Well Differentiated Papillary Mesothelioma of Uncertain Malignant Potential Andrew Churg University of British Columbia Vancouver, Canada

History: 67 year old male with a 2-3 year history of a scrotal mass, initially thought to be associated with the epididymis, but actually found at surgery to be in a hydrocoele. The hydrocoele was resected. The tumor measured approximately 2 cm across and appeared to be a solitary lesion. After the initial diagnosis, a radical orchiectomy was performed. No residual gross or microscopic tumor was identified. The patient is alive and well without clinical evidence of disease 6 months after the initial surgery. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 Low power views showing papillary architecture. Figure 2 Low power views showing papillary architecture. Figure 3 Higher power views showing covering of a single layer of bland mesothelial cells. Figure 4 Higher power views showing covering of a single layer of bland mesothelial cells. Figure 5 Area of apparent invasion of the stalk. Figure 6 Area of apparent invasion of the stalk. Figure 7 Area of apparent invasion of the stalk. Figure 8 Pan-keratin Pan-keratin stain showing that the surface cells are keratin positive. Figure 9 Pan-keratin Pan-keratin stain of an area of invasion in the stalk. Figure 10 Calretinin Calretinin stain showing positivity in the surface cells. Diagnosis: Well differentiated papillary mesothelioma of uncertain malignant potential Clinical and Demographic Features: Well differentiated papillary mesothelioma (WDPM) was initial described and named by Daya and McCaughey in 1990. WPDM are most commonly incidental findings encountered in the peritoneal cavity in women during surgery for some other process. They are also found in the peritoneal cavity in men, although they appear to be less common than in women. WDPM also occur in the pleural cavity in both sexes, and there are a few reports of WDPM of the tunica vaginalis. Although many cases are asymptomatic, WDPM may present with abdominal or chest pain or shortness of breath, or with a scrotal mass. In some cases imaging studies show a pleural effusion or ascites. Because these tumors are called "mesotheliomas," the question of whether they are associated with asbestos exposure (as is true of diffuse malignant mesotheliomas) has arisen. In the original Daya and McCaughey series of 22 cases, only a few had even a suggestion of such exposure. The more recent series of 14 cases reported by Butnor et al contained 9 patients with histories of asbestos exposure, including some with pleural plaques, while the series of 24 patients of Galateau-Salle et al had 12 with asbestos exposure. However, as pointed out by Galateau-Salle et al, their series and that of Butnor et al suffer from severe selection bias because the authors are typically referred patients with known asbestos exposure. Thus the issue of asbestos as a caused of WDPM is unresolved, but the fact that the majority of these tumors occur in women and in the peritoneal cavity suggests that asbestos exposure is unlikely as an etiologic agent, since few women have had significant asbestos exposure, and the induction of peritoneal diffuse malignant mesothelioma requires a high level exposure to amphibole asbestos. Morphology: The 2004 WHO classification defined WDPM as a "distinct tumor with a papillary architecture, bland cytologic features, and a tendency toward superficial spread without invasion." Grossly WDPM may appear as solitary nodules or as multiple nodules ranging from a few mm to, rarely, as much as 9 cm in diameter. In some cases the serosal surface has a velvety appearance because of the presence of innumerable nodules. Microscopically WDPM appear as papillary lesions that may be complex. In early lesions the papillae have a myxoid core, but with age they may become fibrotic. The covering of the papillae is a single layer of flattened to cuboidal mesothelial cells that are monotonous in appearance, do not have mitoses, and usually have inconspicuous nucleoli. Psammoma bodies are occasionally seen. Larger tumors may have a central scar. Immunochemically WDPM are identical to ordinary diffuse malignant mesotheliomas. Differential Diagnosis and Identification of Malignancy in WDPM: Most WDPM are readily diagnosed. Care must be taken with small biopsies because ordinary diffuse malignant mesotheliomas can be focally or sometimes extensively papillary, and a small biopsy may sample only the papillary areas. Invasion of the tissue underlying a putative WDPM is good evidence that the lesion in question is really a diffuse malignant mesothelioma. Very rapid progression of disease also suggests that the process is a diffuse malignant mesothelioma. It is common to find a few very innocuous looking small glands or a few isolated mesothelial cells in the stalk in otherwise typical WDPM and these probably are insignificant. More problematic are cases such as this one in which there is obvious invasion of the stalk by proliferating mesothelial cells. The members of the US-Canadian Mesothelioma Reference Panel by and large viewed this case as a WDPM of uncertain malignant potential based on stalk invasion. Prognosis: Most cases of WDPM are incidental findings, and even when multiple do not shorten life expectancy, although the lesions may persist and proliferate; indeed one of the original patients described by Daya and McCaughey was found to still have WDPM at autopsy (for another cause of death) 29 years later. Whether WDPM can turn into diffuse malignant mesotheliomas over time is unclear and the question is confounded by initial misclassification of some diffuse malignant mesotheliomas as WDPM. There are 2 cases in the Galateau-Salle series with well documented WDPM of the pleura where diffuse malignant mesothelioma appeared more than 10 years after the initial diagnosis. Both these patients both had significant asbestos exposure, and in neither patient was there evidence of progression of the WDPM in the interval; thus it is possible that the diffuse malignant mesotheliomas were completely separate tumors. Burrig et al reported a WDPM of the peritoneum which 5 years later caused the death of the patient and the final morphology was that of WDPM; the question of initial misclassification arises in this case. One patient in the series of Butnor et al died of peritoneal tumor after 3 years, but the morphology of the progressive tumor was not described. There is no evidence that WDPM respond to chemo or radiotherapy. Communication with clinicians: A significant problem with WDPM is that clinicians and oncologists see the word "mesothelioma" on a surgical pathology report and interpret that as "diffuse malignant mesothelioma" requiring chemotherapy or radiotherapy, and perhaps cytoreductive surgery as well. There is no good evidence that this approach improves survival. For that reason it is important to include a comment when diagnosing WDPM to call attention to the fact that these lesions generally behave in a functionally benign fashion. Key words: well differentiated papillary mesothelioma; diffuse malignant mesothelioma References: Burrig KF, Pfitzer P, Hort W. Well-differentiated papillary mesothelioma of the peritoneum: a borderline mesothelioma. Virchows Arch A Pathol Anat Histopathol 1990;417:443-447. Butnor KJ, Sporn TA, Hammar SP, Roggli VL. Well-differentiated papillary mesothelioma. Am J Surg Pathol. 2001; 25:1304-1309. Churg A, Cagle PT, Roggli VL: Tumors of the Serosal Membranes, Fascicles Series IV, Washington, DC; American Registry of Pathology, 2006. Churg A et al: Well differentiated papillary mesothelioma. In, WHO Classification of Tumors: Pathology and Genetics of Tumours of the Lung, Pleura, Thymus, and Heart, edited by WD Travis, E Brambilla, HK Muller-Hermelink, CC Harris. Lyon, WHO, 2004, pages 135-136. Daya D, McCaughey WT. Well-differentiated papillary mesothelioma of the peritoneum. A clinicopathologic study of 22 cases. Cancer 1990; 65: 292-296. Galateau-Sallé F, Vignaud JM, Burke L, Gibbs A, Brambilla E, Attanoos R, Goldberg M, Launoy G; Mesopath group. Well-differentiated papillary mesothelioma of the pleura: a series of 24 cases. Am J Surg Pathol 2004; 28: 534-540.