MM a rare malignant disease, and its diagnosis is usually challenging for pathologists[7]. Because its phenotype varies among patients, and it mimics benign reactive mesothelial proliferations and other cancers. In many cases, only cytological material or a limited amount of tissue is available for pathologic evaluation [8]. Sometimes, video-assisted thoracoscopic surgery (VATS) is necessary for a deep and large biopsy and assessment of its respectability[9, 10]. The International Mesothelioma Interest Group recommends that at least 2 mesothelial (calretinin, CK 5 or 5/6, WT1 and podoplanin) and 2 carcinoma markers (Claudin 4, MOC31, CEA, BER-EP4, BG8, TTF-1 and Napsin A) for IHC differential diagnosis[11]. Recent studies showed that BAP1 mutations and p16 deletions by FISH were reliable in differentiating malignant mesotheliomas from benign reactive mesothelial proliferations[7, 12]. Several studies have reported p16/CDKN2A deletions in up to 80% of primary MM, depending on the histologic subtype (90–100% of sarcomatoid type; 70% of epithelioid and biphasic types)[13]. A study reported that P16 immunoreactivity in stromal cells of MM had significant relation with the patients’ high exposure to asbestos[14]. And the presence of a p16 homozygous deletion correlates with shorter survival in patients with MM[15]. Recently, circulating miRNAs and extracellular vesicles (EVs) are discovered to be novel and non-invasive biomarkers for early detection, differential diagnosis and predicting prognosis of MM[16, 17]. The resected tumor specimen of this case was positive for CK5/6, WT1 and podoplanin, and negative for Naspin A and TTF-1, which meets the criteria above. Also, the pathological features of sarcomatous atypical spindle cells of this case indicated sarcomatous type of MM. Further FISH detected homozygous p16/CDKN2A deletion. This result demonstrates that a metastatic mass is also a reliable diagnostic tissue in the intractable MM case, which has not been verified in the previous studies.
CT features of MM include unilateral pleural effusion, nodular pleural thickening, interlobar fissure thickening, calcified pleural plaques, chest wall involvement and hilar and mediastinal lymph nodes enlargement[18]. However, its sensitivity and specificity are only 70%[19]. MRI can provide additional information of invasive growth of MM such as invasion of the diaphragm, endothoracic fascia and chest wall[20]. PET-CT can identify MM from benign disease, but not metastatic pleural malignancy[21]. And PET-CT is able to indentify nodal and extrathoracic metastases. A study found that Mean SUVmax value was higher in sarcomatoid (11.8 ± 4.6) and biphasic type (9.3 ± 7.0) rather than in epithelioid type (6.9 ± 3.8) (P < 0.01), and high SUVmax values were significantly associated with a worse prognosis[22]. We found brain metastases by PET-CT, and the SUVmax of the right lung nodule in this case was as high as 19.0, which indicated highly malignancy.
It is common to see lymph nodes and organ involvement. As we noticed, there were lymph nodes, subcutaneous and brain metastases in this case. The disseminating routes of MM are direct invasion, lymphatic and hematogenous spread[23]. The solitary mass in the back was probably via hematogenous in this case. To our knowledge, there are 18 case reports of cutaneous or subcutaneous metastases from MM [4–6, 23–36] (Fig. 6), but only 3 sarcomatoid type of MM among them[4–6]. The data of the previous researches indicated that the most common cutaneous or subcutaneous metastases from MM occurred on head, chest pain or dyspnea was a main symptom, about half of the patients suffered pleural effusion, they usually received chemotherapy, and 1-year-survival rate was only 20% (Fig. 6).
The majority of patients with MM develop breathlessness with pleural effusion[37]. Therapeutic pleural aspiration and chemical pleurodesis are two ways to control pleural fluid and improve patients’ quality of life[37]. Pleural aspiration and intrapleural chemotherapy of cisplatin was done in this case, but its effectiveness of intrapleural cisplatin was uncertain since the follow-up was too short.
Generally, MM is incurable disease, the median survival period is less than 1 year[38], and the 5-year-survival rate is only 5%[39]. A sarcomatoid type is associated with a worst outcome, with a median survival of just 4 months[37]. This case was found multiple distant metastases and deteriorated very quickly, and the patient died within 3 months since initial diagnosis. Surgery is limited only for MM patients in early stage. Based on our experience, local resection of a subcutaneous metastatic lesion was not a good option, since it turned out a quick recurrence. A needle biopsy might be worthy doing for diagnosis. HIFU therapy rather than radiation showed a therapeutic potential. Systemic treatment of chemotherapy and immunotherapy are delivered on the patient, but MM is highly resistant to them specially the metastastic lesion. A small number of studies showed that pemetrexed/raltitrexed plus cisplatin/carboplatin could achieve better response rates[40, 41]. PD-L1 expression is relatively common (> 30%) for MM samples[42], and it is related to poor prognosis in MM patients[43]. Immunotherapy such as nivolumab is being on clinical trials as a second or third line treatment for MM[2, 44]. In this case, the mediastinal and right infraclavicular lymph nodes seemed sensitive to cytotoxic agents, however, the pulmonary nodule and the subcutaneous mass were both resistant to the agents. Hence, more clinical trials focusing on effective agents should be conducted in the future.
