Langerhans cell histiocytosis

Muir-Torre syndrome (MTS) is a rare genetic condition that predisposes individuals to skin tumors and visceral malignancies. Because of the potentially aggressive nature of internal malignancies and sebaceous carcinoma, and the tendency to have multiple low-grade visceral cancers, close cancer surveillance is required in individuals and their families with this usually autosomal dominant disorder. Although the majority of MTS is caused by mutations in DNA mismatch repair genes resulting in microsatellite instability, a newly described subtype of MTS does not demonstrate microsatellite instability and may be inherited in an autosomal recessive pattern. In addition, MTS may be unmasked in transplant recipients taking specific immunosuppressant drugs or other immunosuppressed patients. Neoplasms may be subject to immunohistochemistry or both immunohistochemistry and genetic testing to confirm the diagnosis of MTS. Here, we offer an update and an approach to the diagnosis and management of MTS with a particular emphasis on the role of immunohistochemistry and genetic testing.

Muir-Torre syndrome (MTS): An update and approach to diagnosis and management

Sebaceous carcinoma is a rare and potentially aggressive cutaneous malignancy. Commonly reported in the periocular area and the head and neck region, sebaceous carcinoma can arise from any sebaceous gland in the skin. The clinical presentation may be nonspecific, and a biopsy is important to establish a diagnosis and to differentiate from mimickers including benign sebaceous neoplasms, other adnexal tumors, and basal cell carcinoma. A diagnosis of Muir Torre syndrome should be considered in patients presenting with a sebaceous neoplasm. Early treatment is important given the potential of sebaceous carcinoma to spread to the regional lymph nodes and beyond. Sentinel lymph node biopsy and imaging to complete tumor staging may be indicated for larger or more aggressive tumors. Surgery, including Mohs micrographic surgery, remains the primary treatment modality for sebaceous carcinoma. Mohs micrographic surgery has the advantage of complete margin evaluation and low recurrence rates. Advanced cases may be treated with orbital exenteration, radiation therapy, chemotherapy, or combination therapy.

Sebaceous Carcinoma: A Review of the Scientific Literature.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare sporadic cystic lung disease of unknown aetiology that is characterised by the infiltration and destruction of the wall of distal bronchioles by CD1a + Langerhans-like cells. In adults, PLCH is frequently isolated and affects young smokers of both sexes. Recent multicentre studies have led to the more standardised management of patients in clinical practice. Smoking cessation is essential and is occasionally the only suitable intervention. Serial lung function testing is important because a significant proportion of patients may experience an early decline in forced expiratory volume in 1 s and develop airflow obstruction. Cladribine was reported to dramatically improve progressive PLCH in some patients. Its efficacy and tolerance are currently being evaluated. Patients who complain of unexplained dyspnoea with decreased diffusing capacity of the lung for carbon monoxide should be screened for pulmonary hypertension by Doppler echocardiography, which must be confirmed by right heart catheterisation. Lung transplantation is a therapeutic option for patients with advanced PLCH. The identification of the BRAF V600E mutation in approximately half of Langerhans cell histiocytosis lesions, including PLCH, and other mutations of the mitogen-activated protein kinase (MAPK) pathway in a subset of lesions has led to targeted treatments (BRAF and MEK (MAPK kinase) inhibitors). These treatments need to be rigorously evaluated because of their potentially severe side-effects.

https://err.ersjournals.com/content/errev/26/145/170070.full.pdf

How I manage pulmonary Langerhans cell histiocytosis

Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors but is not specific to it, as approximately 80% of MSI/mismatch repair-deficient (dMMR) tumors are sporadic. Methods leading to the diagnosis of LS have considerably evolved in recent years and so have tumoral tests for LS screening and for the discrimination of LS-related to MSI-sporadic tumors. In this review, we address the hallmarks of LS, including the clinical, histopathological, and molecular features. We present recent advances in diagnostic and screening strategies to identify LS patients. We also discuss the pitfalls associated with the current strategies, which should be taken into account to improve the diagnosis of LS and avoid inappropriate clinical management.

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors.

AIMS Pulmonary Langerhans cell histiocytosis (PLCH) is an idiopathic cigarette smoking-related disorder of the lung. Molecular changes in cellular or fibrotic stages of PLCH have not been investigated. We studied the prevalence of extracellular signal-regulated kinase (ERK) pathway mutations in different PLCH stages and other non-PLCH smoking-related lung diseases. METHODS AND RESULTS The cohort included 28 PLCH with cellular (n = 10), mixed cellular/fibrotic (n = 4) and fibrotic histology (n = 14). Seven cases had concurrent multi-focal/multi-lobar tumours. Respiratory bronchiolitis interstitial lung disease (RB-ILD, n = 2), desquamative interstitial pneumonia (DIP, n = 4) and mixed RB-ILD/DIP (n = 2) were included for comparison. BRAF(V) (600E) immunohistochemistry, next-generation sequencing (NGS) and peptide nucleic acid (PNA) clamp polymerase chain reaction (PCR) with high analytical sensitivity (<0.1-0.2%) were used to analyse RAS, BRAF and MAP2K1 genes. Of 26 cases with gene mutation data, BRAF(V) (600E) was identified in eight of 12 (67%) cellular cases and in one of 14 (7%) fibrotic cases. MAP2K1 or KRAS mutations were observed in four of 14 (29%) fibrotic cases and three of the 12 (25%) cellular cases. Multi-focal/multi-lobar specimens carried identical BRAF (n = 5) or non-hotspot MAP2K1 (n = 2) mutations. The other smoking-related disorders were negative for mutations. Patients with cellular lesions or BRAF mutation were significantly younger than patients with fibrotic or BRAF wild-type PLCH. CONCLUSION The presence of identical but mutually exclusive ERK pathway mutations in multi-focal PLCH supports a neoplastic/clonal origin for this disease. Patient age and mutation type differed between cellular and fibrotic histology and may indicate a natural progression or a mutation-specific pathogenicity.

Mutually exclusive extracellular signal-regulated kinase pathway mutations are present in different stages of multi-focal pulmonary Langerhans cell histiocytosis supporting clonal nature of the disease.

BRAF/KRAS gene sequencing of sebaceous neoplasms after mismatch repair protein analysis

PO-1256 Multi-domain automated lung segmentation for inflammatory lung disease (ILD) detection

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Mutually exclusive extracellular signal-regulated kinase pathway mutations are present in different stages of multi-focal pulmonary Langerhans cell histiocytosis supporting clonal nature of the disease.

BRAF/KRAS gene sequencing of sebaceous neoplasms after mismatch repair protein analysis

PO-1256 Multi-domain automated lung segmentation for inflammatory lung disease (ILD) detection