Q1. D
Q2. C
Q3. B
Q4. A

Mesothelioma in situ

The biopsy consisted of four fragments with similar histologic findings. Low-power histologic examination of the fragments (Figure 1) shows adipose tissue and skeletal muscle covered by a mesothelial cell layer. At higher magnification, the mesothelial cell layer is composed of a single layer of epithelioid cells with mild to no cytological atypia (Figure 2). There is no evidence of invasion across multiple serial sections. Immunostaining shows that the atypical cells are positive for AE1/AE3 (Figure 3), Calretinin (Figure 4) and WT1, confirming their mesothelial origin. Notably, there is a loss of BAP1 nuclear expression in the atypical mesothelial cells (Figure 5), while MTAP cytoplasmic staining (Figure 6) and NF2/Merlin expression (not shown) were preserved.

Mesothelioma in situ has been included in the latest WHO Classification of Thoracic Tumors as the preinvasive lesion of mesothelioma. It is characterized by the presence of molecular alterations specific to malignancy in mesothelial cells, such as BAP1 inactivation or CDKN2A homozygous deletion, without any evidence of tissue invasion. Patients typically present with an unexplained, recurring pleural effusion. The diagnosis relies on a combination of radiologic findings (absence of pleural nodules or masses), clinical findings (thoracoscopy for direct examination of the pleura), and pathological findings (absence of invasion on biopsies). There is no consensus on the minimal amount of tissue needed for diagnosis, but the WHO suggests a biopsy of at least 100-200 mm2. 

Histologic findings include a non-invasive proliferation of flat to cuboidal epithelioid mesothelial cells, which may be cytologically bland or exhibit mild cytologic atypia. Immunohistochemistry is useful for demonstrating mesothelial differentiation but highlighting the loss of BAP1 nuclear expression or loss of MTAP cytoplasmic expression (serving as a surrogate for CDKN2A homozygous deletion, see below) is essential to the diagnosis (Question 2). The differential diagnosis includes reactive mesothelial proliferation, well-differentiated papillary mesothelial tumor (both of which show no molecular alteration), and epithelioid mesothelioma (characterized by the presence of invasion) (Question 1).

BAP1 inactivation is found in 60-70% of mesotheliomas, mostly in the epithelioid type, and represent the most frequent alteration in mesothelioma in situ (Question 4). The alteration is reflected by the loss of BAP1 expression by immunohistochemistry. CDKN2A/p16 homozygous deletion is found in about 70% of mesotheliomas, mostly in sarcomatoid type, and it is typically detected by FISH. More practically, the loss of MTAPcytoplasmic expression by immunohistochemistry can be used as a surrogate for the deletion as MTAP and CDKN2A are co-deleted in 75 to 90% of cases. Lastly, NF2/Merlin immunostaining is a promising new marker and shows a loss of apico-lateral staining in around 50% of epithelioid mesotheliomas. Its incidence in mesothelioma in situ remains to be reported. In distinguishing between benign and malignant mesothelial proliferations, all three markers exhibit 100% specificity for malignancy. In other words, detecting any of these molecular alterations in a non-invasive mesothelial proliferation confirms its malignant potential, enabling the identification of a precursor lesion for invasive mesothelioma.

Only few cases of mesothelioma in situ have been reported to date. However, the reported patients are at high risk of progressing to invasive mesothelioma. In two small cohort studies, approximately 75% of patients with mesothelioma in situ eventually developed invasive mesothelioma, with a median progression time of 60 months. There is no established consensus on the treatment of these patients, but close clinical follow-up is recommended (Question 3). However, in a case report, a patient underwent total parietal pleurectomy for mesothelioma in situ, with no radiological evidence of recurrence after five years.

Take home message for trainees: Consider mesothelioma in situ in patients with a recurrent pleural effusion without a clear etiology. The diagnosis requires integration of clinical and radiological data (absence of pleural nodules or masses on imaging and thoracoscopy) with pathological finding of BAP1 and/or MTAP loss by immunohistochemistry in mesothelial cells, without evidence of invasion.

Chapel DB, et al. Clinical and molecular validation of BAP1, MTAP, P53, and Merlin immunohistochemistry in diagnosis of pleural mesothelioma. Mod Pathol 2022;35(10):1383-97.

Churg A, et al. Malignant mesothelioma in situ: morphologic features and clinical outcome. Mod Pathol 2020;33(2):297-302.

Dacic S, et al. Mesothelioma in situ. In: WHO Classification of Tumours Editorial Board. Thoracic tumours [Internet]. Lyon (France): International Agency for Research on Cancer 2021 [cited 2024 Oct].

Danuzzo F, et al. Pleural mesothelioma in situ: a comprehensive review. Eur J Cancer Prev 2024;33(6):545-51.

Husain AN, et al. Guidelines for Pathologic Diagnosis of Mesothelioma. Arch Pathol Lab Med 2024.

Michaël Maranda-Robitaille, MD
Postgraduate year 2, Diagnostic and Molecular Pathology
Laval University
Quebec City, Quebec, Canada

Andréanne Gagné, MD PhD
Thoracic Pathologist
Institut Universitaire de Cardiologie et de Pneumologie de Québec – Université Laval (Quebec Heart and Lung Institute – Laval University)
Quebec City, Quebec, Canada