Mesothelioma is a rare malignant tumor with variable clinical presentations, radiological features, and morphological patterns, accounting for 0.2% of all new cases of malignant tumors worldwide.1 Depending on whether the lesion is localized or diffuse, mesothelioma is divided into localized and diffuse mesothelioma, both share an identical but wide range of morphological features and immunohistochemical phenotypes. Diffuse mesothelioma often manifests as unilateral pleural effusion, dyspnea, chest pain, and even progressive pleural thickening leading to the compression of lung parenchyma. Localized mesothelioma is significantly rare, accounting for 0.5% to 1.6% of all mesothelioma.2 Patients with localized mesothelioma have an insidious onset and are often asymptomatic. In particular, localized mesothelioma is most challenging to diagnose when it presents as intrapulmonary growth in the absence of overt pleural disease and is often misinterpreted as a pulmonary adenocarcinoma.3,4 The rarity of the disease, insidious onset, predominantly intrapulmonary growth, and diverse histological features result in a low rate of definite diagnosis and a high rate of misdiagnosis of localized mesothelioma. Herein, we report a 53-year-old female patient with biphasic mesothelioma who had an incidental finding of a mass in the right lower lobe of the lung that was misdiagnosed as poorly differentiated adenocarcinoma with focal sarcomatoid carcinoma at initial presentation. Furthermore, Mesothelioma with a predominantly intrapulmonary growth does pose a diagnostic challenge. This unique entity is discussed, along with a literature review (Table 1) and potential diagnostic pitfalls.

Table 1 Literature Review of Mesothelioma with a Predominantly Intrapulmonary Growth

A 53-year-old female without any symptoms was admitted to our hospital on 14th February 2022, due to a nodule in the lower lobe of the right lung found fortuitously for more than 7 months. Computed tomography (CT) scan of the chest revealed a solid lobulated nodule measuring 20 × 15 mm in the basal segment of the lower lobe of the right lung (Figure 1A). Radiologists considered it as suspicious of primary lung cancer. The remaining laboratory and imaging examinations are unremarkable. The patient had a history of partial thyroidectomy for unknown reasons, while no history of smoking or asbestos exposure. She underwent a lobectomy on 22nd February 2022, and a pathological biopsy was carried out. Gross examination showed a subpleural lobulated mass with medium texture and well-defined borders, measuring 2.0 × 1.5 × 1.0 cm.

Figure 1 Chest CT image, morphological characteristics, and immunohistochemistry results of lung mass. Chest CT showed a lobulated nodule in the lower lobe of the right lung (red arrow points to the nodule) (A); Under low magnification, large areas of necrosis (B), well-defined borders, and nests of tumor cells (C) can be observed; Under high magnification, nested of epithelioid cells were intermingled with spindle cells and lymphocytes (D); epithelioid cells were characterized abundant eosinophilic cytoplasm, vacuolated nuclei, and obvious nucleoli (E); Both epithelioid and spindle cells were positive for CK7 (F). [figures magnification: B, 40x; C,F, 100x; D,200x; E,400x].

Under low magnification, the lobulated tumor was composed of nests of tumor cells with patchy necrosis and circumscribed margins (Figure 1B and C). Under high magnification, the nests of tumor cells were composed of epithelioid cells with abundant eosinophilic cytoplasm, vacuolated nuclei, and obvious nucleoli. Upon careful observation, spindle cells and infiltrating lymphocytes distributed around the nests of tumor cells can be seen (Figure 1D and E). However, it was difficult to distinguish morphologically whether these spindle cells are reactive fibrous tissue or tumor cells. Based on morphological features, poorly differentiated adenocarcinoma or squamous cell carcinoma, mesenchymal tumors, and malignant melanoma were considered. The immunohistochemical analysis showed that both the epithelioid and spindle cells were diffusely and strongly positive for CK7 (Figure 1F), while negative for TTF-1, Napsin A, P40, Melan A, S-100, SMA, and CD34. EBER in situ hybridization was negative as well. The pathological diagnosis at the initial presentation was poorly differentiated adenocarcinoma with focal sarcomatoid carcinoma.

Subsequently, the patient was treated with albumin-paclitaxel and nedaplatin regularly in outpatient. However, she was readmitted to the hospital 21 months after surgery because of the discovery of a nodule in the right diaphragmatic angle. Chest CT showed a nodule in the right diaphragmatic angle, measuring approximately 23 × 12 mm. Microscopically, the morphological characteristics of the nodule in the right diaphragmatic angle were similar to those of lung lesion. Nests of epithelioid tumor cells intermingled with spindle tumor cells as well as the special location reminded us of biphasic mesothelioma. Both epithelioid and spindle tumor cells were diffusely positive for calretinin and D2-40, focally positive for WT-1, GATA-3, and negative for Cytokeratin 5/6 (CK5/6), BerEP4, MOC31, and BAP-1, supporting the diagnosis of biphasic mesothelioma as well (Figure 2A–D). True for lung lesions is the same (Figure 2E–H). Finally, a diagnosis of biphasic mesothelioma was rendered. The patient received chemotherapy combined with pemetrexed and carboplatin. After 11 months of follow-up, the patient recovers well without recurrence or metastasis.

Figure 2 Morphological features and immunohistochemistry results of the right diaphragmatic angle and lung masses. Tumor cells of the right diaphragmatic angle were composed of epithelioid and spindle-shaped cells (A), as well as positive for calretinin (B), but negative for BerEP4 (C) and BAP-1 (D). True for lung is the same (E,H&E; F, calretinin, G, BerEP4; H, BAP-1). [figures magnification: A-H,200x].

In 1976, Harwood et al reported 6 patients with a unique type of primary lung cancer, which possessed a close resemblance to mesothelioma on radiological examination, clinical presentation, and gross examination, and proposed for the first time the name of “pseudomesotheliomatous carcinoma”.13 In turn, mesothelioma characterized by a broad spectrum of radiologic features, clinical manifestations, and morphological patterns can also mimic lung cancer3 and, more rarely, resemble interstitial lung disease14 or epithelioid hemangioendothelioma.11 Especially when localized mesothelioma mainly involves the lung parenchyma, the results of chest radiography and macroscopic examination are highly suggestive of lung cancer, while histological examination is inconclusive. This is more likely to lead to misdiagnosis. Rossi G et al reported that a patient with a solid subpleural nodule that showed the predominant lepidic growth pattern microscopically was misinterpreted as primary lung cancer during an intraoperative examination.3 Furthermore, Muramatsu Y et al reported a case of local mesothelioma with predominantly intrapulmonary growth and centrally hyaline stroma similar to epithelioid hemangioendothelioma.11

In addition, there is another rare intrapulmonary growth pattern of mesothelioma – diffuse intrapulmonary mesothelioma (DIM), which presents with diffuse lesions with predominantly intrapulmonary growth patterns and no or minimal pleural involvement. DIM has a variety of histological growth patterns that are very similar to lung adenocarcinoma, such as lepidic, alveolar, papillary, or micropapillary.15

In these cases, imaging studies, gross examination, and clinical symptoms are of little help in distinguishing mesothelioma from lung adenocarcinoma, and similar histologic features can further be confusing. However, some clues to cytologic features, immunohistochemical results, and electron microscopic features can aid in confirming the diagnosis.

The common cytologic features of epithelioid mesothelioma are mildly atypical low columnar to cuboidal cells characterized by abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Meanwhile, the tumor cells of lung adenocarcinoma are characterized by a hobnail-like appearance with hyperchromatic nuclei and inconspicuous nucleoli.16 Just like the case reported by Rossi G et al, even if a lepidic growth, the tumor cells presented with a globous appearance with abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli, which is different from the cytological features of lung adenocarcinoma, thus avoid misdiagnosis.3

Establishing mesothelial origin is the first and vital step in diagnosing mesothelioma. A panel of immunohistochemical markers of calretinin, CK5/6, WT-1 (nuclear staining only), and D2-40 (Podoplanin) is recommended for mesothelial origin. For epithelioid mesothelioma, the sensitivities of calretinin, CK5/6, WT-1, and D2-40 were 80–100%, 51–100%, 70–100%, and 80–100%, respectively, while for sarcomatoid mesothelioma were 50–60%, 13–29%, 10–45%, and 75–90%, respectively.17 Furthermore, BAP-1 loss and homozygous CDKN2A deletion have a specificity of nearly 100% but low sensitivity in differentiating mesothelioma from benign mesothelial proliferation. BAP-1 loss has been detected in approximately 50–65% of pleural mesothelioma, with epithelial mesothelioma being the most common (61–77%), followed by biphasic mesothelioma (33–49%), and finally sarcomatoid mesothelioma (0–22%).17 Similarly, the homozygous deletion of CDKN2A detected by fluorescence in situ hybridization (FISH) harbors only 50–65% sensitivity for pleural mesothelioma, 80–100% for sarcomatoid mesothelioma.17 Loss of cytoplasmic MTAP staining could be a substitute for CDKN2A homozygous deletion, due to the frequent co-deletion of the MTAP and CDKN2A gene.18

Currently, two epithelial markers and two mesothelial markers are recommended for distinguishing epithelioid mesothelioma from cancer, such as lung adenocarcinoma.19 Claudin-4 is the best epithelial marker to distinguish non-small cell lung cancer, including poorly differentiated lung adenocarcinoma, from epithelioid mesothelioma, with high specificity and comparable sensitivity, even in effusion cytology specimens.20–22 Sarcomatoid mesothelioma is poorly sensitive to mesothelial markers and loss of BAP-1 nuclear staining. On the other hand, epithelial markers like claudin 4, BerEP4, and MOC31 are also less sensitive to sarcomatoid areas of sarcomatoid lung carcinoma.19 These add difficulty in distinguishing sarcomatoid carcinoma and sarcomatoid mesothelioma. Focal positivity of TTF-1, Napsin A, or P40 may provide clues for the diagnosis of sarcomatoid lung carcinoma. Furthermore, diffuse expression of GATA-3 is found in 70% of sarcomatoid mesothelioma but lacks specificity.19 Therefore, a panel of immunostains including multiple epithelial and mesothelial markers should be performed in rare cases that are difficult to diagnose.

It has been reported that in some diagnostically challenging cases, electron microscopy can provide valuable clues to confirm the mesothelial origin of tumor cells. The main distinctive ultrastructural features of epithelioid mesothelioma are abundant, branched, elongated microvilli, tight junctions, and giant desmosomes.23 Fortarezza F et al reported a case of epithelioid pleural mesothelioma with a history of breast cancer, whose immunohistochemical results were not decisive for the distinction of mesothelioma or breast cancer metastasis, which was diagnosed by electron microscopy.23

Mesothelioma has a poor prognosis and few treatment options. Currently, trimodal treatment consisting of surgery, chemotherapy (neoadjuvant or adjuvant), and radiotherapy are indicated for resectable mesothelioma, particularly in patients without nodal involvement.24 According to the 2023 Chinese expert consensus on the treatment of malignant pleural mesothelioma, the first-line chemotherapy regimen for mesothelioma is a combination of pemetrexed and cisplatin or a triple-drug combination of pemetrexed, cisplatin and bevacizumab.25 After a complete surgical resection of the lesions, our patient received a chemotherapy regimen of carboplatin combined with pemetrexed and is currently recovering well.

In conclusion, we reported a case with biphasic mesothelioma, predominantly intrapulmonary growth, misdiagnosed as poorly differentiated adenocarcinoma with focal sarcomatoid carcinoma. The rarity of this entity and the similarities to primary lung cancer concerning imaging and even histological features make diagnosis challenging. However, some subtle cytologic features, selection of immunohistochemical markers, and electron microscopy can aid in the definite diagnosis of diagnostically challenging cases.

CT, computed tomography; DIM, diffuse intrapulmonary mesothelioma; CK5/6, cytokeratin 5/6; FISH, fluorescence in situ hybridization.

This study was approved by the Ethics Committee of Guiqian International Hospital. Our institution approved the publication of the case details. Written informed consent has been obtained from the patient for the release of relevant clinical and imaging data from their cases, including consent for the publication of the case details.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

No funding was available to support this research.

The authors declare no conflicts of interest in this work.

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