Indeterminate DC histiocytosis is distinct from LCH and often associated with other hematopoietic neoplasms.

Indeterminate dendritic cell histiocytosis (IDCH) is a rare and poorly understood entity characterized by accumulation of CD1a+/S100+ histiocytes (as Langerhans cell histiocytosis (LCH)), but with reduced-absent expression of Langerin/CD207. We assembled 43 cases of IDCH (defined by CD1a+/CD207<20% immunophenotypic profile) examining the clinical, pathologic, and molecular landscape. Median age at presentation was 70 years (IQR: 44-80 years) with cutaneous (31/43; 72%) and nodal (11/43; 26%) involvement predominating. Eighteen (42%) individuals had an associated non-histiocytic hematopoietic neoplasm ('secondary' IDCH) while 7 of 43 (16%) had a concurrent non-IDCH histiocytosis ('mixed' histiocytosis). Most cases exhibited morphology indistinguishable from LCH but with a CD1c+/CSF1R(CD115)-phenotype, mirroring the signature of normal indeterminate cells and conventional dendritic cell type 2. Mutational analysis revealed frequent KRAS (13/32; 41%), and BRAF p.V600E (11/36, 31%) mutations that were nearly mutually exclusive. RNAseq analysis uncovered ETV3::NCOA2 fusion in 6 other patients presenting as a sole genetic alteration without any other concurrent histiocytic or hematopoietic neoplasm. BRAF and MAP2K1 alterations were significantly associated with partial/retained (1-20%) Langerin expression (P = .005) and mixed histiocytosis (P = .002). Remarkably, myeloid alterations (DNMT3A, TET2 and SRSF2) co-occurred in IDCH tissues of several individuals. Paired sequencing of IDCH and concurrent non-IDCH hematopoietic neoplasm in four individuals revealed shared mutations. Age at diagnosis and any nodal involvement at diagnosis predicted inferior overall survival, but BRAF/RAS pathway alterations did not impact outcome. These data have implications for the diagnostic evaluation, classification, and therapeutic management of IDCH.

Proliferative Verrucous Leukoplakia Presenting as a Ring Around the Collar and Cancer: A Case Report.

Proliferative verrucous leukoplakia (PVL) is an oral mucosa lesion with a high rate of malignant transformation. The diagnosis is often difficult, especially when the initial lesion is a simple homogeneous white leukoplakia, and when located only on the gingiva or palate. Moreover, the anatomopathological analysis is non-specific in the initial stages. The gingival PVL localisation (gPVL) is described as the most aggressive form with the highest rate of malignant transformation. Cases with a unique gingival localisation are rare, described with a "ring around the collar" clinical form. Considering the difficulty of early diagnosis of gPVL, we report the case of a 72-year-old woman, who presented "white lesions on her gingiva" with a slight discomfort in February 2019. The lesion was initially limited to the buccal part of the mandibular right gingiva, but rapidly extended to all the lingual and buccal mandibular gingiva during follow-up, leading to a diagnosis of gPVL. Two biopsies were performed, which concluded a verrucous hyperplasia and papilloma with a lichenoid part. The diagnosis of gPVL was made after a six-month follow-up based on clinical and anatomopathological factors. The gPVL transformed into a squamous cell carcinoma (SCC) after 18 months of follow-up. A surgical right mandibular bone excision with an autologous left fibula graft associated with radiotherapy was performed. Three years after the surgery, the patient remains under monitoring, with several gPVL and SCC recurrences treated. This case highlights that gPVL is a rare and aggressive form of PVL, with a high risk of fast malignant transformation. Knowledge about its aetiology, anatomic pathology, and biological markers is highly needed to speed up the diagnosis and develop specific follow-up and treatment.

Deep cutaneous fungal infections in solid-organ transplant recipients.

BACKGROUND: Deep cutaneous fungal infections (DCFIs) are varied in immunosuppressed patients, with few data for such infections in solid-organ transplant recipients (s-OTRs). OBJECTIVE: To determine DCFI diagnostic characteristics and outcome with treatments in s-OTRs. METHODS: A 20-year retrospective observational study in France was conducted in 8 primary dermatology-dedicated centers for s-OTRs diagnosed with DCFIs. Relevant clinical data on transplants, fungal species, treatments, and outcomes were analyzed. RESULTS: Overall, 46 s-OTRs developed DCFIs (median delay, 13 months after transplant) with predominant phaeohyphomycoses (46%). Distribution of nodular lesions on limbs and granulomatous findings on histopathology were helpful diagnostic clues. Treatments received were systemic antifungal therapies (48%), systemic antifungal therapies combined with surgery (28%), surgery alone (15%), and modulation of immunosuppression (61%), leading to complete response in 63% of s-OTRs. LIMITATIONS: Due to the retrospective observational design of the study. CONCLUSIONS: Phaeohyphomycoses are the most common DCFIs in s-OTRs. Multidisciplinary teams are helpful for optimal diagnosis and management.

Glomeruloid haemangioma: a possible consequence of elevated VEGF in POEMS and Erdheim-Chester disease.

Glomeruloid haemangioma (GH) is considered a specific marker of POEMS syndrome, despite some published GH cases unrelated to POEMS syndrome. To present two cases with GH and atypical presentations of Erdheim-Chester disease (ECD) or POEMS syndrome, as well as a retrospective monocentric study of histologically-confirmed GH. Clinical, biological and histological data of the patients is presented. In addition to the two presented cases, 11 GH histologically-confirmed cases were retrospectively identified. Six patients were female (46.2%; 95 CI: 12-64.9) and median age was 54 years (31-85). For 11 patients (84.6%; 95 CI: 65-104.2), a diagnosis of POEMS syndrome was retained, one patient had autoimmune hepatitis, and another had ECD. GH was localised to the trunk in 10 cases (76.9%; 95 CI: 54-99) and the legs in the other three. The median number of haemangiomas in the cohort was three (SD: 3.08). Median level of VEGF was 1,490 (610-12,000) ng/mL. All immunohistochemical staining for human herpesvirus 8 (HHV-8) was negative. Of the 13 cases of GH, of which two were not clear-cut POEMS syndrome, we report the first case of GH associated with ECD. In this cohort, all patients had high serum levels of VEGF but no in situ HHV-8 latent infection. We hypothesise that GH might be linked to a high level of VEGF in these two rare diseases.

Livedoid Vasculopathy: A French Observational Study Including Therapeutic Options.

Livedoid vasculopathy is a rare thrombotic cutaneous disease. This observational study aimed to assess the clinical and biological features of livedoid vasculopathy and the efficacy of treatments. Patients enrolled had typical livedoid vasculopathy both clinically and histologically. Investigation of thrombophilia was performed. Electromyography was undertaken in the presence of symptoms suggesting peripheral neuropathy. Eighteen women and 8 men were included, with a mean age of 35.5 years at onset. Twenty patients had at least one thrombophilia factor. Ten patients had a peripheral neuropathy with 2 of these patients demonstrating a specific thrombo-occlusive vasculopathy on muscle biopsy. Anticoagulation with low molecular weight heparin was the most prescribed therapy and was associated with the best outcome (effective in 14 patients). Eight patients had severe disease refractory to anticoagulation and required intravenous immunoglobulins, producing a good response in 6 patients.

Cutaneous manifestations of Erdheim-Chester disease (ECD): Clinical, pathological, and molecular features in a monocentric series of 40 patients.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis with possible cutaneous-specific involvement. OBJECTIVES: We sought to describe the clinical, pathological, and molecular features of the cutaneous manifestations of 40 patients with ECD identified from a cohort of 123 patients. METHODS: Confirmed cases of patients with ECD were included in a single-center retrospective observational study. Clinical and pathological cutaneous features were analyzed and BRAF(V600E) mutation was determined. RESULTS: The most frequent ECD cutaneous manifestations were xanthelasma-like lesions (XLL), which occurred in 31 (25%) patients. Other ECD cutaneous lesions were patches or papulonodular lesions. Mixed form of ECD and cutaneous Langerhans cell histiocytosis presented with crusty papules of the folds in some patients. Compared with classic xanthelasma palpebrarum, ECD XLL pathology more frequently involved the reticular dermis, displayed more multinucleated or Touton cells, and showed less extensive fibrosis. BRAF(V600E) mutation was more frequently detected in patients with cutaneous involvement than in those without (76% vs 52%; P = .005) and constantly found in 10 XLL. LIMITATIONS: Some clinical data were not available because of the retrospective design of the study. CONCLUSIONS: XLL are the most frequent cutaneous ECD manifestations and might be targeted both for pathology and determination of BRAF mutational status.

Vascular invasion and other invasive features in granular cell tumours of the skin: a multicentre study of 119 cases.

BACKGROUND: Incidental finding of vascular invasion has been described in some benign granular cell tumours. Malignancy in granular cell tumours is excessively rare and its assessment relies on necrosis and cytological criteria. AIMS: To assess histopathological invasive features, particularly vascular invasion, in a large series of granular cell tumours of the skin. METHODS: 119 granular cell tumours of the skin were collected in 114 patients between 2001 and 2011. Histopathological and epidemiological data were collected. Five step sections and one orcein staining were performed in all cases. RESULTS: Mean age of the patients was 43.7±18 years. Granular cell tumours were multiple in 7% of patients. They were classified as benign in 111 cases, and atypical in eight cases. No malignant granular cell tumour was present. Tumours had 1.48±1.3 cm mean diameter, showed peripheral invasive growth pattern in 71% of cases, had a mean depth of 8.8±4.7 mm, and reached the subcutis in 66% of cases. Infiltration of arrector pili muscle occurred in 23% (95% CI 16% to 32%), and perineural spread in 66% (95% CI 56% to 74%) of cases. Vascular invasion occurred in 23% (95% CI 16% to 32%) of cases, with subendothelial layers infiltration or vascular obliteration. No intraluminal embolus was found. No association was found between vascular invasion and clinical outcome. CONCLUSIONS: Histopathological features of local invasion are frequent in otherwise benign granular cell tumours. Vascular invasion consists of an infiltration of the subendothelial layers, without intraluminal cells, and may not be considered as a marker of adverse prognosis.

Additional conjunctival and penile pigmentation in Laugier-Hunziker syndrome: a report of two cases.

BACKGROUND: Laugier-Hunziker syndrome is a rare acquired hyperpigmentation of the oral mucosa and lips which is often associated with longitudinal melanonychia. We report two patients exhibiting the classical features of Laugier-Hunziker syndrome with additional and previously unreported conjunctival and penile pigmentation. PATIENTS AND METHODS: Two patients presented with a history of progressive acquired macular pigmentation of the oral mucosa, the lips, the ocular conjunctiva and the penis. Longitudinal melanonychia was found in one patient. Microscopic features (basal epithelial melanosis, moderate acanthosis and superficial pigmentary incontinence) and ultrastructural details (increased number of normal-appearing melanosomes inside basal keratinocytes and dermal melanophages) were characteristic of Laugier-Hunziker syndrome. CONCLUSIONS: These two observations illustrate the topographical variations of Laugier-Hunziker syndrome and highlight the need to expand the originally described features to include more widespread areas of hyperpigmentation.