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Lipid-rich diffuse malignant mesothelioma: A case report
HUMAN PATHOLOGY
Volume 31, No. 7 (July 2000)
LIPID-RICH DIFFUSE MALIGNANT MESOTHELIOMA: A CASE REPORT HOWARD T. CHANG, MD, RHONDA K. YANTISS, MD, G. PETUR NIELSEN, MD, GRACE T. MCKEE, MD, AND EUGENE J. MARK, MD An 80-year old man presented with shortness of breath and was found to have a large right pleural effusion. Cytology of the pleural fluid showed atypical papillary clusters of epithelioid cells. Multiple white-yellow nodules studding the pleural surfaces were seen at thoracoscopy, and biopsies showed solid and papillary clusters of large epithelioid cells with abundant cytoplasm filled with clear vacuoles. Special stains and electron microscopic findings indicated that the tumor was a diffuse malignant mesothelioma with numerous
intracytoplasmic lipid vacuoles. Fat stain may be useful at time of frozen section for a pleural-based tumor with vacuolated cells, and the presence of lipid vacuoles in a pleural-based tumor does not exclude diffuse malignant mesothelioma. HUM PATHOL 31:876-879. Copyright 娀 2000 by W.B. Saunders Company Key words: malignant mesothelioma, intracytoplasmic lipid. Abbreviations: PTA, prior to admission; VATS, video-assisted thoracoscopy.
Several types of diffuse malignant mesothelioma of the pleura have been described based on their distinctive light microscopic appearances. These include epithelioid, mixed (biphasic), sarcomatoid, desmoplastic, and transitional/ poorly differentiated variants. Epithelioid malignant mesotheliomas may have a tubulopapillary or glandular architecture, but some are solid and others have a microcystic pattern. One may see large or giant cells, small cells, or even signet-ring cells. We report a case of an unusual epithelioid mesothelioma characterized by numerous intracytoplasmic lipid vacuoles.
PTA. Imaging studies showed a large right-sided pleural effusion that was aspirated to yield straw-colored fluid with moderate numbers of white and red blood cells and pH, 7.7; glucose, 100 mg/dL (plasma glucose, 161 mg/dL); total protein, 4.6 g/dL (blood total protein, 7.2 g/dL); albumin, 2.8 g/dL (blood albumin, 3.8 g/dL); and lactate dehydrogenase (LDH), 503 U/L (blood LDH, 209 U/L). The blood prostate specific antigen was 1.9 ng/mL (normal, 0-4). Cultures were negative for acid-fast, fungal, or bacterial organisms. Cytological examination showed numerous atypical papillary clusters that were interpreted to be reactive mesothelial cells (Fig 1A), though the possibility of an adenocarcinoma could not be excluded. Subsequent video-assisted thoracoscopy (VATS) showed multiple white-yellow nodules, 1-2 cm in size, studding the right pleural surface. Biopsies were obtained and submitted for intraoperative consultation. A second sample of pleural fluid obtained at this time showed clusters of malignant cells with features of both adenocarcinoma and mesothelioma (Fig 1B). The patient then underwent pleurodesis with insufflated talc and was later discharged in stable condition.
REPORT OF A CASE An 80-year-old man presented with progressive shortness of breath and chest pain over a period of several weeks. His medical history was significant for in situ ductal carcinoma of the breast that was treated by mastectomy with negative lymph nodes 10 years prior to admission (PTA), a colonic tubulovillous adenoma resected 8 years PTA, and prostate carcinoma (Gleason grade 3/5) treated with radiation implants 4 years
From the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Address correspondence and reprint requests to Eugene J. Mark, MD, Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. Copyright 娀 2000 by W.B. Saunders Company 0046-8177/00/3107-0019$10.00/0 doi:10.1053/hupa.2000.7628
PATHOLOGICAL FINDINGS The tumor consisted of branching glands and papillae lined by plump epithelioid cells (Fig 2A). Infiltrating nests, cords, and single cells were also present within desmoplastic stroma. The cells were cytologically atypical with large, slightly irregular nuclei, coarse chromatin, and prominent nucleoli
876
CASE STUDIES
FIGURE 1. (A) The original pleural fluid sample shows papillary clusters of atypical cells. (B) The second pleural fluid sample shows malignant cells, several with vacuolated cytoplasm.
FIGURE 2. (A) Low-power view of papillary lesion with branching glands. (B) The tumor is composed of cytologically atypical cells with enlarged nuclei and prominent central nucleoli. (C) In some areas, the nuclei are compressed by numerous intracytoplasmic vacuoles. (D) An Oil Red-O stain shows that the intracytoplasmic vacuoles contain abundant lipid. (E) The tumor cells are strongly and diffusely positive for calretinin. (F) Cytoplasmic staining for Leu-M1 is also present throughout the tumor.
877
HUMAN PATHOLOGY
Volume 31, No. 7 (July 2000)
of mesothelial cells, were identified on the cell surfaces (Fig 3B).
COMMENTS
FIGURE 3. (A) Cohesive epithelioid cells with abundant intracytoplasmic lipid (L), microvilli (asterisk), and intercellular junctions (arrowhead). (B) High magnification of long microvilli on surfaces of tumor cells.
and scattered mitotic figures (Fig 2B). The most striking finding, however, was the presence of large cytoplasmic vacuoles that contained lipid by Oil Red-O stain (Fig 2C, D) in many cells. Mucin stains (mucicarmine, alcian blue) were negative. Immunohistochemical studies performed on formalin-fixed, paraffin-embedded tissue showed staining of tumor cells for calretinin (Fig 2E), keratin, Leu M-1 (Fig 2F), and focal staining for carcinoembryonic antigen (CEA). The tumor cells were negative for estrogen and progesterone receptors, GCDFP-15, prostatic acid phosphatase, prostate specific antigen, and B72.3. Electron microscopic examination showed that the tumor cells were cohesive with external basal lamina and intercellular junctions. The cytoplasm contained an admixture of various organelles, including tonofibrils as well as abundant intracytoplasmic lipid (Fig 3A). Numerous long, delicate, branching, and intertwining microvilli, characteristic
The current case posed a diagnostic challenge in many respects. First, the patient had a history of multiple neoplasms (in situ adenocarcinoma of the breast, prostatic adenocarcinoma, and colonic adenoma), all of which are composed of cells that can contain intracytoplasmic vacuoles, and many of the neoplastic cells in the pleura had numerous cytoplasmic vacuoles more characteristic of adenocarcinoma than malignant mesothelioma. Furthermore, review of the previous prostate biopsies showed numerous cytoplasmic vacuoles within those tumor cells as well. Moreover, the immunostains were of limited value in that the tumor cells stained for calretinin, as would be expected in mesothelioma,1 but also stained for Leu-M1 and CEA, which is more characteristic of carcinoma.2 However, the issue was resolved by electron microscopy, which showed long microvilli on the tumor cells consistent with mesothelial differentiation.3-5 The mesothelioma reported herein is best categorized as a malignant epithelioid mesothelioma with a tubulopapillary architecture composed of cells containing prominent intracytoplasmic vacuoles. The differential diagnosis includes other variants of malignant mesothelioma such as the relatively rare signet-ring cell malignant mesothelioma as well as many other tumors known to have cytoplasmic lipid vacuoles, such as those arising from the kidney, adrenal gland, and soft tissues. However, the signet-ring cell mesothelioma is characterized by mucin-containing cytoplasmic vacuoles.6 The architectural growth pattern of our tumor in conjunction with the cytologic features of the non-vacuolated cells are characteristic of mesothelioma. Lipid-laden vacuoles have been described in rare case reports of pleural or peritoneal malignant mesothelioma.7,8 Sheets of large vacuolated cells resembling lipoblasts and reminiscent of liposarcoma have also been described.9 The relative paucity of information in the literature regarding lipids in malignant mesothelioma may reflect the underutilization of fat stains and electron microscopy in the evaluation of these tumors, as most efforts have been concentrated on the immunohistochemical properties of these neoplasms. However, some authors consider the presence of lipid vacuoles to be an occasional feature of malignant mesothelioma and feel that, when present, they may be useful in distinguishing mesothelial cells from adenocarcinoma in cytology specimens.7,8,10 Acknowledgment. We thank Robert Holmes and Martin Selig for their assistance in ultrastructural analysis and Stephen Conley and Michelle Forrestall for their assistance in photography.
REFERENCES 1. Ordonez NG: Value of calretinin immunostaining in differentiating epithelial mesothelioma from lung adenocarcinoma. Mod Pathol 11:929-933, 1998 2. Ordonez NG: Role of immunohistochemistry in differentiating epithelial mesothelioma from adenocarcinoma, review and update. Am J Clin Pathol 112:75-89, 1999 3. Davis JM: Ultrastructure of human mesotheliomas. J Natl Cancer Inst 52:1715-1725, 1974 4. Ordonez NG, Mackay B: Electron microscopy in tumor diagnosis: Indications for its use in the immunohistochemical era. HUM PATHOL 29:14031411, 1998
878
CASE STUDIES 5. Oury TD, Hammar SP, Roggli VL: Ultrastructural features of diffuse malignant mesothelioma. HUM PATHOL 29:1382-1392, 1998 6. Hammar SP, Bolen JW: Pleural neoplasms, in Dail DH, Hammar SP (eds): Pulmonary Pathology. New York, NY, Springer-Verlag, 1988, pp 973-1028 7. Boon ME, Veldhuizen RW, Ruinaard C, et al: Qualitative distinctive differences between the vacuoles of mesothelioma cells and of cells from metastatic carcinoma exfoliated in pleural fluid. Acta Cytol 28:443-449, 1984
8. Kitazawa M, Kaneko H, Toshima M, et al: Malignant peritoneal mesothelioma with massive foamy cells. Codfish roe-like mesothelioma. Acta Pathol Jpn 34:687-692, 1984 9. Enzinger FM, Weiss SW: Mesothelioma, in Enzinger FM, Weiss SW (eds): Soft Tissue Tumors, (ed 3). St Louis, MO, Mosby, 1995, pp 787-819 10. Yu GH, Baloch ZW, Gupta PK: Cytomorphology of metastatic mesothelioma in fine needle aspiration specimens. Diagn Cytopathol 20:328-332, 1999
879
Volume 31, No. 7 (July 2000)
LIPID-RICH DIFFUSE MALIGNANT MESOTHELIOMA: A CASE REPORT HOWARD T. CHANG, MD, RHONDA K. YANTISS, MD, G. PETUR NIELSEN, MD, GRACE T. MCKEE, MD, AND EUGENE J. MARK, MD An 80-year old man presented with shortness of breath and was found to have a large right pleural effusion. Cytology of the pleural fluid showed atypical papillary clusters of epithelioid cells. Multiple white-yellow nodules studding the pleural surfaces were seen at thoracoscopy, and biopsies showed solid and papillary clusters of large epithelioid cells with abundant cytoplasm filled with clear vacuoles. Special stains and electron microscopic findings indicated that the tumor was a diffuse malignant mesothelioma with numerous
intracytoplasmic lipid vacuoles. Fat stain may be useful at time of frozen section for a pleural-based tumor with vacuolated cells, and the presence of lipid vacuoles in a pleural-based tumor does not exclude diffuse malignant mesothelioma. HUM PATHOL 31:876-879. Copyright 娀 2000 by W.B. Saunders Company Key words: malignant mesothelioma, intracytoplasmic lipid. Abbreviations: PTA, prior to admission; VATS, video-assisted thoracoscopy.
Several types of diffuse malignant mesothelioma of the pleura have been described based on their distinctive light microscopic appearances. These include epithelioid, mixed (biphasic), sarcomatoid, desmoplastic, and transitional/ poorly differentiated variants. Epithelioid malignant mesotheliomas may have a tubulopapillary or glandular architecture, but some are solid and others have a microcystic pattern. One may see large or giant cells, small cells, or even signet-ring cells. We report a case of an unusual epithelioid mesothelioma characterized by numerous intracytoplasmic lipid vacuoles.
PTA. Imaging studies showed a large right-sided pleural effusion that was aspirated to yield straw-colored fluid with moderate numbers of white and red blood cells and pH, 7.7; glucose, 100 mg/dL (plasma glucose, 161 mg/dL); total protein, 4.6 g/dL (blood total protein, 7.2 g/dL); albumin, 2.8 g/dL (blood albumin, 3.8 g/dL); and lactate dehydrogenase (LDH), 503 U/L (blood LDH, 209 U/L). The blood prostate specific antigen was 1.9 ng/mL (normal, 0-4). Cultures were negative for acid-fast, fungal, or bacterial organisms. Cytological examination showed numerous atypical papillary clusters that were interpreted to be reactive mesothelial cells (Fig 1A), though the possibility of an adenocarcinoma could not be excluded. Subsequent video-assisted thoracoscopy (VATS) showed multiple white-yellow nodules, 1-2 cm in size, studding the right pleural surface. Biopsies were obtained and submitted for intraoperative consultation. A second sample of pleural fluid obtained at this time showed clusters of malignant cells with features of both adenocarcinoma and mesothelioma (Fig 1B). The patient then underwent pleurodesis with insufflated talc and was later discharged in stable condition.
REPORT OF A CASE An 80-year-old man presented with progressive shortness of breath and chest pain over a period of several weeks. His medical history was significant for in situ ductal carcinoma of the breast that was treated by mastectomy with negative lymph nodes 10 years prior to admission (PTA), a colonic tubulovillous adenoma resected 8 years PTA, and prostate carcinoma (Gleason grade 3/5) treated with radiation implants 4 years
From the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Address correspondence and reprint requests to Eugene J. Mark, MD, Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. Copyright 娀 2000 by W.B. Saunders Company 0046-8177/00/3107-0019$10.00/0 doi:10.1053/hupa.2000.7628
PATHOLOGICAL FINDINGS The tumor consisted of branching glands and papillae lined by plump epithelioid cells (Fig 2A). Infiltrating nests, cords, and single cells were also present within desmoplastic stroma. The cells were cytologically atypical with large, slightly irregular nuclei, coarse chromatin, and prominent nucleoli
876
CASE STUDIES
FIGURE 1. (A) The original pleural fluid sample shows papillary clusters of atypical cells. (B) The second pleural fluid sample shows malignant cells, several with vacuolated cytoplasm.
FIGURE 2. (A) Low-power view of papillary lesion with branching glands. (B) The tumor is composed of cytologically atypical cells with enlarged nuclei and prominent central nucleoli. (C) In some areas, the nuclei are compressed by numerous intracytoplasmic vacuoles. (D) An Oil Red-O stain shows that the intracytoplasmic vacuoles contain abundant lipid. (E) The tumor cells are strongly and diffusely positive for calretinin. (F) Cytoplasmic staining for Leu-M1 is also present throughout the tumor.
877
HUMAN PATHOLOGY
Volume 31, No. 7 (July 2000)
of mesothelial cells, were identified on the cell surfaces (Fig 3B).
COMMENTS
FIGURE 3. (A) Cohesive epithelioid cells with abundant intracytoplasmic lipid (L), microvilli (asterisk), and intercellular junctions (arrowhead). (B) High magnification of long microvilli on surfaces of tumor cells.
and scattered mitotic figures (Fig 2B). The most striking finding, however, was the presence of large cytoplasmic vacuoles that contained lipid by Oil Red-O stain (Fig 2C, D) in many cells. Mucin stains (mucicarmine, alcian blue) were negative. Immunohistochemical studies performed on formalin-fixed, paraffin-embedded tissue showed staining of tumor cells for calretinin (Fig 2E), keratin, Leu M-1 (Fig 2F), and focal staining for carcinoembryonic antigen (CEA). The tumor cells were negative for estrogen and progesterone receptors, GCDFP-15, prostatic acid phosphatase, prostate specific antigen, and B72.3. Electron microscopic examination showed that the tumor cells were cohesive with external basal lamina and intercellular junctions. The cytoplasm contained an admixture of various organelles, including tonofibrils as well as abundant intracytoplasmic lipid (Fig 3A). Numerous long, delicate, branching, and intertwining microvilli, characteristic
The current case posed a diagnostic challenge in many respects. First, the patient had a history of multiple neoplasms (in situ adenocarcinoma of the breast, prostatic adenocarcinoma, and colonic adenoma), all of which are composed of cells that can contain intracytoplasmic vacuoles, and many of the neoplastic cells in the pleura had numerous cytoplasmic vacuoles more characteristic of adenocarcinoma than malignant mesothelioma. Furthermore, review of the previous prostate biopsies showed numerous cytoplasmic vacuoles within those tumor cells as well. Moreover, the immunostains were of limited value in that the tumor cells stained for calretinin, as would be expected in mesothelioma,1 but also stained for Leu-M1 and CEA, which is more characteristic of carcinoma.2 However, the issue was resolved by electron microscopy, which showed long microvilli on the tumor cells consistent with mesothelial differentiation.3-5 The mesothelioma reported herein is best categorized as a malignant epithelioid mesothelioma with a tubulopapillary architecture composed of cells containing prominent intracytoplasmic vacuoles. The differential diagnosis includes other variants of malignant mesothelioma such as the relatively rare signet-ring cell malignant mesothelioma as well as many other tumors known to have cytoplasmic lipid vacuoles, such as those arising from the kidney, adrenal gland, and soft tissues. However, the signet-ring cell mesothelioma is characterized by mucin-containing cytoplasmic vacuoles.6 The architectural growth pattern of our tumor in conjunction with the cytologic features of the non-vacuolated cells are characteristic of mesothelioma. Lipid-laden vacuoles have been described in rare case reports of pleural or peritoneal malignant mesothelioma.7,8 Sheets of large vacuolated cells resembling lipoblasts and reminiscent of liposarcoma have also been described.9 The relative paucity of information in the literature regarding lipids in malignant mesothelioma may reflect the underutilization of fat stains and electron microscopy in the evaluation of these tumors, as most efforts have been concentrated on the immunohistochemical properties of these neoplasms. However, some authors consider the presence of lipid vacuoles to be an occasional feature of malignant mesothelioma and feel that, when present, they may be useful in distinguishing mesothelial cells from adenocarcinoma in cytology specimens.7,8,10 Acknowledgment. We thank Robert Holmes and Martin Selig for their assistance in ultrastructural analysis and Stephen Conley and Michelle Forrestall for their assistance in photography.
REFERENCES 1. Ordonez NG: Value of calretinin immunostaining in differentiating epithelial mesothelioma from lung adenocarcinoma. Mod Pathol 11:929-933, 1998 2. Ordonez NG: Role of immunohistochemistry in differentiating epithelial mesothelioma from adenocarcinoma, review and update. Am J Clin Pathol 112:75-89, 1999 3. Davis JM: Ultrastructure of human mesotheliomas. J Natl Cancer Inst 52:1715-1725, 1974 4. Ordonez NG, Mackay B: Electron microscopy in tumor diagnosis: Indications for its use in the immunohistochemical era. HUM PATHOL 29:14031411, 1998
878
CASE STUDIES 5. Oury TD, Hammar SP, Roggli VL: Ultrastructural features of diffuse malignant mesothelioma. HUM PATHOL 29:1382-1392, 1998 6. Hammar SP, Bolen JW: Pleural neoplasms, in Dail DH, Hammar SP (eds): Pulmonary Pathology. New York, NY, Springer-Verlag, 1988, pp 973-1028 7. Boon ME, Veldhuizen RW, Ruinaard C, et al: Qualitative distinctive differences between the vacuoles of mesothelioma cells and of cells from metastatic carcinoma exfoliated in pleural fluid. Acta Cytol 28:443-449, 1984
8. Kitazawa M, Kaneko H, Toshima M, et al: Malignant peritoneal mesothelioma with massive foamy cells. Codfish roe-like mesothelioma. Acta Pathol Jpn 34:687-692, 1984 9. Enzinger FM, Weiss SW: Mesothelioma, in Enzinger FM, Weiss SW (eds): Soft Tissue Tumors, (ed 3). St Louis, MO, Mosby, 1995, pp 787-819 10. Yu GH, Baloch ZW, Gupta PK: Cytomorphology of metastatic mesothelioma in fine needle aspiration specimens. Diagn Cytopathol 20:328-332, 1999
879