
Field & Wood, New York, 1990 : 189-213. Okike N, Bernatz PE, and Woolner LB. Carcinoid tumors of the lung. Ann Thorac Surg 22 : 270-277, 1976. Cooney T, Sweeney EC, and Luke D. Pulmonary carcinoid tumours: A comparative regional study. J Clin Pathol 3 2 : 1100-1109, 1979. Cohen MH and Mattews MJ. Small cell bronchogenic carcinoma : A distinct clinicopathologic entity. Semin Oncol 5 : 234-243, 1978. Eguchi K. Small cell lung carcinoma. In National Cancer Center, ed. Cancer of the lung. Diagnosis and treatment, vol. 4. Kodansha, Tokyo, 1 9 8 3 : 107122 ( i n Japanese). Nomori H, Shimosato Y, Kodama T, et a/. Subtypes of small cell carcinoma of the lung : Morphometric, ultrastructural, and immunohistochemical analyses. Hum
615
Pathol 1 7 : 604-613, 1986. 19. Abeloff MD, Eggleston JC, Mendelsohn G, Ettinger DS, and Baylin S. Changes in morphologic and biochemical characteristics of small cell carcinoma of the lung. Am J Med 6 6 : 757-764, 1979. 20. Gazdar AF, Carney DN, Guccion JG, and Baylin SB. Small cell carcinoma of the lung: Cellular origin and relationship to other pulmonary tumors. In Greco FA, Oldham RK, and Bunn PA Jr, eds. Small cell lung cancer. Grune & Stratton, New York, 1981 : 145175. 21. Shimase J. An immunohistochemical study of differentiation toward neuroendocrine cell in small cell carcinoma of the lung, bronchial carcinoid, and pulmonary tumorlet. Haigan 2 4 : 401-413, 1984 ( i n Japanese with English abstract).
0 1990
The Japanese Society of Pathology
Atypical Carcinoid Tumor of the Lung, Associated with Giant-cell Transformation in Bone Metastasis
Yutaka Tsutsumi', Koji Yazaki1V2,and Koichiro Yoshioka'J A case of neuroendocrine lung tumor located beneath the pleura in a 71-year-old woman is reported. At autopsy, the tumor was found to have metastasized to the bones and liver without involving the hilar lymph nodes. Histologically, the tumor cells at the primary site and in the liver metastasis exhibited a carcinoid-like organoid structure, whereas pleomorphic giant cells were noted in the bone metastasis. The argyrophilic tumor cells were immunoreactive for neuron-specific enolase, chromogranin A, serotonin, calcitonin, calcitonin gene-related peptide, gastrin-releasing peptide, neuropeptide Y, gastrin, pancreatic polypeptide, glicentin, the alpha-subunit of human chorionic gonadotropin, keratin, epithelial membrane antigen, Leu M1 and carcinoembryonic antigen. Electron microscopy revealed abundant neurosecretory granules in the cytoplasm. This was considered t o be a rare case of neuroendocrine lung tumor showing carcinoid-like histology at the primary site and large-cell transformation in bone metastasis. Acta Pathol Jpn 40: 609-615, 1990. Key words : Atypical bronchial carcinoid, Peripheral small cell lung carcinoma resembling carcinoid tumor, Neuroendo-
crine lung tumor
INTRODUCTION Pulmonary neuroendocrine tumors show a spectrum of histologic variations ranging from classic carcinoid tumors to small cell carcinomas (1-5). Occasionally, tumors with intermediate histologic characteristics are encountered. These have been called atypical carcinoid (4-6), well differentiated neuroendocrine carcinoma (3, 7) and peripheral small cell lung carcinoma resembling carcinoid tumor (8). Large-cell variants of neuroendocrine lung carcinomas have also been reported (9-12). ____
Received March 26, 1990. Accepted for publication May 17, 1990. Departments of 'Pathology and 21nternal Medicine, Tokai University School of Medicine, Isehara. Mailing address: Yutaka Tsutsumi, M.D. Department of Pathology, Tokai University School of Medicine, Bohseidai, lsehara, Kanagawa 259-1 1, Japan.
(tz z),
In the present paper, we describe an autopsy case of peripheral neuroendocrine lung tumor showing a carcinoid-like organoid arrangement at the primary site and in liver metastasis, and anaplastic giant-cell change in generalized bone metastasis. No lymph nodal involvement was observed. Multiple hormone production by the tumor cells was revealed immunohistochemically.
CLINICAL SUMMARY A 71-year-old woman noticed progressive back pain in September, 1986. She visited a local hospital in October, and received analgesics for 3 months. The pain continued and necessitated admission to hospital in December. By myelography, metastatic tumors to the vertebrae a t Th 2, 4 and 7 were found. She was therefore referred to Tokai University Hospital, Isehara, on March 3, 1987. Gallium bone scintigraphy showed multiple hot lesions in the skull, vertebrae and long bones. Despite detailed examinations, the primary focus was not identified. Shortly after admission, she developed paraplegia below Th 7, due to compression of the spinal cord by a metastatic tumor mass. Radiation therapy, total 2 0 Gy for 5 days, was given to the vertebra at Th 7. On March 27, massive vomiting occurred, and abdominal roentgenography revealed marked dilatation of bowel loops (ileus). Her general condition deteriorated progressively and was complicated a t the terminal stage by septicemia. She died of acute renal failure on April 4, 1987. No chemotherapy was given throughout the clinical course. No clinical signs or symptoms indicating overproduction of hormones were noted. Serum levels of alpha-fetoprotein (AFP; less than 12 ng/ml), carcinoembryonic antigen (CEA, 2.5 ng/ml) and CA19-9 (6 U/ml) were all within the normal ranges.
AUTOPSY FINDINGS At autopsy performed 2 h after death, massive metastatic deposits were observed throughout the bone tis-
610
Neuroendocrine Lung Cancer with Giant Cells (Tsutsumi et a/.)
Figure 1. Gross appearance of thoracic spine and the spinal cord at the corresponding level. Massive metastasis to the spine has caused compression of the spinal cord at Th 7 (arrows).
Figure2. Macroscopic view of the primary focus in the right lung (S1 segment). The tumor, white in color with ill-defined margins, is located just beneath the pleura, and measures 1 3 x 12 x 9 mm. Arrows indicate disseminated small abscesses.
sue, including the vertebrae, skull, scapulae, ribs, pelvic bones and left femoral head. The Th 7 vertebra bore a tumor 7 cm in diameter, protruding into both the retromediastinum and the vertebral canal, compressing the spinal cord at this level (Fig. 1). The bone metastasis showed pronounced necrosis. In the liver, there were a few small, necrotic metastatic nodules up to 1 cm in size in both lobes. The primary focus, measuring 1 3 x l 2 x 9 m m , was found in the S1 segment of the right lung, just beneath the pleura (Fig. 2). The lung
generally showed disseminated multiple small abscesses in association with marked congestion and edema. Neither intrapulmonary metastasis nor hilar lymph nodal involvement was noted. Histologically, the primary lung lesion consisted of relatively uniform round or polygonal cells. The neoplastic cells showed an organoid structure arranged mainly in solid nests or in a ribbon-like pattern, and contained eosinophilic granular cytoplasm and a centrally located nucleus with finely dispersed chromatin, a
Figure 3. Carcinoid-like organoid structure seen in the primary lung lesion. Hematoxylin and eosin (HE) (a,b). The presence of nuclear atypia, focal necrosis and mitotic figures indicates the malignant nature of this tumor. Venous involvement is focally observed (inset).
611
Acta Pathologica Japonica 40 (8) : 1990
Figure 4. Highly pleomorphic cellular features in bone metastasis (lumbar spine). HE (a, b). A large number of giant tumor cells are seen in association with frequent mitosis and necrosis of the tumor cells.
distinct nuclear rim and inconspicuous nucleoli (Fig. 3a). Nuclear pleomorphism, patchy necrosis, mitosis and venous invasion were observed occasionally (Fig. 3b). The liver metastasis also showed similar carcinoid-like histologic features with massive central necrosis. By contrast, it was characteristic that the tumor cells metastasized to the bone were highly pleomorphic and frequently associated with giant-cell formation (Fig. 4). The carcinoid-like arrangement was focal and incomplete. Tumor necrosis was conspicuous in the bone, and
fable 1. Final Anatomical Diagnoses 1. Atypical carcinoid tumor of the lung (right S1 segment, peripheral type, 1 3 X 1 2 X 9 mm) A) Metastasis: a) Bones (vertebrae, skull, scapulae, ribs, pelvic bones, left femora I head)* * Numbers of pleomorphic tumor giant cells seen b) Liver (bilateral lobes, up to 1 c m in size, 1,400 g) B) Treatment: Irradiation (spine Th 7, 2 0 Gy) 2. Multiple lung abscesses (bilateral, left 300 g : right 580 g) a) Bacterial culture : Pseudomonas aeruginosa and Escherichia coli 3. Septicemia (blood culture : Pseudomonas aeruginosa) a) Acute splenitis (130 g) 4. Acute tubular necrosis of the kidneys (210 g : 2 1 0 g) 5. Ischemic colitis (terminal ileum through sigmoid colon) a) Ulcer formation (marked at the splenic flexure) b) Dilatation of the colon 6. Compression myelopathy (Th 7) 7. Chronic duodenal ulcer (bulb, UI 4) 8. Systemic congestion 2 ml 9. HVDerDlaStiC DOIVDof the gallbladder ( 4 ~ 4 x m 10. Post-hysterectomy status-due to hydatidiform mole
mitotic figures were frequently noted. Such anaplastic transformation was seen in all of the metastatic foci in the bone (vertebrae Th 4, Th 7, Th 9, Th 12, L 3, rib and left femoral head were examined microscopically). This ruled out the possibility that these morphologic changes had been induced by the irradiation therapy applied only a t the Th 7 level. The final anatomical diagnoses are shown in Table 1. lleus was caused by ischemic colitis. Septicemia due to Pseudomonas aeruginosa resulted in multiple lung abscesses, acute splenitis and acute tubular necrosis of the kidneys. Secondary degeneration of the long tracts of the spinal cord was confirmed histologically.
HISTOCHEMICAL FINDINGS Grimelius silver staining showed abundant argyrophilic granules in the cytoplasm of a number of tumor cells in both the primary and metastatic foci (Fig. 5). FontanaMasson silver staining for argentaffin cells was negative. Periodic acid-Schiff (PAS) staining after diastase digestion, and alcian blue staining, showed mucin-positive intracytoplasmic lumina formed by the anaplastic tumor cells in the bone (Fig. 5, inset). Such mucin production was seen only in the bone metastases. lmmunohistochemical findings demonstrated by the indirect immunoperoxidase technique with methyl green counterstaining are summarized in Table 2. The specificities of the polyclonal and monoclonal antibodies used have been described previously (13). The tumor cells were immunoreactive for neuron-specific enolase
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Neuroendocrine Lung Cancer with Giant Cells (Tsutsumi et d.)
Figure 5. Argyrophilic tumor cells at the primary focus (a) and in bone metastasis (b). Grimelius silver. Many tumor cells, including giant cells in the bone, contain abundant argyrophilic granules in the cytoplasm. Inset : PAS-positive intracytoplasmic lumina formed in tumor cells that have metastasized to the bone. PAS staining after diastase digest ion.
(NSE), chromogranin A, serotonin, calcitonin, calcitonin gene- related peptide (CGR P), gastrin- releasing peptide (GRP), neuropeptide Y (NPY), gastiin, pancreatic poly peptide (PP), glicentin and the alpha-subunit of human chorionic gonadotropin (HCGa) (Fig. 6). Among these hormones, serotonin and calcitonin were most frequently demonstrated. NSE, chromogranin A, serotonin and calcitonin were found as frequently in bone metastases as in the primary lesion. Expression of these neuroendocrine substances was less frequent in the liver tumor. GRP, PP and glicentin were expressed in the primary focus but not in the bone, whereas NPY was demonstrat-
ed only in bone metastases. Adrenocorticotropic hormone (ACTH), methionine-enkephalin, insulin and somatostatin were negative. In addition, epithelial antigens such as keratin, epithelial membrane antigen (EMA), Leu M1 and CEA were detected in the tumor cells. lmmunostaining for vimentin, secretory component (SC), S-100 protein, AFP, CA125 and CA19-9 was negative.
ELECTRON MICROSCOPIC FINDINGS Electron microscopic studies were performed using formalin-fixed autopsy material. Although fine-struc-
Table 2. Summary of Histochemical Staining Staining/Marker Grimelius Fo nta na - Mas o n NSE Chromogranin A Serotonin Calcitonin CGRP GRP Neuropeptide Y Met-enkephalin Gastrin Glicentin PP Somatostatin Insulin ACTH HCG. a-subunit
Primary Lung 9
Metastasis Liver Bone it 9
Staining/Marker EMi1 Keratin Vimentin CEA Leu M1 S-100 protein
Primary Lung
+
Metastasis Liver Bone it
sc
CA125 CA19-9 Diastase-PAS Alcian blue
-
-
+
itit : Most tumor cells positive, 9 : More than half of tumor cells positive, it : A modest number of tumor cells positive, A few tumor cells positive, - : Negative.
+:
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Acta Pathologica Japonica 40 (8) : 1990
Figure 6. l m m u n o r e a c t i v e chrornogranin A (a), serotonin (b), calcitonin gene-related p e ptide (CGRP) (c), and keratin (d) demonstrated in bone metastasis. Indirect immunoperoxidase staining. A considerable number of pleomorphic tumor cells are positive immunohistochemically for chromogranin A and serotonin. A few CGRP-immunoreactive cells can be identified. Keratin, revealed by a monoclonal antibody KL1, is expressed in almost all of the tumor cells.
Figure 7. Electron micrographs of two different pleomorphic tumor cells in the bone fixed in 10% formalin ~ 3 5 , 0 0 0(a) and ~ 3 1 , 0 0 0(b). The cytoplasm is rich in dense cored neurosecretory type granules, which have a mean diameter of 270 nm. Bar indicates 500 nm
614
Neuroendocrine Lung Cancer with Giant Cells (Tsutsumi et a/.)
tural preservation was poor, the presence of dense-cored neurosecretory granules was confirmed in the cytoplasm of the tumor cells in both the primary lesion and bone metastases (Fig. 7). The size of the neurosecretory granules was similar at both sites, ranging from 130 t o 360 nm (mean : 270 nm).
DISCUSSION Pulmonary neuroendocrine tumors occur occasionally in the peripheral region of the lung. Eighteen percent of bronchial carcinoids are seen at the periphery (14, 15), whereas the frequency of small cell carcinomas of the peripheral type has been reported to range from 19% to 39% (16-18). In 1985, Mark and Ramirez proposed a subtype of neuroendocrine lung neoplasm termed “peripheral small cell carcinoma of the lung resembling carcinoid tumor”. The histologic and clinicopathologic features of this subtype are intermediate between classic carcinoid tumor and usual small cell carcinoma (8). The tumor in the present case was categorized under this subtype in view of its malignant nature, its site in the lung and the histology of the primary tumor and liver metastasis. This subtype also corresponds to tumors reported as “well differentiated neuroendocrine carcinoma of the lung”(3, 7) and “Kulchitzky cell carcinoma, grade 11” (4) when located at the periphery of the lung. On the other hand, the occurrence and/or predominance of large-sized tumor cells in neuroendocrine lung carcinomas has also been reported(1, 2, 9-12); the names “atypical endocrine tumor of the lung” (lo), “large cell neuroendocrine tumor of the lung” (12), and “mixed small and large cell bronchogenic carcinoma” (11) have been given to such large-cell variants. The bone metastasis in the present case evidently belongs to this large-cell category of neuroendocrine carcinoma. So far, large-cell transformation of small cell carcinomas has been shown to occur as a result of chemotherapy (19) or heterotransplantation into nude mice (20). Such secondary iatrogenic modification of the tumor morphology can be ruled out in the present case, since the giantcell features were observed in all of the bone lesions examined. By contrast, the presence of undifferentiated lung carcinomas of the small cell type without accompanying neuroendocrine differentiation has been pointed out by a Japanese group(l8). To our knowledge, there has been no detailed report describing neuroendocrine lung tumors associated with the simultaneous occurrence of a carcinoid-like histology in the primary lesion and large-cell transformation in metastatic foci. The lack of any hilar lymph nodal involvement is a feature quite distinct from common-
type small cell lung carcinomas(1, 2, 16, 17). The pattern of metastasis indicates purely hematogenous tumor cell spread. Ultrastructural demonstration of abundant neurosecretory granules and immunohistochemical detection of a variety of neuroendocrine substances are common in bronchial carcinoids, but in small cell carcinomas neurosecretory granules are usually sparse and immunoreactive substances show more limited variety (3,7, 13, 21). In this sense, the neoplasm in the present case can be regarded as the “malignant” form of bronchial carcinoid tumor.
REFER ENC ES 1. Yesner R. Small cell tumors of the lung. Am J Surg Pathol 7 : 775-785, 1983. 2. Carter DC. Small-cell carcinoma of the lung. Am J Surg Pathol 7 : 787-795, 1983. 3. Gould VE, Linnoila RI, Memoli VA, and Warren WH. Neuroendocrine cells and neuroendocrine neoplasms of the lung. Pathol Annu 18 (Part I): 287-330, 1983. 4. Eggleston JC. Bronchial carcinoids and their relationship to other pulmonary tumors with endocrine features. In Becker KL and Gazdar AF, eds. The endocrine lung in health and disease. W.B. Saunders, Philadelphia, 1984: 389-405. 5. Paladugu RR, Benfield JR, Pak HY, Ross RK, and Teplitz RL. Bronchopulmonary Kulchitzky cell carcinomas. A new classification scheme for typical and atypical carcinoids. Cancer 55: 1303-1311, 1985. 6. Mills SE, Walker AN, Cooper PH, and Kron IL. Atypical carcinoid tumor of the lung. A clinicopathologic study of 17 cases. Am J Surg Pathol 6 : 643654, 1982. 7. Warren WH, Memoli VA, and Gould VE. Immunohistochemical and ultrastructural analysis of bronchopulmonary neuroendocrine neoplasms. II. Welldifferentiated neuroendocrine carcinomas. Ultrastr Pathol 7 : 185-199, 1984. 8. Mark EJ and Ramirez JF. Peripheral small-cell carcinoma of the lung resembling carcinoid tumor. A clinical and pathologic study of 14 cases. Arch Pathol Lab Med 109: 263-269, 1985. 9. Gould VE and Chejfec G. Ultrastructural and biochemical analysis of “undifferentiated” pulmonary carcinomas. Hum Pathol 9 : 377-384, 1978. 10. McDowell EM, Wilson TS, and Trump BF. Atypical endocrine tumors of the lung. Arch Pathol Lab Med 105: 20-28, 1981. 11. Radice PA, Mattews MJ, lhde DC, et a/. The clinical behavior of “mixed” small cell/large cell bronchogenic carcinoma compared to “pure” small cell subtypes. Cancer 50 : 2894-2902, 1982. 12. Hammond ME and Sause WT. Large cell neuroendocrine tumors of the lung. Clinical significance and histopathologic definition. Cancer 56: 1624-1629, 1985. 13. Tsutsumi Y. lmmunohistochemical analysis of neuroendocrine substances in nonneoplastic lung and in neuroendocrine lung tumors. In Lechago J and Kameya T, eds. Endocrine pathology update, vol. 1.
Acta Pathologica Japonica 40 (8): 1990
14. 15.
16. 17.
18.
Field & Wood, New York, 1990 : 189-213. Okike N, Bernatz PE, and Woolner LB. Carcinoid tumors of the lung. Ann Thorac Surg 22 : 270-277, 1976. Cooney T, Sweeney EC, and Luke D. Pulmonary carcinoid tumours: A comparative regional study. J Clin Pathol 3 2 : 1100-1109, 1979. Cohen MH and Mattews MJ. Small cell bronchogenic carcinoma : A distinct clinicopathologic entity. Semin Oncol 5 : 234-243, 1978. Eguchi K. Small cell lung carcinoma. In National Cancer Center, ed. Cancer of the lung. Diagnosis and treatment, vol. 4. Kodansha, Tokyo, 1 9 8 3 : 107122 ( i n Japanese). Nomori H, Shimosato Y, Kodama T, et a/. Subtypes of small cell carcinoma of the lung : Morphometric, ultrastructural, and immunohistochemical analyses. Hum
615
Pathol 1 7 : 604-613, 1986. 19. Abeloff MD, Eggleston JC, Mendelsohn G, Ettinger DS, and Baylin S. Changes in morphologic and biochemical characteristics of small cell carcinoma of the lung. Am J Med 6 6 : 757-764, 1979. 20. Gazdar AF, Carney DN, Guccion JG, and Baylin SB. Small cell carcinoma of the lung: Cellular origin and relationship to other pulmonary tumors. In Greco FA, Oldham RK, and Bunn PA Jr, eds. Small cell lung cancer. Grune & Stratton, New York, 1981 : 145175. 21. Shimase J. An immunohistochemical study of differentiation toward neuroendocrine cell in small cell carcinoma of the lung, bronchial carcinoid, and pulmonary tumorlet. Haigan 2 4 : 401-413, 1984 ( i n Japanese with English abstract).
