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Carcinoid tumor of the thymus with divergent sarcomatoid differentiation: Report of a case with histogenetic consideration
Case studies CARCINOID TUMOR OF THE THVMUS WITH DIVERGENT SARCOMATOID REPORT OF A CASE WITH HISTOGENETIC CONSIDERATION
DIFFERENTIATION:
TSENGTONC Kuo, MD, PHD
riety of histologic variants of thymic carcinoid tumor have been described.%’ These variants include spindle cell, sclerotic, pigmented, microfilamentous, diffuse lymphoma-like, and medullary carcinoma of the thyroid-like thymic carcinoid tumors. We encountered a carcinoid tumor of the thymus with divergent sarcomatoid differentiation. One similar but not identical tumor was described by Paties et al’ in 1991. Our case is reported with immunohistochemical and ultrastructural studies with a discussion of its histogenesis.
An anterior mediastinal tumor resected f;rom a Nyear-old man without parane#astic symptoms was found to be an unusual biphasic thymic tumor composed of carcinoid tumor in sarcomatous stroma characterized byjbrosarcoma-like spindle cells with areas of chondroid
and osseous differentiation. Immunohistoclwmical and ultrastructural studies verified that the tumor described was a carcinoid tumor with divergent sarcomatoid differatiation rather than a mixed carcinoid tumor and sarcoma. The chondroid and osseous differentiations observed were unique features. This tuw is rare and provides an opportunity for understanding tumors with divergent components. The sarcomatoid transformation of thymic carcinoid tumor might denote highly malignant clinical behavior as illustrated by this case. HUM PATHOI. 25:319-323. Copyright 0 1994 by W.B. Saunders Company
CASE REPORT A 56year-old fisherman presented with a l-month history of dry cough, dyspnea, and tightness of the chest and was found to have a huge anterior mediastinal mass by chest roentgenographic examination and computed tomographic scan (Fig 1, left and center). Routine laboratory tests were all within normal limits. Serum alpha-fetoprotein and beta-human cho rionic gonadotropin were not elevated. A percutaneous needle biopsy specimen of the mass showed spindle tumor cells. Exploratory thoracotomy with debulking operation was performed. The tumor already invaded into the upper and middle lobes of the right lung and between the aorta and superior vena cava. Postoperatively, the patient received radiotherapy with a total dose of 4,600 cGy followed by chemotherapy. Seven months later a follow-up chest roentgenograph revealed a recurrent tumor mass at the right hilar region. A postoperative test of 24hour urinary 5-hydroxyindol acetic acid (5-HIAA) revealed no elevation.
Since the report of primary thymic carcinoid tumor by Rosai and Higa in 19’72,’ approximately 100 cases of thymic carcinoid tumor have been reported in the literature.* A va-
From the Department of Pathology, Chang Gung Medical College and Chang Gung Memorial Hospital, Kwei San, Tao Yuan, Taiwan. Accepted for publication October 20, 1993. Supported by-grants from the National Science Council of the Republic of China (NXXlJI412-B182-28 and NSC824412-B182-052) and the Chang Gung Medical Research Fund (NMRP178, NMRP274, and CMRP217) @ wurds: thymus, carcinoid tumor, sarcomatoid carcinoid tumor, sarcomatoid differentiation. Address correspondence and reprint requests to Tseng-tong Kuo, MD, PhD, Department of Pathology, Chang Gung Medical College, 259 Wen Hwa 1st Rd, Kwei San, Tao Yuan, Taiwan. Copyright 0 1994 by W.B. Saunders Company 0046-S177/94/2503-0016$5.00/0
MATERIALS AND METHODS Formalin-fixed, paraffinembedded tissues were used for light microscopic and immunohistochemical studies. Forma-
FIGURE 1. (Left) A huge anterior mediastinal tumor revealed on chest x-ray. (Center) Computed tomographic scan showing the tumor with heterogeneous densities. (Right) Gross appearance of the resected tumor. It was incompletely encapsulated, with a cystic space divlding the tumor into two solid parts that showed a variegated cut surface with hemorrhage and necrosis.
319
HUMAN
PATHOLOGY
Volume 25, No. 3 (March 1994)
FIGURE 2. (Top left) Photomicrograph showing a biphasic tumor composed of organoid epithelial islands in a cellular sarcomatous stroma. (Hematoxylin-eosin stain; original magnification x 160.) (Top center) Higher magnification of the sarcomatous stroma showing interlacing fascicles of spindle cells simulating fibrosarcoma. (Hematoxylin-eosin stain; original magnification x400.) (Top right) Higher magnification of the organoid epithelial tumor component showing islands of interconnecting ribbons of small uniform tumor cells with small round nuclei in a spindle cell sarcomatous stroma. (Hematoxylin-eosin stain: original magnification x400.) (Bottom left) The epithelial tumor growing in an ossifying stroma with osteocyte-like lacunar cells. (Hematoxylin-eosin stain; original magnification x 160.) (Bottom right) Focal hyaline cartilage-like or chondroid stroma. (Hematoxylin-eosin stain; original magnification x400.)
lin-fixed tissue also was used for electron microscopic study. Immunohistochemical study was performed with the avidinbiotin-peroxidase complex method.g The antibodies used included vimentin, chromogranin A, ACTH, calcitonin (BioGenex, San Ramon, CA), epithelial membrane antigen, neuron-specific enolase (NSE) , synaptophysin, somatostatin, SlOO protein, KPl (Dakopatts, Glostrup, Denmark), HHF-35 (Enzo, New York, NY), and AEl, AE2, and AE3 (Dr T.T. Sun, New York University Hospital). RESULTS Patholqic
Findings
Gross Pathology The resected tumor was a partially encapsulated mass measuring 8 X 11.5 X 15 cm and weighing 710 g. There was a cystic space dividing the tumor into two solid parts (Fig 1,
320
right). The cut surface was variegated and gray-tan in color, had foci of hemorrhage and necrosis, and was soft to hard in consistency. Microscopic Pathology Microscopic examination revealed a biphasic tumor composed of organoid epithelial islands in a cellular sarcomatous stroma (Fig 2, top left). The bulk of the tumor was composed of fibrosarcoma-like interlacing fascicles of spindle cells (Fig 2, top center). The epithelial tumor component was found scattered in the sarcomatous spindle cell stroma, mainly in the peripheral portion of the tumor. The epithelial component consisted of small uniform cells with small round nuclei, indistinct nucleoli, and granular eosinophilic cytoplasm. Some of them had a columnar cell appearance. They formed solid, glandular, and insular structures with an organoid appearance (Fig 2, top left). The latter were formed by interconnecting
CASE STUDIES
FIQURE 3. (Top left) The epitheiial tumor ceils were immunostained by anti-keratin AEl. Note that the dissociated plump cells (arrows) also were positive, but the spindle stromai cells were largely negative. (Original magnification x400.) (Top right) The epithelial tumor ceils and the dissociated plump ceils were strongly immunostained by anti-vimentin. Some spindle cells were slightly stained in this area. (Original magnification x400.) (Bottom) The epitheliai tumor cells and the dissociated plump cells were strongly lmmunoreactive for NSE. The spindle cells were negatlve. (Original magnification x400.)
ribbons of tumor cells (Fig 2, top right). In some areas the epithelial tumor component was seen embedded in an ossifying stroma characterized by irregular networks of bright eosinophilic osteoid with osteocyte-like lacunar cells and osteo blast-like cells rimming the borders (Fig 2, bottom left). No
321
overt calcification was seen. Other areas showed hyaline cartilage-like or chondroid stroma (Fig 2, bottom right). However, no myoid cells were found. Around the epithelial tumor components there were dissociated plump tumor cells intermingled with spindle tumor cells. Frequent mitosis was seen
HUMAN TABLE
1. lmmunohistochemical
Antibody Vimentin AEl AE2 AE3 EMA HHF-35 KPl NSE Synaptophysin Chromogranin A Somatostatin ACTH Calcitonin Sl 00 protein
Epithelial Cells
PATHOLOGY
Volume 25, No. 3 (March 1994)
Study
Isolated Plump Cells
+++ +++ _ _ _
+++ +++ _ _ _ _
+++ % _
+++ 5 _
5 _ _ -
5 _ _
Electron MicroscopY The epithelial tumor cells contained a few to moderate number of scattered membrane-bound neurosecretory granules, many mitochondria, lipid droplets, rough endoplasmic reticulum, and ribosomal particles with cellularjunctions (Fig 4). A variable amount of intermediate filaments also was seen and occasionally formed paranuclear whorling aggregates. The isolated plump tumor cells showed similar features, but the spindle tumor cells had few organelles. Neurosecretory granules were not found in the latter cells.
Spindle Cells + or ++or_ _ _ _ _ _ _ _ _ _ _ _
DISCUSSION
Abbreviation: EMA, epithelial membrane antigen. Symbols: -, negative; +, weakly positive; + +, moderately positive;
+ + +, strongly positive; ?, very weaklypositive.
in both tumor components. Other features observed included spotty calcification, small and large cystic spaces without special lining cells, and areas of hemorrhage and necrosis. Thymic tissue was present around the tumor. All six of the regional lymph nodes that were found contained metastatic deposits of only the epithelial tumor component. Zmmunohistiemistyy The results of the immunohistochemical study are summarized in Table 1. The epithelial tumor cells and the isolated plump cells were positive for anti-keratin AEl, vimentin, and NSE (Fig 3). They also were weakly positive for synaptophysin and somatostatin. Some but not all the spindle tumor cells were positive for AEl and/or vimentin (Fig 3, top left and top right) but negative for all other antibodies tested. The hyaline cartilage-like stroma was not positive for S-100 protein.
The tumor described in this report was a biphasic tumor composed of an epithelial tumor component embedded in sarcomatous stroma with predominantly fibrosarcoma-like spindle cells and areas of chondroid and osseous differentiation. The tumor was located within the thymus. Therefore, other mediastinal biphasic tumors, such as mesothelioma, mali nant peripheral nerve sheath tumor, and synovial sarcoma, Y” were not considered. A biphasic tumor of the thymus can be a carcinosarcoma or sarcomatoid carcinoma,” depending on the nature of the sarcomatous component, and the epithelial component usually is a thymic carcinoma. However, the epithelial component seen in this tumor was different from ordinary thymic carcinoma. It had an .organoid histologic ap pearance suggesting a carcinoid tumor, which was confirmed by immunohistochemical and ultrastructural studies (including ositive immunostaining for cytokeratin, vimentin, and NSE P‘-r“) and the presence of neurosecretory granules and occasional pamnuclear whorls of intermediate filaments5~“~‘“‘” The stromal component was fibrosarcomatous with chondroid and osseous differentiation. However, only a limited number of the sarcomatous spindle cells were positive for vimentin, while some spindle cells also expressed cytokeratin staining. Although they were negative for NSE, the decreased vimentin reactivity along with the occasional detection of cytokeratin seemed to link them more closely to the carcinoid tumor cells than the mesenchymal cells, because co-expres-
FIQURE 4. Electron micrograph of the carcinoid tumor cells showing scattered membrane-bound neurosecretory granules (arrows), abundant mitochondria, rough endoplasmic reticulum, and ribosomal particles. (Inset) A group of enlarged neurosecretory granules and intermediate filaments. (Original magnification x2.400. Inset: original magnification x36,000.)
322
CASE STUDIES
sion of cytokeratin and vimentin has been well documented for carcinoid tumors.i4 The presence of dissociated plump tumor cells with immunohistochemical and ultrastructural features similar to the carcinoid tumor cells further linked the spindle tumor cells to the carcinoid tumor cells. Presumably, the spindle tumor cells might have evolved from the carcinoid tumor cells via an intermediate form of dissociated plump tumor cells with a gradual loss of the epithelial nature of the carcinoid tumor cells. This single clonal evolution hypothesis is supported by increasing evidence and observations made on tumors composed of mixed cellular components.‘g”J Therefore, the tumor described here appeared to be a carcinoid tumor with divergent sarcomatoid differentiation rather than a mixed carcinoid tumor and sarcoma. The chondroid and osseous areas merely represented further metaplastic change of the spindle cells. There have been reports of variants of thymic carcinoid tumors..97 Only the case reported by Paties et al8 resembled the present tumor with minor differences in sarcomatoid components and immunophenotype of the cellular components. No osseous or chondroid components were described in their tumor. Nevertheless, their results of immunohistochemical study also supported a sarcomatoid carcinoid tumor rather than a mixed carcinoid tumor and sarcoma. The hormone most commonly detected in thymic carcinoid tumors has been ACTH,*.’ which was not found in this tumor. Only weak somatostatin staining was detected. Thymic carcinoid tumors usually do not manifest carcinoid syndrome. The case reported by Paties et al’ was an exception. Although the present tumor shared similar morphologic features with the latter case, the patient did not have carcinoid syndrome or an elevated urinary 5-HIAA. However, the highly malignant clinical behavior of the present tumor was similar to the case reported by Paties et al.’ A sarcomatoid divergent differentiation of a thymic carcinoid tumor might denote a worse prognosis.
2. Wollensak G, Herbst EW, Beck A, et al: Primary thymic carcinoid with Gushing’s syndrome. Virchows Arch A Pathol Anat Histopathol 420:191-195, 1992 3. Levine GD, Rosai J: A spindle cell variant of thymic carcinoid tumor. A clinical, histologic, and fine structural study with emphasis on its distinction from spindle cell thymoma. Arch Pathol Lab Med 100:293-300,1976 4. Ho FCS, Ho JCI: Pigmented carcinoid tumor of the thymus. Histopathology 1:365369,1977 5. FetissofF, Boivin F. Arbeille-Brassart B, et al: Microtilamentous carcinoid of the thymus: Correlation of uluastructural study with Grimelius stain. Ultrastr Path01 3:415,1982 6. Lagrange W, Dahm H-H, Earsten J, et al: Melanocytic neuroendocrine carcinoma of the thymus. Cancer 59:484X(8,1987 7. Wick MR, Rosai J: Neuroendocrine neoplasms of the mediastinum. Semin Diagn Pathol8:35-51, 1991 8. Paties C, Zangrandi A, Vassal10 G: Multidirectional carcinoma of the thymus with neuroendocrine and sarcomatoid components and carcinoid syndrome. Pathol Res Pratt 187:170-177,199l 9. Hsu SM, Raine L, Fanger H: Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577-580,198l 10. Witkin GB, Miettinen M, Rosai J: A biphasic tumor of the mediastinum with features of synovial sarcoma. A report of four cases. Am J Surg Pathol 13:490-499,1989 11. Levine CD, Rosai J: Thymic hyperplasia and neoplasia: A review of current concepts. HUM PATHOL9:495515,1978 12. Wick MR, Scheithauer BW: Thymic carcinoid. A histologic, immune histochemical, and ultrastructural study of 12 cases. Cancer 53:475484, 1984 13. Herbst WM, Kummer W, Hofmann W, et al: Carcinoid tumors of the thymus. An immunohistochemical study. Cancer 60:2465-2470,1987 14. Kimura N, Sasano N, Namiki T, et al: Coexpression of cytokeratin, neurofilament and vimentin in carcinoid tumors. Virchows Arch A Pathol Anat Histopathol 415:69-77. 1989 15. Carstens PHB, Broghamer WL, Jr: Duodenal carcinoid with cytoplasmic whorls of microfilaments. J Path01 124:235-238, 1978 16. Alvarez-Fernandez E: Intracytoplasmic fibrillaty inclusions in bronchial carcinoid. Cancer 46:144151,1980 17. Wick MR. Carney JA, Bernatz PE, et al: Primary mediastinal carcinoid tumors. Am J Surg Path01 6195205,1982 18. Wick MR, Rosai J: Neuroendocrine neoplasms of the thymus. Pathol Res Pratt 183:18&199.1988 19. Gould VE, Memoli VA, Dardi LE: Multidirectional differentiation in human epithelial cancers. J Submicrosc Cytol 13~97-115, 1981 20. Brooks J: The significance of double phenotypic patterns and markers in human sarcomas. Am J Pathol 125:11%123,1986 21. Masuda A, Takeda A, Fukami H, et al: Characteristics of cell lines es tablished from a mixed mesodermal tumor of the human ovaly. Carcinomatous cells are changeable to sarcomatous cells. Cancer 60:269&2703,1987 22. Doglioni C, Ferlito A, Chiamenti C, et al: Laryngeal carcinoma showing multidirectional epithelial neuroendocrine and sarcomatom differentiation. ORL J Otorhinolayngol R&t Spec 52:316326,1990 23. Gorai I, Doi C, Minaguchi H: Establishment and characterization of carcinosarcoma cell line of the human wetus. Cancer 71:77.5786,1993
Acknowledgmat. The author thanks Dr Juan Rosai for reviewing this case and Dr Tung-Tien Sun for providing the anti-keratin antibodies AEl, AEZ, and AE3. Shiu-Ming Cheng typed the manuscript.
REFERENCES 1. Rosai J, Higa E: Mediastinal endocrine neoplasm of probable thymic origin, related to carcinoid tumor. Clinicopathologic study of 8 cases. Cancer 29:1061-1074.1972
EARLY
RECURRENCE
OF CHRONIC
ACTIVE
MYOCARDITIS
AFTER
HEART
TRANSPLANTATION
KIM LORIA, MD, JOSE JESSURUN, MD, SARAJ. SHUMWAY, MD, AND SPENCER H. KUBO, MD
transplantation recurrent disease has been reported for amyloid,” sarcoidosis,s Chagas’ disease,4 and giant cell myocarditis.“.‘j In this report we describe the first apparent case of chronic active myocarditis that was found unexpectedly in the explanted heart and that recurred in the allograft within 6 months after transplantation.
One relative contraindication to heart transplantation is a disease process that is likely to recur in the allograft. Recurrent disease has been well documented in renal transplantation and is associated with decreased graft survival.’ In heart From the Heart Failure-Heart Transplantation ProRram, Cardiovascular Division, Department of Medicine; the Department of Surgical Pathology; and the Division of Cardiothoracic Surgery, University of Minnesota Medical School, Minneapolis, MN. Accepted for publication October 29, 1993. @ words: myocarditis, heart transplantation, chronic active myocarditis. Address correspondence and reprint requests to Spencer H. Kubo, MD, Heart Failure-Heart Transplantation Program, Cardiovas cular Division, Department of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. Copyright 0 1994 by W.B. Saunders Company 004&S177/94/2503-0017$5.00/0
CASE REPORT The patient was a 49-year-old white woman who was in good health until she developed a viral syndrome with fever, arthralgias, myalgias, and a nonproductive cough. After she developed dyspnea on exertion and orthopnea, an echocardiogram revealed a dilated cardiomyopathy with global left ventricular dysfunction. The ejection fraction was 9% by gated blood pool scan. The pulmonary artery pressure was 39/24 mm Hg, the mean pulmonary wedge pressure was 22 mm Hg, and the cardiac output was 2.6 L/min. An endomyocardial
323
DIFFERENTIATION:
TSENGTONC Kuo, MD, PHD
riety of histologic variants of thymic carcinoid tumor have been described.%’ These variants include spindle cell, sclerotic, pigmented, microfilamentous, diffuse lymphoma-like, and medullary carcinoma of the thyroid-like thymic carcinoid tumors. We encountered a carcinoid tumor of the thymus with divergent sarcomatoid differentiation. One similar but not identical tumor was described by Paties et al’ in 1991. Our case is reported with immunohistochemical and ultrastructural studies with a discussion of its histogenesis.
An anterior mediastinal tumor resected f;rom a Nyear-old man without parane#astic symptoms was found to be an unusual biphasic thymic tumor composed of carcinoid tumor in sarcomatous stroma characterized byjbrosarcoma-like spindle cells with areas of chondroid
and osseous differentiation. Immunohistoclwmical and ultrastructural studies verified that the tumor described was a carcinoid tumor with divergent sarcomatoid differatiation rather than a mixed carcinoid tumor and sarcoma. The chondroid and osseous differentiations observed were unique features. This tuw is rare and provides an opportunity for understanding tumors with divergent components. The sarcomatoid transformation of thymic carcinoid tumor might denote highly malignant clinical behavior as illustrated by this case. HUM PATHOI. 25:319-323. Copyright 0 1994 by W.B. Saunders Company
CASE REPORT A 56year-old fisherman presented with a l-month history of dry cough, dyspnea, and tightness of the chest and was found to have a huge anterior mediastinal mass by chest roentgenographic examination and computed tomographic scan (Fig 1, left and center). Routine laboratory tests were all within normal limits. Serum alpha-fetoprotein and beta-human cho rionic gonadotropin were not elevated. A percutaneous needle biopsy specimen of the mass showed spindle tumor cells. Exploratory thoracotomy with debulking operation was performed. The tumor already invaded into the upper and middle lobes of the right lung and between the aorta and superior vena cava. Postoperatively, the patient received radiotherapy with a total dose of 4,600 cGy followed by chemotherapy. Seven months later a follow-up chest roentgenograph revealed a recurrent tumor mass at the right hilar region. A postoperative test of 24hour urinary 5-hydroxyindol acetic acid (5-HIAA) revealed no elevation.
Since the report of primary thymic carcinoid tumor by Rosai and Higa in 19’72,’ approximately 100 cases of thymic carcinoid tumor have been reported in the literature.* A va-
From the Department of Pathology, Chang Gung Medical College and Chang Gung Memorial Hospital, Kwei San, Tao Yuan, Taiwan. Accepted for publication October 20, 1993. Supported by-grants from the National Science Council of the Republic of China (NXXlJI412-B182-28 and NSC824412-B182-052) and the Chang Gung Medical Research Fund (NMRP178, NMRP274, and CMRP217) @ wurds: thymus, carcinoid tumor, sarcomatoid carcinoid tumor, sarcomatoid differentiation. Address correspondence and reprint requests to Tseng-tong Kuo, MD, PhD, Department of Pathology, Chang Gung Medical College, 259 Wen Hwa 1st Rd, Kwei San, Tao Yuan, Taiwan. Copyright 0 1994 by W.B. Saunders Company 0046-S177/94/2503-0016$5.00/0
MATERIALS AND METHODS Formalin-fixed, paraffinembedded tissues were used for light microscopic and immunohistochemical studies. Forma-
FIGURE 1. (Left) A huge anterior mediastinal tumor revealed on chest x-ray. (Center) Computed tomographic scan showing the tumor with heterogeneous densities. (Right) Gross appearance of the resected tumor. It was incompletely encapsulated, with a cystic space divlding the tumor into two solid parts that showed a variegated cut surface with hemorrhage and necrosis.
319
HUMAN
PATHOLOGY
Volume 25, No. 3 (March 1994)
FIGURE 2. (Top left) Photomicrograph showing a biphasic tumor composed of organoid epithelial islands in a cellular sarcomatous stroma. (Hematoxylin-eosin stain; original magnification x 160.) (Top center) Higher magnification of the sarcomatous stroma showing interlacing fascicles of spindle cells simulating fibrosarcoma. (Hematoxylin-eosin stain; original magnification x400.) (Top right) Higher magnification of the organoid epithelial tumor component showing islands of interconnecting ribbons of small uniform tumor cells with small round nuclei in a spindle cell sarcomatous stroma. (Hematoxylin-eosin stain: original magnification x400.) (Bottom left) The epithelial tumor growing in an ossifying stroma with osteocyte-like lacunar cells. (Hematoxylin-eosin stain; original magnification x 160.) (Bottom right) Focal hyaline cartilage-like or chondroid stroma. (Hematoxylin-eosin stain; original magnification x400.)
lin-fixed tissue also was used for electron microscopic study. Immunohistochemical study was performed with the avidinbiotin-peroxidase complex method.g The antibodies used included vimentin, chromogranin A, ACTH, calcitonin (BioGenex, San Ramon, CA), epithelial membrane antigen, neuron-specific enolase (NSE) , synaptophysin, somatostatin, SlOO protein, KPl (Dakopatts, Glostrup, Denmark), HHF-35 (Enzo, New York, NY), and AEl, AE2, and AE3 (Dr T.T. Sun, New York University Hospital). RESULTS Patholqic
Findings
Gross Pathology The resected tumor was a partially encapsulated mass measuring 8 X 11.5 X 15 cm and weighing 710 g. There was a cystic space dividing the tumor into two solid parts (Fig 1,
320
right). The cut surface was variegated and gray-tan in color, had foci of hemorrhage and necrosis, and was soft to hard in consistency. Microscopic Pathology Microscopic examination revealed a biphasic tumor composed of organoid epithelial islands in a cellular sarcomatous stroma (Fig 2, top left). The bulk of the tumor was composed of fibrosarcoma-like interlacing fascicles of spindle cells (Fig 2, top center). The epithelial tumor component was found scattered in the sarcomatous spindle cell stroma, mainly in the peripheral portion of the tumor. The epithelial component consisted of small uniform cells with small round nuclei, indistinct nucleoli, and granular eosinophilic cytoplasm. Some of them had a columnar cell appearance. They formed solid, glandular, and insular structures with an organoid appearance (Fig 2, top left). The latter were formed by interconnecting
CASE STUDIES
FIQURE 3. (Top left) The epitheiial tumor ceils were immunostained by anti-keratin AEl. Note that the dissociated plump cells (arrows) also were positive, but the spindle stromai cells were largely negative. (Original magnification x400.) (Top right) The epithelial tumor ceils and the dissociated plump ceils were strongly immunostained by anti-vimentin. Some spindle cells were slightly stained in this area. (Original magnification x400.) (Bottom) The epitheliai tumor cells and the dissociated plump cells were strongly lmmunoreactive for NSE. The spindle cells were negatlve. (Original magnification x400.)
ribbons of tumor cells (Fig 2, top right). In some areas the epithelial tumor component was seen embedded in an ossifying stroma characterized by irregular networks of bright eosinophilic osteoid with osteocyte-like lacunar cells and osteo blast-like cells rimming the borders (Fig 2, bottom left). No
321
overt calcification was seen. Other areas showed hyaline cartilage-like or chondroid stroma (Fig 2, bottom right). However, no myoid cells were found. Around the epithelial tumor components there were dissociated plump tumor cells intermingled with spindle tumor cells. Frequent mitosis was seen
HUMAN TABLE
1. lmmunohistochemical
Antibody Vimentin AEl AE2 AE3 EMA HHF-35 KPl NSE Synaptophysin Chromogranin A Somatostatin ACTH Calcitonin Sl 00 protein
Epithelial Cells
PATHOLOGY
Volume 25, No. 3 (March 1994)
Study
Isolated Plump Cells
+++ +++ _ _ _
+++ +++ _ _ _ _
+++ % _
+++ 5 _
5 _ _ -
5 _ _
Electron MicroscopY The epithelial tumor cells contained a few to moderate number of scattered membrane-bound neurosecretory granules, many mitochondria, lipid droplets, rough endoplasmic reticulum, and ribosomal particles with cellularjunctions (Fig 4). A variable amount of intermediate filaments also was seen and occasionally formed paranuclear whorling aggregates. The isolated plump tumor cells showed similar features, but the spindle tumor cells had few organelles. Neurosecretory granules were not found in the latter cells.
Spindle Cells + or ++or_ _ _ _ _ _ _ _ _ _ _ _
DISCUSSION
Abbreviation: EMA, epithelial membrane antigen. Symbols: -, negative; +, weakly positive; + +, moderately positive;
+ + +, strongly positive; ?, very weaklypositive.
in both tumor components. Other features observed included spotty calcification, small and large cystic spaces without special lining cells, and areas of hemorrhage and necrosis. Thymic tissue was present around the tumor. All six of the regional lymph nodes that were found contained metastatic deposits of only the epithelial tumor component. Zmmunohistiemistyy The results of the immunohistochemical study are summarized in Table 1. The epithelial tumor cells and the isolated plump cells were positive for anti-keratin AEl, vimentin, and NSE (Fig 3). They also were weakly positive for synaptophysin and somatostatin. Some but not all the spindle tumor cells were positive for AEl and/or vimentin (Fig 3, top left and top right) but negative for all other antibodies tested. The hyaline cartilage-like stroma was not positive for S-100 protein.
The tumor described in this report was a biphasic tumor composed of an epithelial tumor component embedded in sarcomatous stroma with predominantly fibrosarcoma-like spindle cells and areas of chondroid and osseous differentiation. The tumor was located within the thymus. Therefore, other mediastinal biphasic tumors, such as mesothelioma, mali nant peripheral nerve sheath tumor, and synovial sarcoma, Y” were not considered. A biphasic tumor of the thymus can be a carcinosarcoma or sarcomatoid carcinoma,” depending on the nature of the sarcomatous component, and the epithelial component usually is a thymic carcinoma. However, the epithelial component seen in this tumor was different from ordinary thymic carcinoma. It had an .organoid histologic ap pearance suggesting a carcinoid tumor, which was confirmed by immunohistochemical and ultrastructural studies (including ositive immunostaining for cytokeratin, vimentin, and NSE P‘-r“) and the presence of neurosecretory granules and occasional pamnuclear whorls of intermediate filaments5~“~‘“‘” The stromal component was fibrosarcomatous with chondroid and osseous differentiation. However, only a limited number of the sarcomatous spindle cells were positive for vimentin, while some spindle cells also expressed cytokeratin staining. Although they were negative for NSE, the decreased vimentin reactivity along with the occasional detection of cytokeratin seemed to link them more closely to the carcinoid tumor cells than the mesenchymal cells, because co-expres-
FIQURE 4. Electron micrograph of the carcinoid tumor cells showing scattered membrane-bound neurosecretory granules (arrows), abundant mitochondria, rough endoplasmic reticulum, and ribosomal particles. (Inset) A group of enlarged neurosecretory granules and intermediate filaments. (Original magnification x2.400. Inset: original magnification x36,000.)
322
CASE STUDIES
sion of cytokeratin and vimentin has been well documented for carcinoid tumors.i4 The presence of dissociated plump tumor cells with immunohistochemical and ultrastructural features similar to the carcinoid tumor cells further linked the spindle tumor cells to the carcinoid tumor cells. Presumably, the spindle tumor cells might have evolved from the carcinoid tumor cells via an intermediate form of dissociated plump tumor cells with a gradual loss of the epithelial nature of the carcinoid tumor cells. This single clonal evolution hypothesis is supported by increasing evidence and observations made on tumors composed of mixed cellular components.‘g”J Therefore, the tumor described here appeared to be a carcinoid tumor with divergent sarcomatoid differentiation rather than a mixed carcinoid tumor and sarcoma. The chondroid and osseous areas merely represented further metaplastic change of the spindle cells. There have been reports of variants of thymic carcinoid tumors..97 Only the case reported by Paties et al8 resembled the present tumor with minor differences in sarcomatoid components and immunophenotype of the cellular components. No osseous or chondroid components were described in their tumor. Nevertheless, their results of immunohistochemical study also supported a sarcomatoid carcinoid tumor rather than a mixed carcinoid tumor and sarcoma. The hormone most commonly detected in thymic carcinoid tumors has been ACTH,*.’ which was not found in this tumor. Only weak somatostatin staining was detected. Thymic carcinoid tumors usually do not manifest carcinoid syndrome. The case reported by Paties et al’ was an exception. Although the present tumor shared similar morphologic features with the latter case, the patient did not have carcinoid syndrome or an elevated urinary 5-HIAA. However, the highly malignant clinical behavior of the present tumor was similar to the case reported by Paties et al.’ A sarcomatoid divergent differentiation of a thymic carcinoid tumor might denote a worse prognosis.
2. Wollensak G, Herbst EW, Beck A, et al: Primary thymic carcinoid with Gushing’s syndrome. Virchows Arch A Pathol Anat Histopathol 420:191-195, 1992 3. Levine GD, Rosai J: A spindle cell variant of thymic carcinoid tumor. A clinical, histologic, and fine structural study with emphasis on its distinction from spindle cell thymoma. Arch Pathol Lab Med 100:293-300,1976 4. Ho FCS, Ho JCI: Pigmented carcinoid tumor of the thymus. Histopathology 1:365369,1977 5. FetissofF, Boivin F. Arbeille-Brassart B, et al: Microtilamentous carcinoid of the thymus: Correlation of uluastructural study with Grimelius stain. Ultrastr Path01 3:415,1982 6. Lagrange W, Dahm H-H, Earsten J, et al: Melanocytic neuroendocrine carcinoma of the thymus. Cancer 59:484X(8,1987 7. Wick MR, Rosai J: Neuroendocrine neoplasms of the mediastinum. Semin Diagn Pathol8:35-51, 1991 8. Paties C, Zangrandi A, Vassal10 G: Multidirectional carcinoma of the thymus with neuroendocrine and sarcomatoid components and carcinoid syndrome. Pathol Res Pratt 187:170-177,199l 9. Hsu SM, Raine L, Fanger H: Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577-580,198l 10. Witkin GB, Miettinen M, Rosai J: A biphasic tumor of the mediastinum with features of synovial sarcoma. A report of four cases. Am J Surg Pathol 13:490-499,1989 11. Levine CD, Rosai J: Thymic hyperplasia and neoplasia: A review of current concepts. HUM PATHOL9:495515,1978 12. Wick MR, Scheithauer BW: Thymic carcinoid. A histologic, immune histochemical, and ultrastructural study of 12 cases. Cancer 53:475484, 1984 13. Herbst WM, Kummer W, Hofmann W, et al: Carcinoid tumors of the thymus. An immunohistochemical study. Cancer 60:2465-2470,1987 14. Kimura N, Sasano N, Namiki T, et al: Coexpression of cytokeratin, neurofilament and vimentin in carcinoid tumors. Virchows Arch A Pathol Anat Histopathol 415:69-77. 1989 15. Carstens PHB, Broghamer WL, Jr: Duodenal carcinoid with cytoplasmic whorls of microfilaments. J Path01 124:235-238, 1978 16. Alvarez-Fernandez E: Intracytoplasmic fibrillaty inclusions in bronchial carcinoid. Cancer 46:144151,1980 17. Wick MR. Carney JA, Bernatz PE, et al: Primary mediastinal carcinoid tumors. Am J Surg Path01 6195205,1982 18. Wick MR, Rosai J: Neuroendocrine neoplasms of the thymus. Pathol Res Pratt 183:18&199.1988 19. Gould VE, Memoli VA, Dardi LE: Multidirectional differentiation in human epithelial cancers. J Submicrosc Cytol 13~97-115, 1981 20. Brooks J: The significance of double phenotypic patterns and markers in human sarcomas. Am J Pathol 125:11%123,1986 21. Masuda A, Takeda A, Fukami H, et al: Characteristics of cell lines es tablished from a mixed mesodermal tumor of the human ovaly. Carcinomatous cells are changeable to sarcomatous cells. Cancer 60:269&2703,1987 22. Doglioni C, Ferlito A, Chiamenti C, et al: Laryngeal carcinoma showing multidirectional epithelial neuroendocrine and sarcomatom differentiation. ORL J Otorhinolayngol R&t Spec 52:316326,1990 23. Gorai I, Doi C, Minaguchi H: Establishment and characterization of carcinosarcoma cell line of the human wetus. Cancer 71:77.5786,1993
Acknowledgmat. The author thanks Dr Juan Rosai for reviewing this case and Dr Tung-Tien Sun for providing the anti-keratin antibodies AEl, AEZ, and AE3. Shiu-Ming Cheng typed the manuscript.
REFERENCES 1. Rosai J, Higa E: Mediastinal endocrine neoplasm of probable thymic origin, related to carcinoid tumor. Clinicopathologic study of 8 cases. Cancer 29:1061-1074.1972
EARLY
RECURRENCE
OF CHRONIC
ACTIVE
MYOCARDITIS
AFTER
HEART
TRANSPLANTATION
KIM LORIA, MD, JOSE JESSURUN, MD, SARAJ. SHUMWAY, MD, AND SPENCER H. KUBO, MD
transplantation recurrent disease has been reported for amyloid,” sarcoidosis,s Chagas’ disease,4 and giant cell myocarditis.“.‘j In this report we describe the first apparent case of chronic active myocarditis that was found unexpectedly in the explanted heart and that recurred in the allograft within 6 months after transplantation.
One relative contraindication to heart transplantation is a disease process that is likely to recur in the allograft. Recurrent disease has been well documented in renal transplantation and is associated with decreased graft survival.’ In heart From the Heart Failure-Heart Transplantation ProRram, Cardiovascular Division, Department of Medicine; the Department of Surgical Pathology; and the Division of Cardiothoracic Surgery, University of Minnesota Medical School, Minneapolis, MN. Accepted for publication October 29, 1993. @ words: myocarditis, heart transplantation, chronic active myocarditis. Address correspondence and reprint requests to Spencer H. Kubo, MD, Heart Failure-Heart Transplantation Program, Cardiovas cular Division, Department of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. Copyright 0 1994 by W.B. Saunders Company 004&S177/94/2503-0017$5.00/0
CASE REPORT The patient was a 49-year-old white woman who was in good health until she developed a viral syndrome with fever, arthralgias, myalgias, and a nonproductive cough. After she developed dyspnea on exertion and orthopnea, an echocardiogram revealed a dilated cardiomyopathy with global left ventricular dysfunction. The ejection fraction was 9% by gated blood pool scan. The pulmonary artery pressure was 39/24 mm Hg, the mean pulmonary wedge pressure was 22 mm Hg, and the cardiac output was 2.6 L/min. An endomyocardial
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