- Email: [email protected]
Malignant peritoneal mesothelioma, clear cell variant, in a female and its differentiation from clear cell carcinoma
Accepted Manuscript Title: Malignant peritoneal mesothelioma, clear cell variant, in a female and its differentiation from clear cell carcinoma Author: Hiroko Hayashi Takuya Kawata Isao Shimokawa PII: DOI: Reference:
S0344-0338(16)30570-2 http://dx.doi.org/doi:10.1016/j.prp.2016.12.025 PRP 51712
To appear in: Received date:
24-10-2016
Please cite this article as: Hiroko Hayashi, Takuya Kawata, Isao Shimokawa, Malignant peritoneal mesothelioma, clear cell variant, in a female and its differentiation from clear cell carcinoma, Pathology - Research and Practice http://dx.doi.org/10.1016/j.prp.2016.12.025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Teaching Case Malignant peritoneal mesothelioma, clear cell variant, in a female and its differentiation from clear cell carcinoma
Hiroko Hayashi*, Takuya Kawata1, Isao Shimokawa
Department of Pathology, Nagasaki University School of Medicine and Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
*Corresponding author: Hiroko Hayashi, Department of Pathology, Nagasaki University School of Medicine and Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. Tel: +81-95-819-7050; Fax: +81-95-819-7052 E-mail: [email protected]
1
Present address: Department of Pathology, Shizuoka Cancer Center, 1007
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan
2
Abstract Epithelial type malignant mesothelioma with a clear cell morphology is rare, and no case arising in the peritoneum of a female patient has been reported. Here we report a case of clear cell mesothelioma that developed in the peritoneum of a 61-year-old female. The patient died from massive ascites and respiratory failure 11 days after her hospital admission. The autopsy demonstrated marked thickening of the omentum and a yellowish-whitish tumor diffusely covering the abdominal organs. The predominantly solid tumor was characterized microscopically by the growth of atypical cells with an abundant clear cytoplasm. The immunohistochemical study suggested mesothelioma rather than carcinoma. Electron microscopy showed the long and slender villi of the tumor cells, confirming the diagnosis. Primary clear cell carcinoma of the peritoneum, like clear cell mesothelioma, is rare and was also a diagnostic consideration in this patient. The differentiation between these two tumors is discussed herein. Keywords: malignant epithelial mesothelioma, clear cell subtype, clear cell carcinoma, peritoneum, female
3
Introduction Primary malignant peritoneal mesothelioma is relatively rare compared with pleural mesothelioma. However, its incidence in Japan is expected to increase as the use of asbestos in Japan peaked 30–40 years ago and the symptoms of malignant mesothelioma appear ~30–50 years after asbestos exposure [1]. Histopathologically, mesothelioma is difficult to distinguish from adenocarcinoma. The clear cell variant of malignant epithelial mesothelioma is even more rare, and the involvement of the female peritoneum has yet to be reported [2-5]. Here we describe a case of primary malignant epithelial mesothelioma, clear cell variant, that developed in the peritoneum of a female patient. Although the differential diagnosis of primary malignant epithelial mesothelioma from clear cell carcinoma may be extremely difficult, the diagnosis in this case was finally confirmed by electron microscopy of the tumor cells.
Clinical summary A 61-year-old woman hospitalized in a nearby clinic with abdominal distension and pain underwent abdominal computed tomography, which revealed a slight pleural and peritoneal effusion. Over the next 2 months, her pleural and peritoneal effusion
4
gradually increased, accompanied by prominent thickening of her peritoneum and omentum (Fig. 1). She was transferred to our hospital. On physical examination, her abdomen was distended, tense, and showed signs of tenderness. Pitting edema was observed in the patient’s arms and legs. Her oxygen saturation level was 94% with room air; decreased breath sounds were detected in both lower lung fields. Her laboratory results on admission showed a high white blood cell (16,300 /μl) and platelet (44.9×104/μl) counts and high levels of fibrinogen (1,092 mg/dl), fibrin/fibrinogen degradation products (8.2 μg/ml), D-dimer (1.7 μg/ml), lactate dehydrogenase (284 IU/L), alkaline phosphatase (1,391 mg/dl), C-reactive protein (18.27 mg/dl), tissue polypeptide antigen (1,100U/l), soluble mesothelin-related peptides (2.3 nmol/l), and cancer antigen 15-3 (143 U/ml). Her serum sodium level was low (120 mEq/dl). Analysis of a cytology specimen from the ascites revealed non-cohesive large vacuolar cells intermingled with inflammatory cells (Fig. 2a). There were a few small clusters of cells. Nuclear atypia with large nucleoli was prominent. Multinucleated cells were also seen. Microscopy of cell block specimens showed proliferating, atypical polygonal cells with a clear cytoplasm (Fig. 2b). On immunohistochemistry, the tumor cells were weakly positive for WT1 (Fig. 2c), focally positive for CK5/6, and negative for MOC-31. Malignant mesothelioma was therefore suspected. Although the patient was
5
administered albumin and diuretics, the peritoneal effusion continued to accumulate. Pulmonary oxygenation deteriorated and carbon dioxide narcosis developed. On the 11th day of hospitalization, she died. An autopsy was performed. She had no history of asbestos exposure, as determined in detailed interviews.
Pathologic findings Autopsy revealed a prominently thickened tumor-like omentum, referred to radiologically as “omental cake” (Fig. 3a). The yellowish-white tumor had diffusely spread throughout the abdominal cavity, enclosing all of the abdominal organs, including those of the female reproductive system (Fig. 3b). Microscopically, diffusely proliferating clear tumor cells formed sheets (Fig. 3c). Multinucleated giant cells were present sporadically (Fig. 3c). The tumor cells had an abundant clear cytoplasm and frank nuclear atypia (Fig. 3d). In some of the tumor cells, a faint eosinophilic cytoplasm was seen. In addition to the involvement of both ovaries by tumor cells, the tumor had partially infiltrated the ovarian cortex (Fig. 3e). Macroscopically, tumors were not discernible in either of the kidneys, but microscopically, metastases in the lymph ducts of the right kidney were detected. The tumor cells stained positively for periodic acid-Schiff (PAS) stain, which was removed by diastase, and for colloidal iron, which was digested by hyaluronidase. On immunohistochemistry, the tumor cells were positive
6
for AE1/AE3, only weakly positive for calretinin (Fig. 4a), diffusely positive for D2-40 (Fig. 4b), EMA (plasma membrane), and HBME-1, focally positive for Ber-EP4 (Fig. 4c), CK7, and CK5/6, and negative for CEA, CD15 (leuM1) (Fic. 4d), estrogen receptor, progesterone receptor, and CK20. Only a few tumor cells were p53-positive. Electron microscopy analysis of the specimens showed long villi on the surface of the tumor cells (Fig. 5). This feature confirmed the diagnosis of malignant mesothelioma. The tumor also extended to the pleural cavity bilaterally. Metastases to multiple organs, including the lungs, liver, pancreas, and both adrenal glands, were evident. The cause of death was therefore malignant mesothelioma.
Discussion Malignant epithelial mesothelioma extensively composed of clear cells is a rare subtype, with fewer than 30 cases reported in the English medical literature. In other cases of mesothelioma, focal clear cell change is sometimes encountered [2-5]. Among females, the clear cell subtype of malignant epithelial mesothelioma has been reported in the pleura but ours is the first reported case in which the peritoneum in a female was involved. The difficulty in achieving a diagnosis was due to the fact that, because of several similar histopathological and immunohistochemical findings, malignant mesothelioma had to be distinguished from clear cell carcinoma arising in the
7
peritoneum or ovary. Ordóñez [3] reviewed 20 cases of malignant epithelial mesothelioma of the clear cell subtype. Electron microscopy of the specimens from those cases showed that the clear change in the tumor cells was due to the cytoplasmic accumulation of mainly glycogen but also lipid and to mitochondrial swelling. Ultrastructural analysis of the tumor from our patient showed prominent cavities in the cytoplasm of some cells. These may have represented intracytoplasmic glycogen accumulation lost during the processing or reprocessing of the formalin-fixed, paraffin-embedded tissue. This conclusion was supported by the detection elsewhere in the specimen of cytoplasmic PAS-positive material that was removed by diastase. Primary peritoneal clear cell carcinoma is also extremely rare, with only 12 cases reported so far [6,7]. Thus, there is little discussion in the literature of its differential diagnosis from malignant epithelial mesothelioma of the clear cell subtype. While both tumors are characterized by a papillotubular or solid growth pattern, clear cell carcinoma generally features greater nuclear atypia than malignant mesothelioma and has a characteristic hobnail appearance [8,9]. According to a literature review, the solid to sheet-like pattern of tumor cell proliferation seen in the clear cell subtype of malignant mesothelioma contrasts with the mixed papillary, tubular, and solid growth
8
pattern of clear cell carcinoma [2-7]. In addition, malignant mesotheliomas characteristically show diffuse extension to the pleural or peritoneal cavity, whereas clear cell carcinomas generally form bulky masses in the abdominal cavity [6,7]. Immunohistochemically, positive markers for malignant epithelial mesothelioma are calretinin, WT1, CK5/6, thrombomodulin, and D2-40, whereas those for clear cell carcinoma are Ber-EP4, Leu-M1(CD15), MOC-31, PAX8, and BG8 [7,10,11]. Of these, calretinin and WT1 are the most sensitive and specific antigens for differentiating epithelioid malignant mesothelioma from clear cell carcinoma [11,12]. In the current case, the immunohistochemical pattern was confusing because the tumor was partially positive for Ber-EP4 and very few cells were positive for calretinin, although the tumor cell membranes were positive for D2-40. WT1 positivity, however, was weak. Accordingly, the pathological and immunohistochemical findings were only suggestive of malignant mesothelioma and the diagnosis was ultimately made by electron microscopy. The significant ultrastructural features of epithelioid mesothelioma are long villi without a glycocalyx, in contrast to the short microvilli of adenocarcinoma, including clear cell carcinoma, and the paucity of microvilli in clear cell carcinoma of the kidney [11,13]. In a recent study, p16/CDKN2A fluorescence in situ hybridization was shown to differentiate malignant mesothelioma from ovarian
9
cancers with 100% specificity [14]. Nonetheless, diagnostic confirmation of a rare tumor such as malignant mesothelioma using a multidisciplinary approach is warranted. In the present case, an analysis of the ultrastructural features of the tumor was of diagnostic value. Because of the history of asbestos use and therefore exposure in Japan, the incidence of malignant mesothelioma in Japan is expected to rise, reaching a peak in the 2030s [1,15]. It is therefore likely that pathologists will increasingly be confronted with this thus far rare subtype of malignant mesothelioma. As the clear cell subtype of malignant epithelial mesothelioma arising in the female peritoneal cavity may be a diagnostic pitfall, pathologists should be aware of the features of this rare variant of malignant mesothelioma.
Conflict of interest statement The authors have no conflicts of interest to declare with respect to the authorship and/or publication of this article.
Funding The authors received no financial support for the research and/or authorship of
10
this article.
Informed consent Our institutional policy waived the need for informed consent in this case report.
Acknowledgement We are grateful to Professor Yoshiki Mikami, Department of Diagnostic Pathology, Kumamoto University Hospital, for the valuable comments and suggestions on the diagnosis of this case.
References [1] T. Myojin, K. Azuma, J. Okumura, I. Uchiyama, Future trends of mesothelioma mortality in Japan based on a risk function, Ind. Health. 50 (2012) 197-204. [2] E. Dessy, M. Falleni, P. Braidotti, B. Del Curto, T. Panigalli, C.G. Pietra, Unusual clear cell variant of epithelioid mesothelioma, Arch. Pathol. Lab. Med. 125 (2001) 1588-1590. [3] N.G. Ordóñez, Mesothelioma with clear cell features: an ultrastructural and
11
immunohistochemical study of 20 cases, Hum. Pathol. 36 (2005) 465-473. [4] N.G. Ordóñez, Clear cell mesothelioma presenting as an incarcerated abdominal hernia, Virchows. Arch. 447 (2005) 823-827. [5] C. Gkogkou, K. Samitas, M. Foteinou, Primary pleural epithelioid mesothelioma of clear cell type: a case report and review of current literature, Ultrastruct. Pathol. 35 (2011) 267-270. doi: 10.3109/01913123.2011.606965. [6] N. Shigeta, K. Yoashino, S. Matsuzaki, E. Morii, Y. Ueda, T. Kimura, Clear cell adenocarcinoma of the peritoneum: a case report and literature review. J. Ovarian. Res. 2;7:86 (2014). doi: 10.1186/s13048-014-0086-2. [7] L. Insabato, V. Natella, A. Somma, M. Persico, L. Camera, N.S. Losito, S. Masone, Primary peritoneal clear cell carcinoma versus ovarian carcinoma versus malignant transformation of endometriosis: a vexing issue, Int. J. Surg. Pathol. 23 (2015) 211-6. doi: 10.1177/1066896915573567. [8] S.A. Kerrigan, R.T. Turnnir, P.B. Clement, R.H. Young, A. Churg, Diffuse malignant epithelial mesotheliomas of the peritoneum in women: a clinicopathologic study of 25 patients, Cancer. 94 (2002) 378-385.
12
[9] P.M. Baker, P.B. Clement, R.H. Young, Malignant peritoneal mesothelioma in women: a study of 75 cases with emphasis on their morphologic spectrum and differential diagnosis, Am. J. Clin. Pathol. 123 (2005) 724-737. [10] N.G. Ordóñez, The diagnostic utility of immunohistochemistry and electron microscopy in distinguishing between peritoneal mesotheliomas and serous carcinomas: a comparative study, Mod. Pathol. 19 (2006) 34-48. doi: 10.1038/modpathol.3800471. [11] A.N. Husain, T. Colby, N. Ordonez, T. Krausz, R. Attanoos, M.B. Beasley, A.C. Borczuk, K. Butnor, P.T. Cagle, L.R. Chirieac, A. Churg, S. Dacic, A. Fraire, F. Galateau-Salle, A. Gibbs, A. Gown, S. Hammar, L. Litzky, A.M. Marchevsky, A.G. Nicholson, V. Roggli, W.D. Travis, M. Wick; International Mesothelioma Interest Group, Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group, Arch. Pathol. Lab. Med. 137 (2013) 647-667. doi: 10.5858/arpa.2012-0214-OA. [12] J.D. Seidman, D.A. Bell, C.P. Crum, C.B. Gilks, R.J. Kurman, D.A. Levine, T.A. Longacre, B. Pasini, C. Riva, M.E. Sherman, I.M. Shih, G. Singer, R. Soslow, R. Vang, High-Grade serous carcinoma, In: R.J. Kurman, M.L. Carcangiu, C.S. Herrington, R.H. Young (Eds.), World health organization classification of tumours of female reproductive organs, 4th edition, IARC, Lyon, 2013, pp. 22-24.
13
[13] K. Ohkawa, H. Amasaki, Y. Terashima, S. Aizawa, E. Ishikawa, Clear cell carcinoma of the ovary: light and electron microscopic studies, Cancer. 40 (1977) 3019-3029. [14] T. Ito, M. Hamasaki, S. Matsumoto, K. Hiroshima, T. Tsujimura, T. Kawai, Y. Shimao, K. Marutsuka, S. Moriguchi, R. Maruyama, S. Miyamoto, K. Nabeshima, p16/CDKN2A FISH in differentiation of diffuse malignant peritoneal mesothelioma from mesothelial hyperplasia and epithelial ovarian cancer, Am. J. Clin. Pathol. 143 (2015) 830-838. doi: 10.1309/AJCPOATJ9L4GCGDA. [15] T. Murayama, K. Takahashi, Y. Natori, N. Kurumatani, Estimation of future mortality from pleural malignant mesothelioma in Japan based on an age-cohort model, Am. J. Ind. Med. 49 (2006) 1-7. doi: 10.1002/ajim.20246.
14
Figure legends
Fig. 1. Computed tomography scan of the abdomen shows a diffusely and prominently thickened omentum (arrows), referred to as “omental cake.”.
15
Fig. 2. Microscopic features and immunohistochemistry of the cytology (a) and cell block (b, c) specimens from the ascites. (a) Large atypical cells with an abundant vacuolar cytoplasm non-cohesively intermingle with inflammatory cells. (b) Clear tumor cells proliferate diffusely. Multinucleated giant cells are also discernible. (c) The tumor cells are weakly positive for WT1.
16
Fig. 3. Macroscopic (a, b) and microscopic (c–e) findings of the tumor in the abdominal cavity. (a) The diffusely thickened, yellow-whitish omentum shows “omental cake”-like features. (b) The uterus and bilateral ovaries are diffusely surrounded by whitish tumor. (c) Tumor cells with a clear cytoplasm proliferate diffusely to form a sheet. Multinucleated giant cells are present sporadically. (d) The tumor cells exhibit frank nuclear atypia. (e) Tumor cells infiltrate the cortex of the left ovary (arrows).
17
Fig. 4. Immunohistochemistry of the tumor. (a) Very few tumor cells are positive for calretinin. (b) The plasma membrane of the tumor cells stains diffusely but intensely for D2-40. (c) The tumor cells are focally positive for Ber-EP4 but (d) negative for CD15 (LeuM1).
18
Fig. 5. Ultrastructural findings of the tumor cells. Long villi can be seen on the cell membrane. The large spaces in the cytoplasm might be glycogen pools that were removed during processing of the specimen since glycogen granules remain at the peripheral region of the cavities (arrows).
S0344-0338(16)30570-2 http://dx.doi.org/doi:10.1016/j.prp.2016.12.025 PRP 51712
To appear in: Received date:
24-10-2016
Please cite this article as: Hiroko Hayashi, Takuya Kawata, Isao Shimokawa, Malignant peritoneal mesothelioma, clear cell variant, in a female and its differentiation from clear cell carcinoma, Pathology - Research and Practice http://dx.doi.org/10.1016/j.prp.2016.12.025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Teaching Case Malignant peritoneal mesothelioma, clear cell variant, in a female and its differentiation from clear cell carcinoma
Hiroko Hayashi*, Takuya Kawata1, Isao Shimokawa
Department of Pathology, Nagasaki University School of Medicine and Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
*Corresponding author: Hiroko Hayashi, Department of Pathology, Nagasaki University School of Medicine and Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. Tel: +81-95-819-7050; Fax: +81-95-819-7052 E-mail: [email protected]
1
Present address: Department of Pathology, Shizuoka Cancer Center, 1007
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan
2
Abstract Epithelial type malignant mesothelioma with a clear cell morphology is rare, and no case arising in the peritoneum of a female patient has been reported. Here we report a case of clear cell mesothelioma that developed in the peritoneum of a 61-year-old female. The patient died from massive ascites and respiratory failure 11 days after her hospital admission. The autopsy demonstrated marked thickening of the omentum and a yellowish-whitish tumor diffusely covering the abdominal organs. The predominantly solid tumor was characterized microscopically by the growth of atypical cells with an abundant clear cytoplasm. The immunohistochemical study suggested mesothelioma rather than carcinoma. Electron microscopy showed the long and slender villi of the tumor cells, confirming the diagnosis. Primary clear cell carcinoma of the peritoneum, like clear cell mesothelioma, is rare and was also a diagnostic consideration in this patient. The differentiation between these two tumors is discussed herein. Keywords: malignant epithelial mesothelioma, clear cell subtype, clear cell carcinoma, peritoneum, female
3
Introduction Primary malignant peritoneal mesothelioma is relatively rare compared with pleural mesothelioma. However, its incidence in Japan is expected to increase as the use of asbestos in Japan peaked 30–40 years ago and the symptoms of malignant mesothelioma appear ~30–50 years after asbestos exposure [1]. Histopathologically, mesothelioma is difficult to distinguish from adenocarcinoma. The clear cell variant of malignant epithelial mesothelioma is even more rare, and the involvement of the female peritoneum has yet to be reported [2-5]. Here we describe a case of primary malignant epithelial mesothelioma, clear cell variant, that developed in the peritoneum of a female patient. Although the differential diagnosis of primary malignant epithelial mesothelioma from clear cell carcinoma may be extremely difficult, the diagnosis in this case was finally confirmed by electron microscopy of the tumor cells.
Clinical summary A 61-year-old woman hospitalized in a nearby clinic with abdominal distension and pain underwent abdominal computed tomography, which revealed a slight pleural and peritoneal effusion. Over the next 2 months, her pleural and peritoneal effusion
4
gradually increased, accompanied by prominent thickening of her peritoneum and omentum (Fig. 1). She was transferred to our hospital. On physical examination, her abdomen was distended, tense, and showed signs of tenderness. Pitting edema was observed in the patient’s arms and legs. Her oxygen saturation level was 94% with room air; decreased breath sounds were detected in both lower lung fields. Her laboratory results on admission showed a high white blood cell (16,300 /μl) and platelet (44.9×104/μl) counts and high levels of fibrinogen (1,092 mg/dl), fibrin/fibrinogen degradation products (8.2 μg/ml), D-dimer (1.7 μg/ml), lactate dehydrogenase (284 IU/L), alkaline phosphatase (1,391 mg/dl), C-reactive protein (18.27 mg/dl), tissue polypeptide antigen (1,100U/l), soluble mesothelin-related peptides (2.3 nmol/l), and cancer antigen 15-3 (143 U/ml). Her serum sodium level was low (120 mEq/dl). Analysis of a cytology specimen from the ascites revealed non-cohesive large vacuolar cells intermingled with inflammatory cells (Fig. 2a). There were a few small clusters of cells. Nuclear atypia with large nucleoli was prominent. Multinucleated cells were also seen. Microscopy of cell block specimens showed proliferating, atypical polygonal cells with a clear cytoplasm (Fig. 2b). On immunohistochemistry, the tumor cells were weakly positive for WT1 (Fig. 2c), focally positive for CK5/6, and negative for MOC-31. Malignant mesothelioma was therefore suspected. Although the patient was
5
administered albumin and diuretics, the peritoneal effusion continued to accumulate. Pulmonary oxygenation deteriorated and carbon dioxide narcosis developed. On the 11th day of hospitalization, she died. An autopsy was performed. She had no history of asbestos exposure, as determined in detailed interviews.
Pathologic findings Autopsy revealed a prominently thickened tumor-like omentum, referred to radiologically as “omental cake” (Fig. 3a). The yellowish-white tumor had diffusely spread throughout the abdominal cavity, enclosing all of the abdominal organs, including those of the female reproductive system (Fig. 3b). Microscopically, diffusely proliferating clear tumor cells formed sheets (Fig. 3c). Multinucleated giant cells were present sporadically (Fig. 3c). The tumor cells had an abundant clear cytoplasm and frank nuclear atypia (Fig. 3d). In some of the tumor cells, a faint eosinophilic cytoplasm was seen. In addition to the involvement of both ovaries by tumor cells, the tumor had partially infiltrated the ovarian cortex (Fig. 3e). Macroscopically, tumors were not discernible in either of the kidneys, but microscopically, metastases in the lymph ducts of the right kidney were detected. The tumor cells stained positively for periodic acid-Schiff (PAS) stain, which was removed by diastase, and for colloidal iron, which was digested by hyaluronidase. On immunohistochemistry, the tumor cells were positive
6
for AE1/AE3, only weakly positive for calretinin (Fig. 4a), diffusely positive for D2-40 (Fig. 4b), EMA (plasma membrane), and HBME-1, focally positive for Ber-EP4 (Fig. 4c), CK7, and CK5/6, and negative for CEA, CD15 (leuM1) (Fic. 4d), estrogen receptor, progesterone receptor, and CK20. Only a few tumor cells were p53-positive. Electron microscopy analysis of the specimens showed long villi on the surface of the tumor cells (Fig. 5). This feature confirmed the diagnosis of malignant mesothelioma. The tumor also extended to the pleural cavity bilaterally. Metastases to multiple organs, including the lungs, liver, pancreas, and both adrenal glands, were evident. The cause of death was therefore malignant mesothelioma.
Discussion Malignant epithelial mesothelioma extensively composed of clear cells is a rare subtype, with fewer than 30 cases reported in the English medical literature. In other cases of mesothelioma, focal clear cell change is sometimes encountered [2-5]. Among females, the clear cell subtype of malignant epithelial mesothelioma has been reported in the pleura but ours is the first reported case in which the peritoneum in a female was involved. The difficulty in achieving a diagnosis was due to the fact that, because of several similar histopathological and immunohistochemical findings, malignant mesothelioma had to be distinguished from clear cell carcinoma arising in the
7
peritoneum or ovary. Ordóñez [3] reviewed 20 cases of malignant epithelial mesothelioma of the clear cell subtype. Electron microscopy of the specimens from those cases showed that the clear change in the tumor cells was due to the cytoplasmic accumulation of mainly glycogen but also lipid and to mitochondrial swelling. Ultrastructural analysis of the tumor from our patient showed prominent cavities in the cytoplasm of some cells. These may have represented intracytoplasmic glycogen accumulation lost during the processing or reprocessing of the formalin-fixed, paraffin-embedded tissue. This conclusion was supported by the detection elsewhere in the specimen of cytoplasmic PAS-positive material that was removed by diastase. Primary peritoneal clear cell carcinoma is also extremely rare, with only 12 cases reported so far [6,7]. Thus, there is little discussion in the literature of its differential diagnosis from malignant epithelial mesothelioma of the clear cell subtype. While both tumors are characterized by a papillotubular or solid growth pattern, clear cell carcinoma generally features greater nuclear atypia than malignant mesothelioma and has a characteristic hobnail appearance [8,9]. According to a literature review, the solid to sheet-like pattern of tumor cell proliferation seen in the clear cell subtype of malignant mesothelioma contrasts with the mixed papillary, tubular, and solid growth
8
pattern of clear cell carcinoma [2-7]. In addition, malignant mesotheliomas characteristically show diffuse extension to the pleural or peritoneal cavity, whereas clear cell carcinomas generally form bulky masses in the abdominal cavity [6,7]. Immunohistochemically, positive markers for malignant epithelial mesothelioma are calretinin, WT1, CK5/6, thrombomodulin, and D2-40, whereas those for clear cell carcinoma are Ber-EP4, Leu-M1(CD15), MOC-31, PAX8, and BG8 [7,10,11]. Of these, calretinin and WT1 are the most sensitive and specific antigens for differentiating epithelioid malignant mesothelioma from clear cell carcinoma [11,12]. In the current case, the immunohistochemical pattern was confusing because the tumor was partially positive for Ber-EP4 and very few cells were positive for calretinin, although the tumor cell membranes were positive for D2-40. WT1 positivity, however, was weak. Accordingly, the pathological and immunohistochemical findings were only suggestive of malignant mesothelioma and the diagnosis was ultimately made by electron microscopy. The significant ultrastructural features of epithelioid mesothelioma are long villi without a glycocalyx, in contrast to the short microvilli of adenocarcinoma, including clear cell carcinoma, and the paucity of microvilli in clear cell carcinoma of the kidney [11,13]. In a recent study, p16/CDKN2A fluorescence in situ hybridization was shown to differentiate malignant mesothelioma from ovarian
9
cancers with 100% specificity [14]. Nonetheless, diagnostic confirmation of a rare tumor such as malignant mesothelioma using a multidisciplinary approach is warranted. In the present case, an analysis of the ultrastructural features of the tumor was of diagnostic value. Because of the history of asbestos use and therefore exposure in Japan, the incidence of malignant mesothelioma in Japan is expected to rise, reaching a peak in the 2030s [1,15]. It is therefore likely that pathologists will increasingly be confronted with this thus far rare subtype of malignant mesothelioma. As the clear cell subtype of malignant epithelial mesothelioma arising in the female peritoneal cavity may be a diagnostic pitfall, pathologists should be aware of the features of this rare variant of malignant mesothelioma.
Conflict of interest statement The authors have no conflicts of interest to declare with respect to the authorship and/or publication of this article.
Funding The authors received no financial support for the research and/or authorship of
10
this article.
Informed consent Our institutional policy waived the need for informed consent in this case report.
Acknowledgement We are grateful to Professor Yoshiki Mikami, Department of Diagnostic Pathology, Kumamoto University Hospital, for the valuable comments and suggestions on the diagnosis of this case.
References [1] T. Myojin, K. Azuma, J. Okumura, I. Uchiyama, Future trends of mesothelioma mortality in Japan based on a risk function, Ind. Health. 50 (2012) 197-204. [2] E. Dessy, M. Falleni, P. Braidotti, B. Del Curto, T. Panigalli, C.G. Pietra, Unusual clear cell variant of epithelioid mesothelioma, Arch. Pathol. Lab. Med. 125 (2001) 1588-1590. [3] N.G. Ordóñez, Mesothelioma with clear cell features: an ultrastructural and
11
immunohistochemical study of 20 cases, Hum. Pathol. 36 (2005) 465-473. [4] N.G. Ordóñez, Clear cell mesothelioma presenting as an incarcerated abdominal hernia, Virchows. Arch. 447 (2005) 823-827. [5] C. Gkogkou, K. Samitas, M. Foteinou, Primary pleural epithelioid mesothelioma of clear cell type: a case report and review of current literature, Ultrastruct. Pathol. 35 (2011) 267-270. doi: 10.3109/01913123.2011.606965. [6] N. Shigeta, K. Yoashino, S. Matsuzaki, E. Morii, Y. Ueda, T. Kimura, Clear cell adenocarcinoma of the peritoneum: a case report and literature review. J. Ovarian. Res. 2;7:86 (2014). doi: 10.1186/s13048-014-0086-2. [7] L. Insabato, V. Natella, A. Somma, M. Persico, L. Camera, N.S. Losito, S. Masone, Primary peritoneal clear cell carcinoma versus ovarian carcinoma versus malignant transformation of endometriosis: a vexing issue, Int. J. Surg. Pathol. 23 (2015) 211-6. doi: 10.1177/1066896915573567. [8] S.A. Kerrigan, R.T. Turnnir, P.B. Clement, R.H. Young, A. Churg, Diffuse malignant epithelial mesotheliomas of the peritoneum in women: a clinicopathologic study of 25 patients, Cancer. 94 (2002) 378-385.
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[9] P.M. Baker, P.B. Clement, R.H. Young, Malignant peritoneal mesothelioma in women: a study of 75 cases with emphasis on their morphologic spectrum and differential diagnosis, Am. J. Clin. Pathol. 123 (2005) 724-737. [10] N.G. Ordóñez, The diagnostic utility of immunohistochemistry and electron microscopy in distinguishing between peritoneal mesotheliomas and serous carcinomas: a comparative study, Mod. Pathol. 19 (2006) 34-48. doi: 10.1038/modpathol.3800471. [11] A.N. Husain, T. Colby, N. Ordonez, T. Krausz, R. Attanoos, M.B. Beasley, A.C. Borczuk, K. Butnor, P.T. Cagle, L.R. Chirieac, A. Churg, S. Dacic, A. Fraire, F. Galateau-Salle, A. Gibbs, A. Gown, S. Hammar, L. Litzky, A.M. Marchevsky, A.G. Nicholson, V. Roggli, W.D. Travis, M. Wick; International Mesothelioma Interest Group, Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group, Arch. Pathol. Lab. Med. 137 (2013) 647-667. doi: 10.5858/arpa.2012-0214-OA. [12] J.D. Seidman, D.A. Bell, C.P. Crum, C.B. Gilks, R.J. Kurman, D.A. Levine, T.A. Longacre, B. Pasini, C. Riva, M.E. Sherman, I.M. Shih, G. Singer, R. Soslow, R. Vang, High-Grade serous carcinoma, In: R.J. Kurman, M.L. Carcangiu, C.S. Herrington, R.H. Young (Eds.), World health organization classification of tumours of female reproductive organs, 4th edition, IARC, Lyon, 2013, pp. 22-24.
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[13] K. Ohkawa, H. Amasaki, Y. Terashima, S. Aizawa, E. Ishikawa, Clear cell carcinoma of the ovary: light and electron microscopic studies, Cancer. 40 (1977) 3019-3029. [14] T. Ito, M. Hamasaki, S. Matsumoto, K. Hiroshima, T. Tsujimura, T. Kawai, Y. Shimao, K. Marutsuka, S. Moriguchi, R. Maruyama, S. Miyamoto, K. Nabeshima, p16/CDKN2A FISH in differentiation of diffuse malignant peritoneal mesothelioma from mesothelial hyperplasia and epithelial ovarian cancer, Am. J. Clin. Pathol. 143 (2015) 830-838. doi: 10.1309/AJCPOATJ9L4GCGDA. [15] T. Murayama, K. Takahashi, Y. Natori, N. Kurumatani, Estimation of future mortality from pleural malignant mesothelioma in Japan based on an age-cohort model, Am. J. Ind. Med. 49 (2006) 1-7. doi: 10.1002/ajim.20246.
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Figure legends
Fig. 1. Computed tomography scan of the abdomen shows a diffusely and prominently thickened omentum (arrows), referred to as “omental cake.”.
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Fig. 2. Microscopic features and immunohistochemistry of the cytology (a) and cell block (b, c) specimens from the ascites. (a) Large atypical cells with an abundant vacuolar cytoplasm non-cohesively intermingle with inflammatory cells. (b) Clear tumor cells proliferate diffusely. Multinucleated giant cells are also discernible. (c) The tumor cells are weakly positive for WT1.
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Fig. 3. Macroscopic (a, b) and microscopic (c–e) findings of the tumor in the abdominal cavity. (a) The diffusely thickened, yellow-whitish omentum shows “omental cake”-like features. (b) The uterus and bilateral ovaries are diffusely surrounded by whitish tumor. (c) Tumor cells with a clear cytoplasm proliferate diffusely to form a sheet. Multinucleated giant cells are present sporadically. (d) The tumor cells exhibit frank nuclear atypia. (e) Tumor cells infiltrate the cortex of the left ovary (arrows).
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Fig. 4. Immunohistochemistry of the tumor. (a) Very few tumor cells are positive for calretinin. (b) The plasma membrane of the tumor cells stains diffusely but intensely for D2-40. (c) The tumor cells are focally positive for Ber-EP4 but (d) negative for CD15 (LeuM1).
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Fig. 5. Ultrastructural findings of the tumor cells. Long villi can be seen on the cell membrane. The large spaces in the cytoplasm might be glycogen pools that were removed during processing of the specimen since glycogen granules remain at the peripheral region of the cavities (arrows).