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Year : 2021  |  Volume : 64  |  Issue : 2  |  Page : 277-281
Histological and immunohistochemical characteristics and p16 status studied by FISH in six incidentally detected cases of well-differentiated papillary mesothelioma of the peritoneum

1 Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
2 Division of Pathology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
3 Department of Pathology, Fukuoka University School of Medicine and Hospital, Fukuoka, Japan
4 Division of Pathology, Osaki Citizen Hospital, Osaki, Japan
5 Division of Pathology, Sendai Medical Center, Sendai, Japan
6 Department of Pathology, Tohoku University Graduate School of Medicine; Division of Pathology, Tohoku University Hospital, Sendai, Japan

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Date of Submission09-Feb-2020
Date of Decision16-Apr-2020
Date of Acceptance08-May-2020
Date of Web Publication9-Apr-2021


Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial neoplasm, which is generally regarded as benign or indolent in terms of its clinical behavior. However, details about WDPM have remained relatively unknown. Therefore, in this study, we examined six incidentally detected cases of WDPM of the peritoneum. All six cases were surgically excised, without any additional therapeutic measures. None of the cases showed recurrence. All six cases presented single lesions and the tumor sizes ranged from 2 to 10 mm. Histologically, all six cases exhibited papillary proliferation of cytologically bland mesothelial cells with a fibroconnective tissue core. One of the cases (Case 6) presented small invasive foci in the stalk. The tumor cells were immunohistochemically positive for mesothelial markers and negative for GLUT-1, p53, and CD146. The Ki-67 labeling index of the tumor cells was lower than 5% at the hot spots. All samples were BAP1-positive. None of the samples presented p16 homozygous deletion, as assessed by fluorescence in situ hybridization (FISH). None of the patients deceased due to WDPM. However, in Case 3, death occurred due to pancreatic cancer. The results of this study indicate the importance of analyzing immunohistochemical markers and p16 status to diagnose WDPM accurately.

Keywords: Immunohistochemistry, malignant mesothelioma, peritoneum, well-differentiated papillary mesothelioma

How to cite this article:
Fujishima F, Konosu-Fukaya S, Nabeshima K, McNamara KM, Sakamoto K, Sakurada J, Sasano H, Nakamura Y. Histological and immunohistochemical characteristics and p16 status studied by FISH in six incidentally detected cases of well-differentiated papillary mesothelioma of the peritoneum. Indian J Pathol Microbiol 2021;64:277-81

How to cite this URL:
Fujishima F, Konosu-Fukaya S, Nabeshima K, McNamara KM, Sakamoto K, Sakurada J, Sasano H, Nakamura Y. Histological and immunohistochemical characteristics and p16 status studied by FISH in six incidentally detected cases of well-differentiated papillary mesothelioma of the peritoneum. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 May 8];64:277-81. Available from: https://www.ijpmonline.org/text.asp?2021/64/2/277/313265

   Introduction Top

Well-differentiated papillary mesothelioma (WDPM) is a rare subtype of mesothelioma, typically localized in the peritoneum in the women of reproductive age, and histologically characterized by papillary proliferation of cytologically bland mesothelial cells.[1],[2],[3],[4],[5]Although WDPM has been reported to develop into malignant mesothelioma (MM),[6],[7]it is generally considered a benign or indolent neoplasm. Unlike, MM, WDPM is rarely life-threatening, even if associated with clinical recurrence or focal invasion.[4]However, the biological characteristics of WDPM remain unknown.[8],[9]The ability to profile WDPM by histology, immunohistochemistry, and p16 status may help to differentiate WDPM from MM accurately. Thus, a detailed histological examination of WDPM biopsies as well as long-term follow-up are required for clarification.

Therefore, in this study, we report six cases of WDPM of the peritoneum with the detailed histological and immunohistochemical examination, as well as assessment of p16 status by fluorescence in situ hybridization (FISH). In addition, we review the literature on WDPM.

   Materials and Methods Top

Six cases of WDPM patients were retrieved from the surgical pathology files of Tohoku University Hospital, Osaki Citizen Hospital, and Sendai Medical Center, all of which are located in Miyagi, Japan. In all six cases, detailed demographics, clinical data, and follow-up information were obtained from the medical records.

Immunohistochemistry and p16 fluorescence in situ hybridization testing

Hematoxylin and eosin (H and E) staining and immunohistochemistry (IHC) were performed on 10% formalin-fixed and paraffin-embedded tissue specimens. [Table 1] summarizes the IHC markers evaluated in this study. Antigen-antibody complexes were visualized using 3, 3'-diaminobenzidine (DAB) and a peroxidase-based Histofine SAB-PO Kit (Nichirei, Tokyo, Japan).
Table 1: Immunohistochemistry markers evaluated in this study

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p16 FISH was performed on 4 mm thick tissue sections from tissue specimens fixed in 10% formalin and embedded in paraffin, using a DAKO Histology FISH Accessory Kit (DAKO, Glostrup, Denmark), as previously reported.[10]

   Results Top

Demographic and clinical features

[Table 2] summarizes the demographic data of the cases examined, including the sites and sizes of the lesions. There were five women and one man, aged 49 to 84 years. No history of asbestos exposure was detected in either of the cases examined. All six cases examined were detected incidentally, and tumors were excised during surgeries for other neoplastic diseases (two cases of gastric cancer, two cases of colorectal cancer, one case of pancreatic cancer, and one case of uterine leiomyoma). All cases of WDPM arose in the peritoneum. Only one patient (Case 3) had a history of cutaneous malignant melanoma. However, the remaining patients did not have any particular medical histories.
Table 2: Clinical data and the sites and sizes of present cases

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Treatment and survival

None of the cases received any additional therapy beyond surgical excision, for either the mesothelioma or the concurrent neoplasm. Of the six patients studied, five had disease-free survival intervals of 5–83 months at the time of the last censor. One patient (Case 3) died of pancreatic cancer 5 months after surgery, without presenting any clinical evidence of recurrence of WDPM.

Pathologic findings

All cases examined presented single lesions. Tumor sizes ranged from 2 to 10 mm. All tumors yielded a histological pattern typical of WDPM, consisting of a largely papillary architecture, with the papillae predominantly formed of fibrous cores covered by a single layer of cuboidal to flat and bland mesothelial cells [Figure 1]a,[Figure 1]b,[Figure 1]c,[Figure 1]d. In Case 6, glandular/tubular formation composed of mesothelial cells with mild cytological atypia in the stalk was detected in a very small area (750 mm) of the tumor [Figure 1]e; this corresponds to the appearance WDPM with invasive foci as proposed by Churg et al.[4]
Figure 1: Papillary structure with fibroconnective tissue cores lined by a single layer of cells (a ; Case 1, b; Case 2). The lining cells were cuboidal and the fibroconnective stromal cores were hyalinous or myxoid. The nuclei of these cells were centrally located and uniformly round, without chromatin clumping (c: Case 1; d: Case 2). These cells lacked mitotic activity and necrosis was not detected. Infiltration of inflammatory cells was not conspicuous in either of the cases. Invasive foci in Case 6 (e). Mesothelial cells with low grade atypia formed glandular/tubular structure

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The results of our immunohistochemistry and p16 FISH experiments are summarized in [Table 3]. All six cases studies were immunohistochemically positive for mesothelial markers, including cytokeratin (CK5/6) [Figure 2]a, calretinin [Figure 2]b, Wilms' tumor (WT) 1, D2-40, and vimentin. Two out of six cases were immunohistochemically weakly positive for desmin [Figure 2]c, and four were negative [Figure 2]d. Four out of six cases were negative for epithelial membrane antigen (EMA), with one weakly positive with a linear pattern. All six cases were focally positive for epidermal growth factor receptor (EGFR), with four cases showing cytoplasmic expression pattern, one case showing membranous expression pattern and one case showing both expression patterns [Figure 2]e. All six cases were negative for glucose transporter (GLUT-1) [Figure 2]f, p53, and CD146. The Ki67 labeling index at the hot spots was lower than 5% in all cases. All six cases were positive for [Breast cancer type 1(BRCA1)-associated protein 1 (BAP1)] [Figure 2]g. Although examined only in one case, estrogen receptor (ER), and progesterone receptor (PgR) were both negative, and paired box 8 (PAX8) was focally weakly positive (data not shown). p16 FISH analysis was performed in all cases; none of the samples showed p16 homozygous deletions [Figure 2]h.
Table 3: Immunohistochemical and FISH findings in present cases

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Figure 2: The neoplastic mesothelial cells were immunohistochemically positive for CK5/6 (a), calretinin (b), EGFR (e) and BAP1 (g); weak positive for desmin (case 4) (c); negative for GLUT-1 (f) and desmin (case 3) (d). FISH did not show deletion of p16 (normal pattern indicated by blue arrows, 95.8%; hemizygous pattern deletion indicated by red arrow, 4.2%; homozygous deletion pattern, 0%) (Case 5) (h)

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   Discussion Top

This case report describes the histological and immunohistochemical features of six cases of incidentally detected WDPM. WDPM is generally considered a benign peritoneal tumor, but its characteristics have not been established to date.

Although WDPM is rare, it is pivotal to differentiate it from MM. This can be difficult because MM can be histologically similar to WDPM, presenting focal areas with well-differentiated papillary structures.[4]Therefore, WDPM-like MM can be misdiagnosed as WDPM. Therefore, a detailed pathological and immunohistochemical study of WDPM lesions is required for the differential diagnosis.[4]In addition, whether WDPM can evolve into MM has remained virtually unknown.[8],[9],[11]GLUT-1, CD146, p53, and a Ki-67 labeling index ≥ 1% have been reported as WDPM immunohistochemical markers that can be useful in its differential diagnosis from MM.[4],[12],[13],[14]In addition, it has been reported that BAP1 loss is uncommon in WDPM.[15]Desmin is usually used to distinguish reactive mesothelial hyperplasia from MM, and desmin is almost negative in MM. Although reports regarding WDPM and desmin are few, there are reports that desmin was positive on WDPM.[7]The absence of p16 deletion, as assessed by FISH, is also considered useful in diagnosing WDPM.[4],[10]In the present study, all cases examined presented the typical immunohistochemical features of WDPM. For distinguishing primary mesothelial tumors from metastatic tumors, ER and PgR were used for breast carcinoma, and PAX8 was used for renal cell carcinoma and primary gynecologic cancers.[16]There are no case reports on ER and PgR positive mesothelial tumors. On the other hand, PAX8 positive cases of WDPM were reported. So in patients who also harbor a gynecologic neoplasm, we need to make a general judgment about the primary lesion.

The next diagnostic problem of WDPM is whether WDPM harboring minimal invasion, termed WDPM with invasive foci,[4],[8],[14]can have a benign clinical course. WDPM with invasive foci has been reported to be associated with multifocality and prone to recurrence, although it is rarely life-threatening.[4]Even when histologically higher cytological grade and/or architectural complexity were detected in the invasive foci or invasion to adjacent adipose tissue was observed, these cases were classified as WDPM with invasive foci due to indolent behavior.[4] Therefore, clinical management strategies and treatment have remained controversial in patients with WDPM harboring invasive foci. In addition, it is challenging to differentiate between WDPM with minimal invasion and MM with a WDPM-like pattern. Therefore, a clear definition of WDPM with invasion is required.[14]Previous reports have suggested the upper size limit of the tumor lesion is required to define the lesion as WDPM with or without invasive foci.[3],[14]However, a consensus definition of this classification is yet to be reached. Churg et al. reported 20 cases of WDPM with invasive foci ranging from <1.0 cm to 12.0 cm.[4]In other studies, cases of WDPM without invasion were rather smaller, ranging from 0.3 to 2.0 cm,[12]0.5 to 2.0 cm,[1] and 0.1 to 5.0 cm,[13]demonstrating the range of factors that may need to be considered when defining these limits.

Relapse of WDPM has been reported in some case,[7]although these had not been thoroughly examined pathologically. A literature review of putative WDPM cases, with emphasis on reported immunohistochemical analysis and the absence of p16 translocations, revealed that none of the patients had died due to underlying disease or malignant transformation, even after a relatively long period of clinical follow-up. A few cases of transformation from WDPM to MM have been reported in the literature [6],[7]although the possibility of metachronism cannot be ruled out. In addition, it is difficult to determine whether the lesions represent relapse or metachronous lesions, especially in cases with a history of exposure to asbestos, though there is no history of exposure to asbestos in our study. Therefore, further investigation, including longer clinical follow-up after diagnosis, is required to define further, the biological behavior of this rare but unique neoplasm.


We thank Mr. Shinji Matsumoto (Department of Pathology, Fukuoka University School of Medicine and Hospital), Ms. Kazue Ise (Division of Pathology, Tohoku Medical and Pharmaceutical University), Mr. Hiroshu Miura and Ms. Yayoi Aoyama (Division of Pathology, Tohoku University Hospital) for their technical assistance.

We would like to thank Editage (www.editage.com) for English language editing.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Daya D, McCaughey WT. Well-differentiated papillary mesothelioma of the peritoneum. A clinicopathologic study of 22 cases. Cancer 1990;65:292-6.  Back to cited text no. 1
Galateau-Sallé F, Vignaud JM, Burke L, Gibbs A, Brambilla E, Attanoos R, et al. Well-differentiated papillary mesothelioma of the pleura: A series of 24 cases. Am J Surg Pathol 2004;28:534-40.  Back to cited text no. 2
Malpica A, Sant'Ambrogio S, Deavers MT, Silva EG. Well-differentiated papillary mesothelioma of the female peritoneum: Aclinicopathologic study of 26 cases. Am J Surg Pathol 2012;36:117-27.  Back to cited text no. 3
Churg A, Allen T, Borczuk AC, Cagle PT, Galateau-Sallé F, Hwang H, et al. Well-differentiated papillary mesothelioma with invasive foci. Am J Surg Pathol 2014;38:990-8.  Back to cited text no. 4
Kim M, Kim HS. Clinic opathological characteristics of well-differentiated papillary mesothelioma of the peritoneum: Asingle-institutional experience of 12 cases.In Vivo 2019;33:633-42.  Back to cited text no. 5
Costanzo L, Scarlata S, Perrone G, Costanzo L, Scarlata S, Perrone G, et al. Malignant transformation of well-differentiated papillary mesothelioma 13 years after the diagnosis: Acase report. Clin Respir J 2014;8:124-9.  Back to cited text no. 6
Sun M, Zhao L, Weng Lao I, Yu L, Wang J. Well- differentiated papillary mesothelioma: A17 year single institution experience with as eries of 75 cases. Ann Diagn Pathol 2019;38:43-50.  Back to cited text no. 7
Torii I, Hashimoto M, Terada T, Torii I, Hashimoto M, Terada T, et al. Well-differentiated papillary mesothelioma with invasion to the chest wall. Lung cancer 2010;67:244-7.  Back to cited text no. 8
Burrig KF, Pfitzer P, Hort W. Well-differentiated papillary mesothelioma of the peritoneum: Aborderline mesothelioma. Report of two cases and review of literature. Virchows Arch A Pathol Anat Histopathol 1990;417:443-7.  Back to cited text no. 9
Ito T, Hamasaki M, Matsumoto S, Hiroshima K, Tsujimura T, Kawai T, et al. p16/CDKN2A FISH in differentiation of diffuse malignant peritoneal mesothelioma from mesothelial hyperplasia and epithelial ovarian cancer. Am J Clin Pathol 2015;143:830-8.  Back to cited text no. 10
Butnor KJ, Sporn TA, Hammar SP, Roggli VL. Well-differentiated papillary mesothelioma. Am J Surg Pathol 2001;25:1304-9.  Back to cited text no. 11
Brimo F, Illei PB, Epstein JI. Mesothelioma of the tunica vaginalis: Aseries of eight cases with uncertain malignant potential. Mod Pathol 2010;23:1165-72.  Back to cited text no. 12
Chen X, Sheng W, Wang J. Well-differentiated papillary mesothelioma: A clinic opathological and immunohistochemical study of 18 cases with additional observation. Histopathology 2013;62:805-13.  Back to cited text no. 13
Shimizu S, Yoon HE, Ito N, Tsuji T, Funakoshi Y, Utsumi T, et al. A case of solitary well-differentiated papillary mesothelioma with invasive foci in the pleura. Pathol Int 2017;67:45-9.  Back to cited text no. 14
Lee HE, Molina JR, Sukov WR, Roden AC, Eunhee SY. BAP1loss is unusual in well-differentiated papillary mesothelioma and may predict development of malignant mesothelioma. Hum Pathol 2018;79:168-76.  Back to cited text no. 15
Xing D, Banet N, Sharma R, Vang R, Ronnett BM, Illei PB. Aberrant Pax-8 expression in well-differentiated papillary mesothelioma and malignant mesothelioma of the peritoneum: A clinic opathologic study. Hum Pathol 2018;72:160-6.  Back to cited text no. 16

Correspondence Address:
Yasuhiro Nakamura
Division of Pathology, Tohoku Medical and Pharmaceutical University School of Medicine, 1-15-1 Fukumuro, Miyagino-ku, Sendai 983-8536
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_111_20

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  [Table 1], [Table 2], [Table 3]


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