Impact of expert pathology review in skin adnexal carcinoma diagnosis: Analysis of 2573 patients from the French CARADERM network.

PURPOSE: To prospectively assess the impact of expert pathological review of skin adnexal carcinoma diagnosis in France. METHODS: From 2014 to 2019, 2573 samples from patients with newly diagnosed or suspected skin adnexal carcinomas were reviewed prospectively by expert pathologists through the national CARADERM (CAncers RAres DERMatologiques) network. Changes in diagnosis between referral and expert review were analysed regarding their potential impact on patient care or prognosis. RESULTS: The samples comprised 2205 newly diagnosed adnexal carcinomas, 129 benign adnexal tumours, 136 basal cell carcinomas, 74 squamous cell carcinomas, six cutaneous metastases and 13 other malignancies. There were 930 (42%) sweat gland carcinomas, of which porocarcinoma (261; 11.8%), microcystic adnexal carcinoma (125; 5.7%) and hidradenocarcinoma (109; 4.9%) were the most frequent subtypes; 778 (35%) hair follicle carcinomas, 238 (11%) sebaceous carcinomas and 212 (10%) extramammary Paget diseases/mammary-like anogenital gland adenocarcinomas. A diagnostic change between referral and expert review occurred in 503 (21.3%) patients, significantly higher for cases sent with a provisional diagnosis seeking an expert second opinion (45.7%) than for cases sent with a formal diagnosis (2.8%) (p < .0001). Sweat gland carcinomas were more prone to diagnostic discrepancies than other tumours (p < .0001), including 1.8% of patients with sweat gland carcinoma subtype misclassification with predicted clinical impact. Changes between benign and malignant conditions occurred in 117 samples (5% of patients). CONCLUSION: The study provides a unique description of the distribution of skin adnexal carcinomas and highlights the importance of expert review for these rare cancers. Optimal clinical management was impacted in a significant proportion of patients.

PD-L1 Expression in 65 Conjunctival Melanomas and Its Association with Clinical Outcome.

Conjunctival melanoma (CM) iss a rare and aggressive tumour that is increasing in frequency. The prognostic value of PD-L1 expression, alone or in combination with CD8 and PD-1 expression and the BRAF and NRAS status, has not been determined in CM to date. We evaluated the expression of PD-L1, CD8, PD-1 in CM and investigated whether there was an association between the expression of these markers and the BRAF and NRAS molecular profile as well as some clinico-pathological criteria. A total of sixty-five CM were assessed for PD-L1, PD-1, and CD8 expression by immunohistochemistry (IHC) and for BRAF and NRAS genomic alterations using molecular biology techniques and anti-BRAF and anti-NRAS antibodies. PD-L1 expression in tumour cells (TC) was very low or absent but detected in tumour-infiltrating immune cells (IC). A correlation was observed between the expression of PD-L1, CD8, and PD-1 in IC. No correlation between PD-L1 expression (in tumour and/or immune cells) and BRAF or NRAS mutations was observed. PD-L1 expression in IC correlated with a higher pTNM stage and PD-L1 expression in TC with worse disease-specific survival. PD-L1 expression is a potential prognostic biomarker that correlates with poor prognosis in CM patients.

Histopathological aspects of cutaneous erythematous-papular eruptions induced by immune checkpoint inhibitors for the treatment of metastatic melanoma.

BACKGROUND: Immune checkpoint blockade therapy (ICBT) for the treatment of melanoma has led to an important improvement of overall survival in advanced stage patients. However, secondary cutaneous maculopapular eruptions (CMPEs) are frequent and remain poorly characterized. METHODS: We performed a retrospective analysis of melanoma patients from our institution who developed CMPEs during ICBT. Clinical information was retrieved, and histopathological and immunohistochemical characterization was performed by two pathologists. For comparison, a group of biopsies from CMPE caused by anti-v-raf murine sarcoma viral oncogene homolog B1 (BRAF) therapy was analyzed. RESULTS: Eleven patients met the inclusion criteria. On clinical grounds, CMPE developed mainly on early onset of immunotherapy and were of low grade. Typical lesions included erythematous papules and macules affecting the trunk and/or extremities with associated pruritus. The histopathological patterns consisted of a superficial perivascular lymphocytic dermatitis (SPLD) with eosinophils followed by a granulomatous dermatitis. Other patterns included lichenoid, spongiotic, and a case of Grover's disease. The inflammatory infiltrate consisted of T lymphocytes (CD3+ ) with a predominance of CD4+ over CD8+ cells; isolated Foxp3+ cells were invariably present, and PD-1 was not expressed. Biopsies from CMPE caused by anti-BRAF therapy showed an SPLD and a similar lymphocytic immunophenotype. CONCLUSIONS: Our study showed the clinical features of a group of melanoma patients with CMPE for ICBT and emphasized the wide spectrum of histological findings as well as their immunohistochemical profile. Differential diagnosis can be difficult with CMPE provoked by other therapies as was seen in our comparison group of anti-BRAF-induced eruptions.

Quantification of dendritic cells and osteoclasts in the bone marrow of patients with monoclonal gammopathy.

The purpose of this study was to find histological clues for reliable differentiation between monoclonal gammopathy of undetermined significance (MGUS) and myeloma when clinical parameters are controversial. Differential appearance of dendritic cells and osteoclasts, two cell types developing from the monocytic lineage upon distinct cytokine activation profile, might be a useful approach. Bone and bone-marrow biopsies performed in 105 patients were studied using histomorphometry after identification of osteoclasts (by histochemical identification of tartrate resistant acid phosphatase) and dendritic cells (by immunohistochemical detection of the S-100 protein). Patients were classified by the World Health Organization criteria but histopathological criteria were more adapted to identify MGUS (53 cases), myeloma (46), B-cell lymphoma (six) since six myeloma were not correctly classified. Histomorphometry was compared to 15 control cases. The number of marrow dendritic cell was significantly increased with B-cell lymphoma >MGUS >myeloma > controls. Dendritic cell were often mixed with lymphoma cells. Myeloma had increased bone resorption with a high osteoclast number and moderate increase in dendritic cells. B-cell lymphomas had a considerable increase in dendritic cell but presented mononucleated osteoclasts. These findings can help in the classification of MGUS in the early stages of the disease and could help to propose preventive treatments.

Inflammatory reaction in rats muscle after implantation of biphasic calcium phosphate micro particles.

Several studies have shown that macro micro porous bioceramics ectopically implanted promote bone tissue formation. This study aims at investigating the inflammatory response towards biphasic calcium phosphate (BCP) ceramic micro particles. BCP composed of hydroxyapatite (HA) and beta-tricalcium phosphate, HA/beta -TCP ratio of 50/50, were prepared by sintering at 1200 degrees C for 5 h. After crushing, 3 fractions of BCP micro particles < 20, 40-80 and 80-200 micro m were sieved. The micro particles were carefully characterized by using X-ray diffraction (XRD), scanning electron microscopy (SEM) and laser scattering. The inflammatory reactions induced by BCP micro particles implanted in quadriceps muscles of rats for 7, 14 and 21 days were studied by histology (n = 8/group). A fibrous tissue encapsulation of the BCP micro particles implanted in muscle tissue was observed and fibrosis was similar for the 3 groups of micro particles. The comparison of the cellular response indicated that the total number of cells was significantly higher for BCP < 20 micro m than for 40-80 and 80-200 micro m (p < 0.0001). The number of macrophages was relatively higher for the smallest than for the intermediate and largest fractions (p < 0.0001). The relative percentage of giant cells was higher for the intermediate and largest size of particles than for the smallest. The number of lymphocytes was comparable for the 3 fractions and after the 3 delays. Therefore, the BCP micro particles < 20 micro m initiated an inflammatory response which might play an important role in osteogenesis.

Formalin-fixed and paraffin-embedded nodal non-Hodgkin's lymphomas demonstrate the same chromosome changes as those found in frozen samples: a comparative study using interphase fluorescence in situ hybridization.

Cytogenetic studies in lymphomas classically require fresh or frozen tissue, whereas in many instances only paraffin-embedded biopsies are available. We applied an interphase FISH assay on nuclei extracted from thick paraffin sections to determine accuracy of molecular cytogenetics in such samples. Twenty-three lymphoma samples and 4 reactive lymph nodes were tested with various commercially available DNA probes, and hybridization patterns were compared with those obtained on frozen nuclei counterparts. Successful hybridization with all probes tested was observed for 23/27 (85%) paraffin-embedded tissues and for all (100%) frozen samples, and cut-off levels defining positivity were superimposable for both situations. Chromosome changes were detected in the same way, without any false-positive or false-negative cases. Hybridization signals observed on dewaxed samples were either those classically expected to define the relevant chromosome change or were atypical: all atypical changes could be demonstrated also into nuclei from the frozen counterpart. Moreover, all typical and atypical chromosome changes observed on frozen nuclei were also detected in paraffin-embedded tissues. Our study shows that our interphase FISH assay performed on paraffin-embedded samples is a valuable alternate to conventional methods to ascertain diagnosis of lymphomas as to include patients into therapeutic trials.

C-cell hyperplasia and medullary thyroid carcinoma: clinicopathological and genetic correlations in 66 consecutive patients.

Routine calcitonin (CT) assay programs and genetic testing for RET proto-oncogene mutations have consistently modified the management and understanding of C-cell proliferative disorders. We report a series of 66 consecutive patients with C-cell hyperplasia (CCH) or medullary thyroid carcinoma (MTC) observed in our institution within an 8-year time period. All the patients had a preoperative basal CT assay and an RET proto-oncogene sequencing. Seventeen patients (F-M ratio: 8:9, mean age: 29.7 y) had a multiple endocrine neoplasia Type 2: 3 children <10 years of age had CCH only, and 14 patients had an MTC, with neoplastic CCH in 10/14 cases. Twenty-seven patients (F-M ratio: 18:9, mean age: 56.6 y) had a sporadic MTC, with physiological CCH in 8 and neoplastic CCH in 3 cases. Twenty-two men (mean age: 46.2 y) had CCH only (physiological CCH in 17 men and neoplastic CCH in 5). We conclude that (1) clinical and pathological characteristics (familial MTC, tumor multifocality, neoplastic CCH) usually associated with hereditary MTC may be misleading and that on the contrary, RET sequencing gives no false positive result; (2) sporadic neoplastic CCH accompanies (and probably precedes) a number of sporadic MTC; and (3) women presenting with a sporadic elevated basal CT have a 100% risk of having an MTC (15/15), but this risk is 3-fold less in men (31%), who will most often have CCH only (69%).

Incidental langerhans cell histiocytosis of thyroid: case report and review of the literature.

We report a case of a 42-yr-old woman with Langerhans cell histiocytosis (LCH) confined to the thyroid and associated with lymphocytic thyroiditis and a papillary microcarcinoma. This patient remains free of symptoms 14 mo after surgery. Thyroid LCH is rare. In children, it usually occurs as part of a multisystemic disease, whereas it is usually exclusive in adults. Isolated thyroid LCH is frequently associated with another thyroid disease, especially lymphocytic thyroiditis, suggesting that it is a reactive process rather than a neoplastic proliferation. The prognosis of isolated thyroid LCH is good. However, because it can rarely precede or reveal a multisystemic disease, additional investigations as well as a prolonged follow-up are justified.