Kao, Steven MBChB*; Mahon, Kate MBBS*; Lin, Betty FRCPA†; Rutland, Jonathan FRACP‡; Pawsey, Charles FRACP§; McCaughan, Brian FRACS∥; Beale, Philip FRACP*
*Department of Medical Oncology, Sydney Cancer Centre; Departments of †Anatomical Pathology, ‡Respiratory Medicine, §Cardiology, Concord Repatriation General Hospital; and ∥Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, Concord, Australia.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Philip Beale, FRACP, Department of Medical Oncology, Concord Repatriation General Hospital, Hospital Road, Concord, NSW 2139, Australia. E-mail: firstname.lastname@example.org
Well-differentiated papillary mesothelioma is a pathologic entity distinct from malignant mesothelioma and has a different tumor biology highlighted by its relatively good prognosis. We report the case of a 27-year-old woman with pleural well-differentiated papillary mesothelioma, who was treated with bilateral pleurodesis and pericardial window to control the production of malignant fluid, without significant systemic anticancer treatment. She survived for 16 years, confirming its indolent nature. This case report also highlights the role of fluid cytology, immunohistochemistry, and electron microscopy in the diagnosis of well-differentiated papillary mesothelioma and the potential use of serum CA-125 as a marker of progression.
A 27-year-old woman who was a nonsmoker with no known asbestos exposure presented with dyspnea and cough in May 1992. On clinical examination and imaging, she had a right pleural effusion. She underwent right pleural decortication and talc pleurodesis. Intraoperatively, a right pleural tumor encasing the hemithorax was identified. Pathology was reported to show fibroadipose tissue infiltrated by mucin-secreting moderately differentiated adenocarcinoma of predominantly acinar or cribriform pattern, but papilliform areas were also present. It showed positive staining for broad-spectrum cytokeratin (Cam 5-2 and AE1/AE3), epithelial membrane antigen, human epithelial antigen, and CA-125. The computed tomography scan of her abdomen and pelvis showed no evidence of ovarian cancer or primary peritoneal carcinomatosis. She was started on tamoxifen 40 mg daily as a breast primary would potentially be most responsive.
She remained on tamoxifen for 2 years with stable radiologic disease of her right pleura. She remained well until May 1999 when she developed a pericardial effusion and a pericardiocentesis was performed.
Pericardial fluid cytology yielded clusters of regular tumor cells of mesothelial appearance. Immunohistochemical stains on cell block sections showed scattered positive staining for the mesothelial marker calretinin, in addition to the above positive stains. The cells contained abundant glycogen, but no epithelial mucin was identified. Electron microscopy was also performed. It revealed cells that contained long microvilli on the free surfaces, prominent clumped tonofilaments in the cytoplasm, and well-formed intercellular junctions, supporting a mesothelial origin of the cells. The overall findings were consistent with well-differentiated papillary mesothelioma (WDPM). On review of the original pathology, the diagnosis was then revised (Figure 1).
She started on imatinib mesylate (STI571, Glivec) as part of a clinical trial1 in February 2002 and continued the same for 4 months. She did not derive any clinical benefit but did experience significant anemia and increased pain.
She had recurrence of pericardial effusion resulting in cardiac tamponade in August 2003. Left thoracotomy and pericardial window were performed. The biopsy of the pericardium was consistent with WDPM.
She had left pleurodesis in November 2006 because of recurrent left pleural effusion suggestive of progressive disease. She declined any specific systemic anticancer treatment but continued on supportive measures.
Her serum CA-125 gradually increased from 97 U/ml in July 1999 to 983 U/ml in March 2008 (Figure 2). In April 2008, she presented with increasing ascites. This was therapeutically drained and cytology was again consistent with WDPM. Her disease gradually progressed and she died of progressively worsening respiratory failure in May 2008.
Well-differentiated papillary mesothelioma is well described in the literature, with most reported cases arising from the peritoneum in women of reproductive age. There have been two small case series of WDPM of the pleura,2,3 along with two other case reports,4,5 with a total of 17 men and 16 women, reported in the English-language papers. This case report describes the youngest patient to have pleural WDPM.
WDPM displays a characteristic histologic pattern with diffuse formation of papillae lined by relatively bland mesothelial cells, often with subnuclear vacuolation and absence of mitoses. Invasion of the submesothelial layer is absent or minimal. Unlike malignant mesothelioma, WDPM have generally lacked an association with asbestos exposure, particularly in the peritoneum.
In 11 patients with a minimal follow-up period of 24 months in the Galateau-Salle et al.3 series, the survival ranged from 36 to 180 months, with an average of 74 months. This case report certainly confirms the indolent natural history of WDPM with a long survival of 16 years from the time of diagnosis.
Cytologic examination of fluids with immunohistochemical stains on cell block sections and electron microscopy are effective in establishing the diagnosis of WDPM and in confirming recurrences. Numerous clusters or “collagen balls” have been described in a recent report.6
The optimal management including the role of chemotherapy in the treatment of pleural WDPM remains unknown. There is no clear pattern as to whether specific treatment such as surgery, radiotherapy, or chemotherapy altered the natural history of this disease.2,3 In the series reported by Daya and McCaughey,7 it was suggested that chemotherapy had an adverse outcome. In contrast, Baratti et al.8 reported that definitive tumor eradication of peritoneal disease by means of cytoreduction and hyperthermic intraperitoneal chemotherapy seems to be effective in preventing disease recurrence and transition to an aggressive malignancy. However, this case report demonstrated the importance of surgical procedures such as pleurodesis and pericardial window in the management of fluid production in the treatment of this condition.
The cancer antigen CA-125 is a high-molecular mass glycoprotein produced by cells of ovarian cancer and normal cells derived from coelomic epithelium. Neither the serum CA-125 nor the immunohistochemical staining of CA-125 in cells is specific, but is most strongly associated with epithelial gynecologic tumors such as the ovarian carcinoma. Other cells of origin that may react positive for CA-125 immunohistochemistry include the lung and breast but also the epithelial cells of the conjunctiva and prostate glandular epithelium. The elevation of serum CA-125 may occur in other malignant conditions such as lung, bladder, gastric, hepatic and pancreatic cancers, leukemia, non-Hodgkin lymphoma, and mediastinal teratoma; benign conditions such as cardiac failure, pleuropulmonary diseases, chronic liver disease, connective tissue disease, peritoneal dialysis, and recent surgery; and up to 2% of normal healthy individuals. There is recent evidence that 85% of diffuse malignant epithelioid mesothelioma stains for CA-125.9 Furthermore, the serum CA-125 is elevated in most patients with peritoneal mesothelioma in one series and the serial measurements paralleled treatment response and relapse, suggesting a potential role of serum CA-125 in the disease monitoring of malignant mesothelioma.10
Interestingly, this woman's serum CA-125 seems to have gradually increased over the years accelerating toward the end of her life. This may indicate that CA-125 could be a marker of WDPM progression. However, it may simply reflect other factors such as gradual accumulation of pleural effusion and ascites. To our knowledge, neither CA-125 immunohistochemical staining for WDPM nor the use of serum CA-125 as a marker of WDPM has been reported in the English literature.
This case report adds the youngest patient so far to the small body of literature on pleural WDPM, confirming the indolent time course of this disease without significant systemic anticancer treatment, but the importance of the surgical procedures to manage malignant pleural and pericardial fluid is demonstrated. It also demonstrates that the involvement of other mesothelial surfaces, such as pericardium and peritoneum, occurs with this tumor. Fluid cytology, immunohistochemistry, and electron microscopy were useful in making the diagnosis of recurrent WDPM. The potential usefulness of serum CA-125 as a marker for WDPM is emphasized.
1. Millward M, Parnis F, Byrne M, et al. Phase II trial of imatinib mesylate in patients with advanced pleural mesothelioma. Proc Am Soc Clin Oncol
2. Butnor KJ, Sporn TA, Hammar SP, Roggli VL. Well-differentiated papillary mesothelioma. Am J Surg Pathol
3. Galateau-Salle F, Vignaud JM, Burke L, et al. Well-differentiated papillary mesothelioma of the pleura: a series of 24 cases. Am J Surg Pathol
4. Hollinger P, Gaeng D. Simultaneous bilateral spontaneous pneumothorax in a patient with peritoneal and pleural papillary mesothelioma. Respiration
5. Shukunami K, Hirabuki S, Kaneshima M, Kamitani N, Kotsuji F. Well-differentiated papillary mesothelioma involving the peritoneal and pleural cavities: successful treatment by local and systemic administration of carboplatin. Tumori
6. Ikeda K, Suzuki T, Tate G, Mitsuya T. Cytomorphologic features of well-differentiated papillary mesothelioma in peritoneal effusion: a case report. Diagn Cytopathol
7. Daya D, McCaughey WT. Well differentiated papillary mesothelioma of the peritoneum: a clinicopathologic study of 22 cases. Cancer
8. Baratti D, Kusamura S, Nonaka D, Oliva GD, Laterza B, Deraco M. Multicystic and well-differentiated papillary peritoneal mesothelioma treated by surgical cytoreduction and hyperthermic intra-peritoneal chemotherapy (HIPEC). Ann Surg Oncol
9. Kushitani K, Takeshima Y, Amatya VJ, Furonaka O, Sakatani A, Inai K. Immunohistochemical marker panels for distinguishing between epithelioid mesothelioma and lung adenocarcinoma. Pathol Int
10. Baratti D, Kusamura S, Martinetti A, et al. Circulating CA125 in patients with peritoneal mesothelioma treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Ann Surg Oncol