Pulmonary enteric adenocarcinoma: an overview.

Most commonly described as sporadic, pulmonary adenocarcinoma with enteric differentiation (PAED) is a rare variant of invasive lung cancer recently established and recognised by the World Health Organization. This tumour is highly heterogeneous and shares several morphological features with pulmonary and colorectal adenocarcinomas. Our objective is to summarise current research on PAED, focusing on its immunohistochemical and molecular features as potential tools for differential diagnosis from colorectal cancer, as well as prognosis definition and therapeutic choice. PAED exhibits an 'entero-like' pathological morphology in more than half cases, expressing at least one of the typical immunohistochemical markers of enteric differentiation, namely CDX2, CK20 or MUC2. For this reason, this malignancy appears often indistinguishable from a colorectal cancer metastasis, making the differential diagnosis laborious. Although standard diagnostic criteria have not been established yet, in the past few years, a number of approaches have been addressed, aimed at defining specific immunohistochemical and molecular signatures. Based on previously published literature, we have collected and analysed molecular and immunohistochemical data on this rare neoplasm, and have described the state of the art on diagnostic criteria as well as major clinical and therapeutic implications.The analysis of data from 295 patients from 58 published articles allowed us to identify the most represented immunohistochemical and molecular markers, as well as major differences between Asian PAEDs and those diagnosed in European/North American countries. The innovative molecular approaches, exploring driver mutations or new gene alterations, could help to identify rare prognostic factors and guide future tailored therapeutic approaches to this rare neoplasm.

Animal-type melanoma: dog or wolf? A review of the literature and a case report.

The human animal type melanoma (ATM) is a rare subtype of melanoma characterised by the proliferation of pigmented dermal epithelioid and spindled melanocytes. However, this variant of melanoma is still lacking a precise nosography definition and classification for the difficulty to be distinguished from other more common melanocytic lesions, as well as for its peculiar biological behaviour. On the other hand, the contribution of scientific literature to this issue is fragmented and limited to the description of very few cases. Starting from the presentation of a case with abnormally aggressive clinical features, here we revisit the current knowledge on ATM from its dermatologic patterns, epidemiology, demography and histopathology to the clinical management. Peculiar accuracy has also been reserved to several histopathologic criteria, which are critical for the differential diagnosis from other melanocytic diseases in junction with molecular data deriving from recent cytogenetic and mutational characterisation of this tumour.

An Italian Retrospective Survey on Bone Metastasis in Melanoma: Impact of Immunotherapy and Radiotherapy on Survival.

BACKGROUND: We performed a multicenter retrospective observational study to investigate the impact of clinical-pathological features and therapeutic strategies on both the complications and survival of patients with bone metastases (BMs) from malignant melanoma. PATIENTS AND METHODS: A total of 305 patients with melanoma and radiological evidence of BMs were retrospectively enrolled from 19 Italian centers. All patients received conventional treatments in accordance with each own treating physician's practice. Both univariate and multivariate models were used to explore the impact of melanoma features, including skeletal-related events (SREs), and different treatments on both overall survival (OS) and time-to-SREs. The chi-squared test evaluated the suitability of several parameters to predict the occurrence of SREs. RESULTS: Eighty-three percent of patients had metachronous BMs. The prevalent (90%) bone metastatic site was the spine, while 45% had involvement of the appendicular skeleton. Forty-seven percent experienced at least one SRE, including palliative radiotherapy (RT) in 37% of cases. No melanoma-associated factor was predictive of the development of SREs, although patients receiving early treatment with bone-targeted agents showed 62% lower risk and delayed time of SRE occurrence. Median OS from the diagnosis of bone metastasis was 10.7 months. The multivariate analysis revealed as independent prognostic factors the number of BMs, number of metastatic organs, baseline lactate dehydrogenase levels, and treatment with targeted therapy or immunotherapy. Subgroup analyses showed the best OS (median = 16.5 months) in the subset of patients receiving both immunotherapy and palliative RT. CONCLUSION: Based on our results, patients undergoing immunotherapy and palliative RT showed an OS benefit suggestive of a possible additive effect. The apparent protective role of bone targeting agent use on SREs observed in our analysis should deserve prospective evaluation.

Cutaneous metastasis as a primary presentation of a pulmonary enteric adenocarcinoma.

BACKGROUND: Primary pulmonary enteric adenocarcinoma (PEAC) is a rare non-small cell lung cancer subtype sharing morphologic and immunohistochemical features with colorectal adenocarcinoma. Given the frequency of lung metastases in colorectal cancer, the differential diagnosis of PEAC according to routine morphological and immunohistochemical findings may be difficult. Genome sequence by next-generation sequencing has recently introduced new perspectives to better define the diagnosis and tumor sensitivity to treatments, while the rarity of this subtype of cancer still limits the current knowledge of its molecular features and provides no information to address patients to tailored therapies. METHODS: We diagnosed a rare case of subcutaneous metastasis as a first symptom of a PEAC. Formalin-fixed paraffin-embedded samples of the primary tumor and subcutaneous metastases were examined by immunohistochemistry, and subsequently by targeted next-generation sequencing analysis. RESULTS: Morphological and immunohistochemical findings suggested a rare case of metastatic pulmonary adenocarcinoma with enteric aspects. Next-generation sequencing analysis performed on both the primary tumor sample and the cutaneous lesion identified two pathogenic variants on CDKN2A and KRAS in both of them. However, the metastasis showed two additional pathogenic mutations located in SMAD4 and FLT3 genes. CONCLUSIONS: We describe for the first time an extensive molecular analysis on a rare case of PEAC with an unusual cutaneous metastasis. Our observation suggests that a specific pattern of mutations is harbored in this neoplasm, and that additional molecular studies may provide further information to identify prognostic and hopefully predictive genes of response to treatment.

Immune-related adverse events during anticancer immunotherapy: Pathogenesis and management.

Immunotherapy is one of the most recent systemic treatments to emerge for use in oncology, and is based on the blocking of inhibitory immune checkpoints to potentiate the immune response to cancer. The anti-cytotoxic T lymphocyte-associated antigen-4 antibody ipilimumab and anti-programmed cell death protein 1 antibodies, including nivolumab and pembrolizumab, are currently available and widely used, and other immune-inhibiting antibodies are now under intensive investigation. These antibodies have shown efficacy in a growing number of tumor types, following initial observations of their notable effects in melanoma treatment. Despite the efficacy of these antibodies, their novel mechanisms of action are also associated with a new class of side effects called immune-related adverse events (IRAEs). These side effects do not share a common pathophysiology with other anticancer treatments and, therefore, they often require specific therapies. When detected early and correctly treated, IRAEs are reversible; however, they can become severe and life-threatening if underestimated or inappropriately treated. This review aims to revisit the pathogenesis of IRAEs, with attention to gastrointestinal manifestations, since these are common and potentially dangerous complications of immunotherapy and represent a major cause of treatment discontinuation. Recommendations and guidelines for the management of IRAEs are also presented, in order to provide a clear and applicable algorithm for use by clinicians.