PMC9928971_01
Imaging features at diagnosis. (A) Chest x-ray at diagnosis showing a right hilar and mediastinal enlargement (white arrow) with tracheal deviation (black star). (B and C) Chest CT after iodine contrast showing a solid mass (33/50 precontrast and postcontrast HU) centered on the right superior and apical bronchi (black arrow), compressing the superior vena cava (short white arrow) and encasing of the upper right pulmonary artery (long white arrow). (D) Abdominal CT (arterial phase) showing a hypodense (33/58 precontrast and postcontrast HU) solid nodule within the pancreatic body (white star). (E) 18F-FDG positron emission tomography showing significant uptake of both thoracic (black arrow) and pancreatic (white star) lesions (SUVmax 12 and 15, respectively). CT, computed tomography; HU, Hounsfield Unit; SUVmax, maximum standard unit value; 18F-FDG, 18F-fluorodeoxyglucose.
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fig1
Chest x-ray and computed tomography (CT) scan revealed a 7-cm large solid mass centered on the right superior and apical bronchi with apical lung segment atelectasis, compressing the superior vena cava and encasing the upper right pulmonary artery (Figs 1A and 1B). Abdominal CT scan identified a 2-cm large hypodense solid nodule within the pancreatic body (Fig 1C). 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography CT showed significant uptake in both thoracic and pancreatic lesions (Fig 1D) without other distant metastases.
Pathological presentation. (A) H&E staining on the pancreatic biopsy showing sheets and nests of tumor cells infiltrating the pancreatic parenchyma, with foci of tumor necrosis. (B) Noncohesive epithelioid cells with moderate atypia and clear to eosinophilic cytoplasm. (C) By immunohistochemistry, tumor cells showed diffuse and intense expression of SMA. (D) HMB 45 was focally expressed in a minority of tumor cells. (E and F) Subtotal loss of MLH1 expression (E) and total loss of PMS2 expression (F) in tumor cells. H&E, hematoxylin and eosin; SMA, sequential multiple analysis.
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Both biopsy specimens demonstrated a similar infiltrating tumoral proliferation of mainly epithelioid cells, arranged in nests or sheets (Fig 2A). The cytoplasms were eosinophilic or clear in places, with indistinct limits (Fig 2B). In immunohistochemistry, tumor cells showed diffuse and intense expression of SMA, and HBM45 was focally expressed in a minority of tumor cells (Figs 2C and 2D). The microscopic and immunohistochemical profiles oriented toward the diagnosis of malignant PEComa. Tumor cells showed subtotal loss of MLH1 expression (> 95% unlabeled tumor cells) and total loss of PMS2 expression (Figs 2E and 2F), in favor of a Lynch syndrome-associated malignancy.
Molecular characterization. (A) The whole-genome copy number (lower profile) and allelic profile (upper profile) assessed by panel sequencing show many losses of heterozygosity including the locus of MLH1 at chromosome 3p22. (B) Zoom of the MLH1 gene showing the homozygous deletion of exon 4 to 5 (enclosed in red). (C) Nucleotidic variants of both thoracic and pancreatic tumors, sequenced by our panel exhibit a lot of indels in homopolymeric sequences and a pathogenic mutation of TP53. All variants presented in the table are found in both tumors, which enables to establish a clear filiation between the pancreatic and the thoracic lesions.
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The known deletion of exon 4-5 of MLH1 was associated to a loss of heterozygosity of the gene on chromosome 3, leading to its complete inactivation in tumor cells (Figs 3A and 3B). TSC1, TSC2, or PI3KCA genes. The tumor mutation burden was slightly elevated (21.4 mutations/Mb). The comparative analysis of the pancreatic and bronchial tumors showed the same genomic alterations and enabled to establish a clear filiation between both tumors (Fig 3C).
Response to pembrolizumab. (A) Chest x-ray at baseline and after one, three, and six cycles of pembrolizumab showing the rapid regression of the right apical mass and the disappearance of tracheal deviation under treatment. (B and C) Thoracic and abdominal CT at baseline and after two, four, and eight cycles of pembrolizumab. Major partial response was observed after only two cycles, and complete response was observed after eight cycles. CT, computed tomography.
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Follow-up imaging confirmed the significant regression of both thoracic and pancreatic lesions after two cycles, and complete response according to RECIST 1.1 criteria was seen after eight cycles of pembrolizumab (Figs 4A-4C).