A man in his mid-70s was diagnosed with a right upper lobe lung cancer, which was clinically stage 1 and moderately avid on positron emission tomography scan. An incidental non–fluorodeoxyglucose-avid mass was noted prior to surgery in the lower lobe, which by imaging was a suspected solitary fibrous tumor. A robotic-assisted right upper lobectomy was performed, and multiple levels 4R and 7 mediastinal lymph nodes sampled. A diagnostic wedge resection for the lower lobe tumor was also performed. The lung cancer was diagnosed as invasive adenocarcinoma, acinar predominant, with focal visceral pleural invasion and negative lymph nodes (pT2aN0). The right lower lobe mass was diagnosed as localized mesothelioma, epithelioid type, visceral pleural based, with ample negative margins. The patient was treated as a surgical cure for both lesions, without systemic therapy. He is alive and well 2 years after the surgery and exercises daily.
The mesothelioma was a well-circumscribed visceral pleural-based nodule measuring 2.2 cm. Its border was discrete without infiltration into lung parenchyma (Fig. 1). The tumor cells were uniform, rounded epithelial cells with ample cytoplasm, and regular round to oval small nuclei without nucleoli. The Ki-67 rate was low (approximately 5%). The tumor was diffusely positive for calretinin, mesothelin, HBME, WT-1, podoplanin, and cam 5.2 and negative for CD34, bcl2, ber-EP4, TTF-1, bcl2, melan-A, and S100 protein. BAP-1 staining was retained.
A woman in her early 50s, lifetime nonsmoker, developed cough and dyspnea. A 6-cm left lower lobe mass was detected by imaging. Positron emission tomography–computed tomography scan showed a markedly hypermetabolic 6.3-cm mass in the left lower lobe, without uptake elsewhere. A biopsy showed a sarcomatoid epithelioid neoplasm, which, because of the location, was diagnosed as consistent with sarcomatoid carcinoma. At surgery, a left lower lobectomy was performed, with negative margins. Lymph nodes were sampled (levels 6, 7, 9, 10, and 11). Unexpectedly, 4 parietal-pleural–based implants (2 chest wall, 2 diaphragm) were found not adherent to the lung and discrete from one another, and all in the region adjacent to the lower lobe. The largest was 1.2 cm in diameter. These were all excised, and intervening pleura biopsied. At pathologic examination, a 6.3-cm mass was found in the lung, with a broad pleural base. There were 2 adjacent pleural-based nodules measuring 1.5 and 1 cm (Fig. 2). Margins were negative. All 7 tumors were histologically identical, composed of spindled pleomorphic cells with areas of necrosis and a high mitotic activity. The intervening pleural was negative. There was microscopic infiltration of lung parenchyma in the lung lesions and invasion of skeletal muscle and fat in the parietal pleural lesions. Immunostaining was negative for TTF1, MUC4, and berEP4 and positive for pancytokeratins, GATA3, and calretinin (Fig. 3). Other mesothelioma markers were negative. The diagnosis of multifocal localized malignant mesothelioma, sarcomatoid type, was made. CDK2NA fluorescence in situ hybridization was negative for homozygous or heterozygous deletion (wild type). The patient has started on a course of chemotherapy.
Localized mesothelioma, or localized malignant mesothelioma, is an extremely rare tumor. The largest series of 23 cases was multi-institutional, without correlation between histologic features and outcome.1 Although many of the cases that have been reported in the literature have long disease-free follow-up, many others have developed metastatic disease within months or years of diagnosis. Although disease-free survival has been correlated with subtype (epithelioid, biphasic and sarcomatoid) in a recent review of the literature,2 epithelioid tumors have not been graded or placed into categories based on pathologic aggressiveness.
Case 1 in this report demonstrates a tumor with many benign histologic features, including cellular features, lack of mitotic figures, and circumscribed growth, all features that are considered low-grade or even benign. The difficulty in this particular patient was communicating to the oncology team that despite the designation of mesothelioma, the lesion appeared to be cured and chemotherapy was not warranted.
Although case 1 in this report is clearly localized, the distinction between localized and diffuse mesothelioma of the pleura depends in part on the definitions employed and is not always straightforward. Marchevsky et al2 did not include multifocal tumors in their review, although in their discussion noted that small nodules near a dominant tumor is sometimes allowed as a “localized” mesothelioma, as in case 2 in this report. The World Health Organization criteria include “no clinical or histological evidence of diffuse serosal spread”; whether small satellite nodules near a dominant mass qualify as “diffuse serosal spread” is unclear. Conversely, case 2 in this report has features very unusual for diffuse malignant mesothelioma, namely, circumscribed growth of all of the nodules and dominant lesion arising from the visceral pleura. In stark contrast to diffuse malignant mesothelioma of the pleura, which almost always begins on the parietal pleural surface, localized pleural mesotheliomas usually arise from the visceral pleura.3 The specific diagnosis in case 2 did not affect therapy, as the patient had already gotten surgical treatment and was referred to chemotherapy for sarcomatoid mesothelioma. However, the distinction could have critical importance if the patient was diagnosed prior to surgery. The pattern of disease in case 2 would not be amenable to standard surgical treatment such as extended pleurectomy and decortication, because all of the visible lesions were removed separate incisions, sparing the vast bulk of the patient pleura on that side. The patient may not have benefitted from surgery and removal of all gross disease, if the diagnosis of diffuse malignant mesothelioma, sarcomatoid type, had been made on biopsy.
Localized mesothelioma of the pleura is classified into epithelioid, biphasic, and sarcomatoid variants, as is done with diffuse malignant mesothelioma. Localized mesotheliomas have been described most commonly in the thorax, but lesions in the abdomen and pelvis have also been reported. As the cases reported in this issue demonstrate, a diagnosis of mesothelioma is almost never suspected by imaging, because of the rarity of the tumor.
From the 160 or so cases that have been reported, there is a male preponderance of 2.7:1. The mean age at presentation is 59 years, with a wide range from 6 to 82 years.2 There is only a loose association with asbestos exposure, at a rate of approximately one-third. There are very few data regarding the molecular alterations in localized mesotheliomas. A series of 6 tumors showed BAP1 mutations with deletions of CDKN2A and NF2 in 2 tumors; TRAF7 mutations in 2 tumors, including one harboring trisomies of chromosomes 3, 5, 7, and X; and genomic near-haploidization, characterized by extensive loss of heterozygosity sparing chromosomes 5 and 7 in the others.4
Histologically, a little over one-half of localized malignant mesotheliomas are epithelioid, the others being sarcomatoid or biphasic. No histologic differences have been noted between localized and diffuse mesotheliomas. Similarly, immunohistochemical findings are identical, although information about BAP-1 expression is very limited.
The differential diagnoses of epithelioid localized mesotheliomas include carcinoma, metastasis, and epithelioid type of solitary fibrous tumor. The major differential diagnoses of sarcomatoid localized mesothelioma are sarcomatoid carcinoma and pleural sarcomas, such as malignant solitary fibrous tumor, synovial sarcoma, and undifferentiated pleomorphic sarcoma. GATA-3 positivity and MUC4 negativity have been described as helpful in distinguishing sarcomatoid mesothelioma from carcinoma.5
In earlier publications, the median survival time of patients with localized mesothelioma was reported at 29 months.6 However, Marchevsky et al2 reported a median survival time of 134 months for 51 localized mesothelioma patients. Patients with complete resection and epithelioid histology have a relatively good prognosis.
Of interest, the tumor presented here was negative for CDKN2A loss, which is typical of sarcomatoid mesothelioma.7 This finding may reflect the more heterogeneous molecular basis for localized mesotheliomas, as reported recently.4
1. Allen TC, Cagle PT, Churg AM, et al. Localized malignant mesothelioma. Am J Surg Pathol
2. Marchevsky AM, Khoor A, Walts AE, et al. Localized malignant mesothelioma, an unusual and poorly characterized neoplasm of serosal origin: best current evidence from the literature and the International Mesothelioma Panel. Mod Pathol
3. Mann S, Khawar S, Moran C, et al. Revisiting localized malignant mesothelioma. Ann Diagn Pathol
4. Hung YP, Dong F, Dubuc AM, et al. Molecular characterization of localized pleural mesothelioma. Mod Pathol
5. Piao ZH, Zhou XC, Chen JY. GATA3 is a useful immunohistochemical marker for distinguishing sarcomatoid malignant mesothelioma from lung sarcomatoid carcinoma and organizing pleuritis. Virchows Arch
6. Gelvez-Zapata SM, Gaffney D, Scarci M, et al. What is the survival after surgery for localized malignant pleural mesothelioma?Interact Cardiovasc Thorac Surg
7. Wu D, Hiroshima K, Yusa T, et al. Usefulness of p16/CDKN2A
fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma. Ann Diagn Pathol