Clinical and histological features of histiocytoid Sweet syndrome associated with VEXAS syndrome.

BACKGROUND: VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by acquired somatic mutations in UBA1. Sweet-syndrome-like skin disorders [and especially histiocytoid Sweet syndrome (HSS)] may be associated with VEXAS syndrome. OBJECTIVES: To characterize the clinical and histopathological features of HSS in patients with VEXAS syndrome. METHODS: Skin biopsies with a histological diagnosis of HSS at Rennes University Medical Center (Rennes, France) between October 2011 and January 2022 were reviewed in this study. Sanger sequencing and digital polymerase chain reaction were used to screen skin, blood and bone marrow samples for UBA1 variants, and thus classify patients as having VEXAS syndrome or not. We evaluated the clinical, histological and molecular (UBA1) characteristics of patients with or without VEXAS syndrome. RESULTS: We compared 15 skin biopsies from 7 patients found to have VEXAS syndrome and 19 skin biopsies from 15 patients without VEXAS syndrome. Persistent C-reactive protein elevation, macrocytosis, anaemia and haematological malignancies were more prevalent in patients with VEXAS syndrome [6/7 (86%), 6/7 (86%), 7/7 (100%) and 6/7 (86%), respectively] than in patients without [5/14 (36%), 6/15 (40%), 8/15 (53%) and 8/15 (53%), respectively]. These features sometimes appeared after the first skin manifestations, and a UBA1 mutation was found in the skin of five patients with VEXAS syndrome. Dermal infiltration by reniform histiocytoid cells (myeloperoxidase-positive and/or CD163-positive) and a periadnexal distribution were more frequently observed in VEXAS syndrome biopsies [15/15 (100%) and 3/15 (20%), respectively, vs. 11/19 (58%) and 0/19 (0%) in non-VEXAS syndrome biopsies, respectively]. CONCLUSIONS: Our findings might help pathologists to consider a diagnosis of VEXAS syndrome and to initiate early genetic testing.

Blood, Cellular, and Tissular Calcineurin Inhibitors Pharmacokinetic-Pharmacodynamic Relationship in Heart Transplant Recipients: The INTRACAR Study.

BACKGROUND: After heart transplantation, calcineurin inhibitors (CNI) (cyclosporin A and tacrolimus) are key immunosuppressive drugs to prevent graft rejection. Whole-blood concentration (C blood )-guided therapeutic drug monitoring (TDM) is systematically performed to improve graft outcomes. However, some patients will still experience graft rejection and/or adverse events despite CNI C blood within the therapeutic range. Other pharmacokinetic parameters, such as the intragraft, or intracellular concentration at the CNI site of action could refine their TDM. Nonetheless, these remain to be explored. The objective of the INTRACAR study was to describe the relationship between whole blood, intragraft, and intracellular CNI concentrations as well as their efficacy in heart transplant recipients (HTR). METHODS: In a cohort of HTR, protocol endomyocardial biopsies (EMB) were collected to assess rejection by anatomopathological analysis. Part of the EMB was used to measure the intragraft concentrations of CNI (C EMB ). C blood and the concentration inside peripheral blood mononuclear cells, (C PBMC ), a cellular fraction enriched with lymphocytes, were also monitored. Concentrations in the 3 matrices were compared between patients with and without biopsy-proven acute rejection (BPAR). RESULTS: Thirty-four HTR were included, representing nearly 100 pharmacokinetic (PK) samples for each CNI. C blood , C EMB , and C PBMC correlated for both CNI. BPAR was observed in 74 biopsies (39.6%) from 26 patients (76.5%), all except one was of low grade. None of the PK parameters (C blood , C EMB , C PBMC , C EMB/blood , and C PBMC/blood ) was associated with BPAR. CONCLUSIONS: In this cohort of well-immunosuppressed patients, no association was observed for any of the PK parameters, including C blood , with the occurrence of BPAR. However, a trend was noticed for the C EMB and C EMB/blood of cyclosporin A. Further studies in higher-risk patients may help optimize the use of C EMB and C PBMC for CNI TDM in HTR.

Chromoblastomycosis Due to a Never-before-Seen Dematiaceous Fungus in a Kidney Transplant Patient.

Chromoblastomycosis is a neglected fungal infection of the epidermis and subcutaneous tissue that predominates in tropical areas and results from the traumatic inoculation of environmental dematiaceous filamentous fungi. We describe the case of an immunosuppressed patient diagnosed with foot chromoblastomycosis due to an uncommon dematiaceous fungus. A 52-year-old Congolese kidney transplant woman presented with a painful lesion located on the foot. No trauma to the lower limbs was reported during the previous months. She lived in France and had not returned to the Congo over the previous eight years. Histology and mycological examination from skin biopsy revealed swollen dark filaments associated with dematiaceous muriform cells, pathognomonic of chromoblastomycosis. Cultures grew with dark pigmented colonies, yielding poor microscopic features. The phylogenetic analysis confirmed that the isolate was a member of Kirschsteiniotheliales (Dothideomycetes) and unrelated to the Chaetotyriales, of which most species commonly responsible for chromoblastomycosis belong. As there was no bone spreading, excision surgery of the entire lesion followed by liposomal amphotericin B therapy resulted in complete healing after six months. This original case illustrates the potential diversity of environmental dematiaceous fungi responsible for phaeohyphomycosis, especially chromoblastomycosis, and the need to send samples to mycology labs for appropriate diagnosis.

One-step nucleic acid amplification for detecting lymph node metastasis of head and neck squamous cell carcinoma.

BACKGROUND: In head and neck squamous cell carcinoma (HNSCC) 30% of cN0 patients have occult metastasis. LN invasion is a major prognostic factor. Sentinel lymph node (SLN) is an option for cN0 neck management. One-step nucleic acid amplification (OSNA) used to analyze SLN in breast cancer is also a candidate to get more reliable intraoperative HNSCC lymph node (LN) staging. OBJECTIVE: To compare OSNA analysis to pathological analysis in cN0 HNSCC. MATERIALS AND METHODS: 157 LN from 26 cN0 HNSCC patients were prospectively analyzed (6.3LN/patient). Exclusion criteria were previous surgery or radiotherapy. Each node was cut into 4 equal pieces alternatively sent to pathological analysis and OSNA technique. IHC CK19 was performed on the primary tumor biopsy and RT-qPCR of CK19, PVA and EPCAM on the LN lysate of discordant cases. RESULTS: OSNA was able to provide intraoperative result in all patients. OSNA detected 21 metastases. There were 139 concordant LN (88.5%). There were 18 initial discordant LN (11.5%), 13 (8.3%) were OSNA positive/pathological analysis negative, 5 (3.2%) were OSNA negative/pathological analysis positive. After elimination of allocation bias, false negative rate was 1.3%, sensitivity and specificity were 90% and 95.6%, PPV and NPV were 75% and 98.5%. CONCLUSION: Our results suggest that OSNA should be considered to improve SNB analysis both for increasing micro metastasis diagnosis and offer extemporaneous results. Study registered under clinicaltrials.gov database number NCT02852343.

Primary cutaneous large B-cell lymphomas: relevance of the 2017 World Health Organization classification: clinicopathological and molecular analyses of 64 cases.

AIMS: We applied the 2017 World Health Organization (WHO) classification criteria to categorise a series of 64 primary cutaneous large B-cell lymphomas (PCLBCLs), containing a majority (≥80%) of large cells and a proliferative rate of ≥40%, raising the problem of the differential diagnosis between PCLBCL, leg type (PCLBCL-LT) and primary cutaneous follicle centre lymphoma, large cell (PCFCL-LC). The aims were to determine the reproducibility and prognostic relevance of the 2017 WHO criteria. METHODS AND RESULTS: Morphology and phenotype identified 32 PCLBCLs-LT and 25 PCFCLs-LC; seven cases (11%) remained unclassified. Morphology was less reproducible than immunophenotype. Pertinent markers for the differential diagnosis were MUM1, FOXP1, CD10, and IgM. bcl-2 and bcl-6 were expressed by both PCFCLs-LC and PCLBCLs-LT at substantial levels. Neither Ki67 expression nor p63 expression was of diagnostic value. MYD88 was found to be mutated only in PCLBCLs-LT (n = 22, 69%). According to Hans/Hans modified algorithms, 23 of 25 PCFCLs-LC had germinal centre (GC) status, and the 32 PCLBCLs-LT had non-GC status. Overall survival was poorer for PCLBCLs-LT than PCFCLs-LC (P = 0.0002). Non-GC cases had poorer overall survival than GC cases (P = 0.0007). In PCLBCLs-LT, MYC expression was associated with cutaneous relapses (P = 0.014). When GC/non-GC status was applied to unclassified cases, only a single case remained discordant. CONCLUSIONS: Our results support the 2017 WHO classification criteria for PCLBCL diagnosis. The Hans modified algorithm using CD10 and MUM1 distinguished PCFCLs-LC from PCLBCLs-LT with optimal diagnostic value without requiring bcl-6 immunolabelling (poorly reproducible). Rare unclassified cases may constitute a provisionally heterogeneous subgroup for which GC/non-GC status (relevant for prognosis) may guide therapeutic decisions.

Tufted angioma with Kasabach-Merritt syndrome mistaken for child abuse.

We report the case of a 2-month-old infant with a single apparently ecchymotic lesion on the shoulder that raised suspicions of abuse. The medicolegal examination concluded that the appearance of the lesion was only mildly suggestive of an ecchymosis. A second, temporally remote examination confirmed this doubt. The evolution of the lesion, notably an increase in its volume, allowed us to rule out a traumatic lesion and was suggestive of a vascular tumor. The histological type of the tumor was a tufted angioma. There was thrombocytopenia and consumptive coagulopathy. All these data confirmed the diagnosis of Kasabach-Merritt syndrome. In contrast to benign infantile hemangiomas, which are frequent and well-known in clinical practice, vascular tumors complicated by Kasabach-Merritt syndrome are rare. They deserve to be widely known because they mandate rapid medical management and because they are one of the only differential diagnoses of ecchymosis, especially in children. When there is doubt about the traumatic nature of a cutaneous lesion, a temporally remote examination is essential. The evolution of the lesion may then suggest a dermatologic origin.

Syringotropic mycosis fungoides: clinical and histologic features, response to treatment, and outcome in 19 patients.

BACKGROUND: A rare variant of mycosis fungoides (MF), syringotropic MF (STMF) is characterized by a particular tropism of the lymphocytic infiltrate for the eccrine structures, and included in the follicular subtype of MF in the World Health Organization-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas. OBJECTIVE: We sought to determine the clinicopathologic features and disease course of patients with STMF. METHODS: A retrospective study was conducted to identify patients with STMF from 1998 to 2013. RESULTS: Nineteen patients were included: 15 men and 4 women, mean age 55 years (range, 24-86). Most had multiple lesions (n=16, 84%) with associated alopecia (n=12, 63%) and/or punctuated aspect (n=12, 63%). Palms or soles were involved in 10 cases (53%). Folliculotropism was found in 13 cases (68%). After a median follow-up of 70 months (range, 2-140), 3 patients died, 1 from disease-related death. The 5-year overall and disease-specific survival were 100%. The disease-specific survival was significantly higher than in 54 patients with folliculotropic MF without syringotropism (5-year disease-specific survival, 74%; 95% confidence interval, 58%-94%, P=.02). LIMITATIONS: Retrospective setting is a limitation. CONCLUSIONS: In the spectrum of adnexotropic MF, STMF appears as a distinct entity from follicular MF, with peculiar clinical characteristics and natural history.

Intimal sarcoma is the most frequent primary cardiac sarcoma: clinicopathologic and molecular retrospective analysis of 100 primary cardiac sarcomas.

We report novel molecular and pathologic features of sarcomas involving the heart. Intimal sarcoma appears as the most frequent primary cardiac sarcoma within the largest described series of 100 primary cardiac sarcomas. Immunohistochemical analysis, fluorescence in situ hybridization, real-time polymerase chain reaction, and array-comparative genomic hybridization were performed on materials from 65 women and 35 men, aged 18 to 82 years (mean 50 y), retrieved from the French Departments of Pathology, between 1977 and early 2013. Right and left heart was involved in 44 and 56 cases, respectively. There were 42 intimal sarcomas, 26 angiosarcomas, 22 undifferentiated sarcomas, 7 synovial sarcomas, 2 leiomyosarcomas, and 1 peripheral neuroectodermal tumor. All but 1 angiosarcomas originated from the right heart, whereas 83% of the intimal sarcomas and 72% of the undifferentiated sarcomas were from the left heart. MDM2 overexpression was immunohistochemically observed in all intimal sarcomas, as well as in 10 of the 22 undifferentiated sarcomas and in 5 of the 26 angiosarcomas. MDM2 amplification was only demonstrated in intimal sarcomas. Genomic analysis showed a complex profile, with recurrent 12q13-14 amplicon involving MDM2, 4q12 amplicon involving KIT and PDGFRA, 7p12 gain involving EGFR, and 9p21 deletion targeting CDKN2A. Immunohistochemical detection of MDM2 overexpression can easily detect intimal sarcoma, provided that molecular aberration is proved. As resections are limited to the left atrium, this histologic subtype could benefit from therapies targeting PDGFRA or MDM2.

A case of atypical chronic subdural hematoma: a spontaneous rupture of dural lymphoma nodule.

In forensic medicine, a chronic subdural hematoma (SDH) usually results from trauma, sometimes minimal for elderly people. The case reported here is a forensic medical description of an atypical chronic subdural hematoma. A woman aged of 40-year-old died following a coma. The autopsy and histological analyses revealed the hemorrhagic disintegration of a lymphoid nodule, a metastasis from generalized lymphoma. The combination of chronic symptomatic SDH and a tumor of the dura mater have been described, but are very rare. The possibility of trauma, even minimal, has never been excluded in these cases. In fact, the clinical picture of these patients suggested a significant movement of the brain within the cranial cavity due to the physiological decrease in brain volume. In the reported case, this particular process was excluded since the spontaneous hemorrhagic effusion produced by the meningeal lymphoid nodule was the cause of the chronic SDH. This pathophysiological explanation was possible because the entire brain and meninges were removed for histological analysis. Trauma, even minimal trauma, is not always involved in the formation of a chronic SDH.

Docetaxel-induced photo-recall phenomenon.

Photo-recall phenomenon is a phototoxic eruption occurring on areas of previous ultraviolet-induced solar erythema following a systemic administration of a drug. It has been mostly described with methotrexate but remains rare with other antineoplastic drugs. We describe a case of docetaxel-induced photo-recall skin rash in a woman treated for a non-small-cell lung cancer. Although the patient has refused to receive a second infusion, chemotherapy can be carried on with photoprotection and the use of topical and/or systemic corticosteroids. In contrast, radiation recall is a well-known reaction by oncologists, most of them may not be aware of a similar phenomenon called photo-recall phenomenon. Recognizing this entity may avoid misdiagnosing a drug allergy and should avoid inappropriate decisions of drug discontinuation.

[Facial primary cutaneous ganglioneuroma]. / Ganglioneurome cutané primitif de la face.

Ganglioneuroma is a benign neoplasm of the sympathetic nervous system most often arising in the posterior mediastinum, retroperitoneum, adrenal medulla and pelvis. The occurrence of ganglioneuroma in the skin is rare with only 10 cases reported in the literature. We report one additional case of primary ganglioneuroma arising in the cheek in a 42-year-old man.

[Multicentric reticulohistiocytosis: report of a case with systemic disease]. / Réticulohistiocytose multicentrique: a propos d'un cas avec atteinte systémique.

Multicentric reticulohistiocytosis (RHM) is a rare non Langherhans cell histiocytosis with skin and joint involvment. Nearly all organs can be involved. Association with cancer occurs in about 25% of cases. Association with auto-immune diseases has also been recorded. Microscopic examination shows a histiocytic nodular infiltrate made of giant cells with ground-glass appearance and PAS positive cytoplasm. Immunostaining shows cell positivity for CD68 and negativity for CD1a and S100 protein. No Birbeck granules are found at ultrastructural examination.