Progression to lung fibrosis in severe COVID-19 patients: A morphological and transcriptomic study in postmortem samples.

The development of lung fibrosis is a major concern in patients recovered from severe COVID-19 pneumonia. This study aimed to document the evolution of diffuse alveolar damage (DAD) to the fibrosing pattern and define the transcriptional programs involved. Morphological, immunohistochemical and transcriptional analysis were performed in lung samples obtained from autopsy of 33 severe COVID-19 patients (median illness duration: 36 days). Normal lung and idiopathic pulmonary fibrosis (IPF) were used for comparison. Twenty-seven patients with DAD and disease evolution of more than 2 weeks had fibrosis. Pathways and genes related with collagen biosynthesis and extracellular matrix (ECM) biosynthesis and degradation, myofibroblastic differentiation and epithelial to mesenchymal transition (EMT) were overexpressed in COVID-19. This pattern had similarities with that observed in IPF. By immunohistochemistry, pathological fibroblasts (pFBs), with CTHRC1 and SPARC expression, increased in areas of proliferative DAD and decreased in areas of mature fibrosis. Immunohistochemical analysis demonstrated constitutive expression of cadherin-11 in normal epithelial cells and a similar pattern of cadherin and catenin expression in epithelial cells from both normal and COVID-19 samples. Transcriptomic analysis revealed downregulation of the Hippo pathway, concordant with the observation of YAP overexpression in hyperplastic alveolar epithelial cells. Progression to fibrosis in severe COVID-19 is associated with overexpression of fibrogenic pathways and increased in CTHRC1- and SPARC-positive pFBs. Whereas the Hippo pathway seemed to be implicated in the response to epithelial cell damage, EMT was not a major process implicated in COVID-19 mediated lung fibrosis.

TERT promoter mutation in sebaceous neoplasms.

TERT promoter (TERTp) mutations widely occur in multiple human neoplasms, and they have been related to different clinicopathological features. To date, this mutation has not been identified in sebaceous tumors. Here, we analyzed TERTp mutations in 91 sebaceous neoplasms (17 adenomas, 45 sebaceomas, and 29 carcinomas). We detected mutations in 26.7% (8 of 29) of sebaceous carcinomas by pyrosequencing and Sanger sequencing. No mutation was detected in adenomas or sebaceomas. The difference was significant between sebaceoma and carcinoma. The most frequent TERTp mutations were C228T and C250T in 37.5% (3 of 8) of mutated cases each one. The mutation was not associated with poor clinical evolution. Using NGS, 20 of 29 (68.5%) sebaceous carcinomas harbored mutations in 8 of the 30 genes analyzed (TP53, TERTp, EGFR, ATRX, PDGFRA, CDKN2A, PTEN, and ACVR1). With immunohistochemistry, only 1 of 8 (12.5%) TERTp-mutated carcinomas lacked mismatch repair (MMR) protein expression compared to 6 of 21 (31.6%) of non-mutated ones. Sebaceous carcinomas with MMR protein expression had significantly higher frequency of total mutations and TP53 and TERTp mutations than MMR protein-deficient carcinomas. In conclusion, TERTp mutation has been detected in sebaceous carcinomas, and its presence could be useful to differentiate sebaceous carcinoma from sebaceoma, a difficult histopathological challenge.

Proliferating Neurocristic Hamartoma Arising in a Giant Congenital Nevus: Comparative Genomic Hybridization Findings.

Neurocristic cutaneous hamartomas (NCHs) are rarely reported tumors with divergent differentiation derived from persistently active pluripotent cells from the neural crest. They result from aberrant development of the neuromesenchyme, and they can express fibrogenic, melanocytic, and/or neurosustentacular differentiation. Thus, congenital melanocytic nevus also represents a neurocristic dysplasia of the skin in which cells are melanogenic cells arrested in development located in the reticular dermis, and nodular proliferative neurocristic hamartoma may arise within a congenital melanocytic nevus. The real importance of NCHs is that, although few cases have been reported in the literature, some cases have shown development of melanoma. Moreover, the only previously reported case of a similar "proliferative neurocristic nodule" analyzed with comparative genomic hybridization showed an aberration pattern similar to melanoma. We present a rare case of NCH associated with a congenital nevus in a 7-year-old boy, with classical histological and immunohistochemical features suggesting a "proliferative neurocristic hamartoma". Comparative genomic hybridization assay showed that chromosomal aberrations were absent in the congenital nevus, whereas, interestingly, the proliferative neurocristic proliferation had an aberration pattern similar to proliferative nodules with gains or losses of entire chromosomes only, similar to typical proliferative nodules and supporting the benign behavior of this lesion.

Lichenoid Granulomatous Mycosis Fungoides.

The presence of a granulomatous reaction in cutaneous lymphomas has been described in the past, especially in mycosis fungoides (MF), where a "granulomatous" variant of the disease is well known. We describe a patient with granulomatous MF (GMF) who has been followed for 13 years presenting with erythematosquamous plaques on his fingers and toes, ankles, heels, and abdomen, which on microscopic examination showed a lichenoid granulomatous reaction admixed with a neoplastic proliferation of small-sized, atypical CD4 lymphocytes. GMF is characterized by a granulomatous reaction intermingled with the dermal infiltrate of MF which may even reach the subcutaneous tissue. Only 7 cases of GMF in which the granulomas were located within the papillary or superficial dermis have been described to date. We report for the first time a unique case of lichenoid GMF where the granulomatous reaction obscures the interface between the epidermis and dermis. Sequential biopsies and complete phenotypic studies were necessary to get an accurate diagnosis.

Desmoplastic melanoma: expression of epithelial-mesenchymal transition-related proteins.

Desmoplastic melanoma (DM) is a rare variant of melanoma. Most frequently, it seems as clinically ambiguous and histologically characterized by a poorly demarcated neoplasm composed of a proliferation of spindle melanocytes dispersed in a prominent collagenous stroma. It often represents a diagnostic challenge, delaying its detection. We analyzed the expression profile of 29 (28 "pure" and 1 "combined") DM. These data were compared with a series of 62 primary vertical growth phase nondesmoplastic melanomas (NDMs) using a set of proteins including melanocytic markers (S-100 protein and melan-A) and epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, N-cadherin, SPARC, WT1, and PKCα). The S-100 protein confirmed the melanocytic origin of the DM (positive in 96%). The significant positive expression of N-cadherin, SPARC, and WT1 in DM (61%, 82%, and 71%) compared with NDM (28%, 43%, and 47%; P < 0.05) and a lower expression of E-cadherin in DM (14%) compared with NDM (61%) support specific adhesive and migratory properties of DM tumor cells. The study was carried out with tissue microarrays that partly limited the study of the tumor sections. This study demonstrates, for the first time, a prominent expression of epithelial-mesenchymal transition-related proteins in DMs and tries to be one more step in refining its knowledge and leading to a better understanding of its biological and clinical behaviors.