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Commenting on a recently published article on sicca syndrome linked to immune checkpoint inhibitor therapy, this letter to the editor shares another viewpoint on the management of this immune-related adverse event.

BACKGROUND Congo red-positive material was described in normal and diseased parathyroids (adenoma and hyperplasia) 50 years ago. However, the incidence and the clinical significance of such observation are unknown, and the causal fibril protein has never been convincingly demonstrated. METHODS We conducted the present study including an exceptional case report accompanied with a retrospective study of 105 parathyroid adenomas. We used histopathological, immunohistochemical, ultrastructural, mass spectrometry-based proteomic analysis of parathyroid adenoma tissue samples, and genetic analysis. RESULTS We describe a 57-year-old man with mild hypercalcemia and elevated parathyroid hormone (PTH) level for whom histopathological analysis revealed a parathyroid adenoma associated with nodular typical amyloid deposits. Tandem mass spectrometry after laser microdissection (LMD-MS) of amyloid adenoma identified PTH as the fibril protein, and no germline mutation in the PTH gene was detected. Congo red-positive PTH-deposits were further observed in 6.6% of the parathyroid adenomas analyzed, and were associated with complete/incomplete or absent universal amyloid signature, but with fibrillar morphology at ultrastructural level. CONCLUSIONS Inappropriate PTH production leads to progressive disease-amyloid aggregation of PTH in a subset of parathyroid adenomas, providing new insights into the pathophysiology of this condition and adding PTH to the list of amyloid protein derived from hormones.

An increasing number of sarcomas displaying a primitive, monomorphic spindle cell phenotype have been shown to harbor recurrent gene fusions, including biphenotypic sinonasal sarcoma (SNS). Occurring in the sinonasal area of middle-aged patients, SNS is a locally aggressive tumor harboring in 90% of cases recurrent gene fusions involving the PAX3 gene, in which the chimeric transcription factor induces an aberrant dual myogenic and neural phenotype. Here, we report an unusual oropharyngeal monomorphic spindle cell sarcoma in a 53-year-old man that revealed a novel RREB1-MKL2 gene fusion by RNA sequencing with the Illumina TruSight RNA Fusion Panel. The gene fusion was validated by RT-PCR. Although the tumor location is unusual (but head and neck seated), most of the other clinical, morphologic, immunophenotypic (focal combined expression of S100 protein, SMA, desmin, and myogenin) and oncogenic data suggest that this biphenotypic "oropharyngeal" sarcoma is closely related to the biphenotypic SNS spectrum. Notably, the RREB1-MKL2 chimeric transcription factor encoded by this fusion gene produced an increase in MKL2 expression, which regulates both neural and myogenic differentiation, mimicking the crucial role of PAX3 reported in SNS oncogenesis. NGS and especially RNA sequencing may be used to identify new candidate fusion oncogenes in soft tissue tumors, which would help in updating the existing classification. In turn, this would lead to better therapeutic management of patients.

Oral lichen planus (OLP) is a chronic inflammatory disease considered as a CD8+ T lymphocyte-mediated autoimmune reaction, which may be triggered by undetermined virus. Recent reports have described the detection of Merkel cell polyomavirus (MCPyV) DNA in oral samples from healthy patients and in patients with different forms of oral cancers. We therefore investigated in a prospective way whether MCPyV was detectable in oral lesions of patients with active OLP. Our preliminary results do not support the hypothesis that OLP may be triggered by MCPyV infection. Further studies are needed to evaluate the involvement of other human polyomaviruses in OLP pathogenesis.

Background Mammary analog secretory carcinoma (MASC) of the salivary gland has been recently described according to morphological, immunohistochemical, and molecular (ETV6-NTRK3 translocation) similarities with the mammary secretory carcinoma. The most important differential diagnostic considerations of MASC are low-grade adenocarcinoma not otherwise specified (NOS), cystadenocarcinoma, and acinic cell carcinoma (AciCC). These tumors may share an overlapping morphology with MASC, and additional immunohistochemical studies are required to reinforce the diagnosis. Mammaglobin, GCDFP-15, and p63 staining have been reported in MASC. Our study was designed to check the specificity of these antibodies in MASC compared to other frequent tumors of salivary glands. Methods A series of 62 salivary gland tumors [10 MASCs, 5 adenocarcinomas NOS and 2 cystadenocarcinomas with MASC features and without ETV6 rearrangement, one low-grade cribriform cystadenocarcinoma (LGCCC), 9 AciCCs, 10 MECs, 10 adenoid cystic carcinomas (AdeCCs), 5 polymorphous low-grade adenocarcinomas (PLGAs), and 10 pleomorphic adenomas (PAs)] was analyzed by immunohistochemistry with mammaglobin, GCDFP-15, and p63 antibodies. Results Positivity for mammaglobin was observed in all MASCs, cystadenocarcinomas, LGCCC, and PLGAs, in some adenocarcinomas NOS, PAs, and MECs, rarely in AciCCs and never in AdeCCs. Positivity for GCDFP-15 was observed in most of the tumor types except in AdeCCs. Interestingly, cytoplasmic positivity for p63 was observed in most of MASCs and PLGAs while rarely in adenocarcinomas NOS and PAs, and never in the other tumor types. Conclusion Our study revealed the usefulness of mammaglobin and p63 cytoplasmic staining to define which tumors are worth to be screened for ETV6 rearrangement.

Introduction Le lichen plan buccal (LPB) est une maladie auto-inflammatoire avec reaction lymphocytaire T CD8+ dirigee contre des cibles antigeniques non encore determinees. Les polyomavirus sont presents de facon ubiquitaire au niveau cutane mais aussi muqueux. Des etudes recentes ont suggere un role potentiel du Merkel cell polyomavirus (MCPyV) dans la carcinogenese orale et dans certaines formes de maladies inflammatoires cutanees, notamment le lichen plan. Nous avons donc recherche, de facon systematique, la presence de MCPyV dans differentes formes de LPB. Materiel et methodes Nous avons extrait l’ADN a partir de prelevements biopsiques de muqueuse buccale fixes au formol 4 % et inclus en paraffine chez 22 patients consecutifs avec differentes formes de LPB (reticule, atrophique ou lesion ulceree) (Figure 1). La quantite et la purete du materiel nucleique extrait ont ete verifiees. Les echantillons trouvant une faible quantite d’ADN total etaient exclus (n = 4). La recherche de MCPyV a ete realisee dans 18 prelevements par PCR ciblant une partie de l’antigene T (LT3) et de la capside virale (VP1) (Figure 2), avec controles d’amplification, et temoins negatif et positif (carcinome cutane a cellules de Merkel). Resultats L’ADN du MCPyV n’etait detectable dans aucun des echantillons testes (n = 18). Discussion Il s’agit de la premiere etude evaluant la presence du MCPyV dans le lichen plan buccal. L’implication de certains virus comme facteur causal du LPB a ete recemment suggeree. Une association significative entre certains sous-types de Papillomavirus (HPV16) et certaines formes de LPB erosif ou atrophique a notamment ete mise en evidence. A l’inverse, les resultats de notre etude ne sont pas en faveur du role potentiel de MCPyV dans le developpement du LPB, quelle qu’en soit la forme clinique. La presence de MCPyV au niveau de la muqueuse buccale a ete rapportee avec une frequence variant de 20 a 69 % de la population generale. Son role potentiel a ete egalement evoque dans certaines formes de carcinomes epidermoides buccaux, de leucoplasies orales ou de carcinomes amygdaliens. Cependant, l’implication de MCPyV, ou d’un autre membre de la famille des polyomavirus (virus BK et JC), dans la carcinogenese orale reste encore hypothetique, tout comme dans le LPB. Conclusion Nos resultats preliminaires ne soutiennent pas l’hypothese d’une implication du MCPyV dans la pathogenese du lichen plan buccal. Une etude complementaire apparait utile afin de determiner le taux de detection des autres membres de la famille des polyomavirus dans ce contexte.

Summary Background Primary hyperparathyroidism (PHP) is caused by parathyroid adenomas or hyperplasia, and occasionally by parathyroid carcinoma. Recently a high third generation/second generation PTH ratio has been observed in some patients with parathyroid carcinoma. Patients and methods We report the case of a 60-year old woman who was presented a fourth episode of PTH-related hypercalcaemia due to a parathyroid carcinoma. Serum PTH levels were measured using a second generation assay and a third generation assay before, 4 and 7 months after the fourth surgery. Then, PTH levels were measured in 294 osteoporotic normocalcaemic patients as well as in 30 consecutive PHP patients. Results Before surgery of the patient with parathyroid carcinoma, second generation PTH was 229 pg/ml, third generation PTH was 675 pg/ml and third generation/second generation PTH ratio was 2·95. Four and 7 months after surgery the third generation/second generation PTH ratio was 0·70 and 0·66, respectively. All osteoporotic patients had a normal third generation/second generation PTH ratio (0·585 ± 0·118) whereas only one patient (3·3%) with PHP had a third generation/second generation PTH ratio > 1 (1·54). Conclusion A high third generation/second generation PTH ratio could be observed in patients with parathyroid carcinoma, is uncommon in benign PHP and is absent in osteoporotic patients without PHP. Therefore, PTH level can be measured using second and third generation assays in some PHP patients, and a specific surgical protocol for possible parathyroid carcinoma could be discussed in patients with a high third generation/second generation PTH ratio.