Original Contributions
Primary and secondary cutaneous angiosarcoma: Distinctive clinical, pathological and molecular features

https://doi.org/10.1016/j.anndiagpath.2020.151597Get rights and content

Highlights

  • Reviews latest knowledge of etiology and biology of cutaneous angiosarcoma

  • Clinical behavior and prognostic factors are discussed.

  • Highlights morphological clues for diagnosis

  • A wide spectrum of neoplasms is discussed in differential diagnosis.

Abstract

Angiosarcomas are ubiquitous neoplasms involving both cutaneous and soft tissue and visceral locations. Accumulating biomolecular evidences suggest that cutaneous angiosarcomas are distinctive entities with molecular, clinical and pathological peculiarities. Despite several ongoing clinical trials with promising therapeutic agents, the prognosis of cutaneous angiosarcomas is dismal and survival still rely on early diagnosis and surgery. An accurate diagnosis and the knowledge of the underlying molecular landscape are therefore essential to improve the prognosis. We detail the molecular, clinical, dermoscopic, morphological and prognostic features of cutaneous angiosarcoma. Although the molecular landscape of cutaneous angiosarcoma is not completely understood, accumulating evidences suggest that there are characteristic molecular alterations including dysregulation of angiogenesis and several complex molecular pathways. Secondary cutaneous angiosarcomas, arising in correlation with chronic lymphedema and ionizing radiation, have different molecular hallmarks, which are also leading to the first diagnostic applications. The diagnosis of cutaneous angiosarcoma may be challenging, as well-differentiated forms can be hard to distinguish from benign and low-grade vascular neoplasms, while poorly differentiated forms can be easily confounded with other non-vascular high-grade neoplasms. An accurate and early diagnosis, which is mandatory to ensure the best survival for the patients, is mainly based on morphological hallmarks.

Introduction

Angiosarcomas (ASs) are a heterogenous group of malignant neoplasms characterized by endothelial differentiation [1]. ASs are ubiquitous neoplasms, involving both visceral and cutaneous and soft tissue locations. Rarely, they occur in association with other neoplasms [2]. Cutaneous angiosarcomas (cASs) are highly aggressive tumours arising in the skin, mainly seen in elderly patients with chronic solar damage, lymphedema or history of ionizing radiation [3]. Molecular findings in cASs partially differ from those occurring in visceral ASs. Despite several ongoing clinical trials with promising therapeutic agents, the prognosis of cASs is dismal and currently available treatment options are still limited. Consequently, an accurate and early diagnosis is essential for the best management of the patient. However, cASs are heterogeneous in terms of clinical presentation and histomorphology, and the differential diagnosis is wide, including benign vascular neoplasms, vascular tumours of uncertain malignant potential and high-grade neoplasms with differentiation other than endothelial.

This review aims to describe the biological, molecular, clinical and histolopathological features of cASs, with particular reference to the tools for correct recognition of these tumours and recently introduced diagnostic and prognostic factors.

Section snippets

Epidemiology and localizations

Cutaneous angiosarcoma (cAS) is a rare neoplasm with an incidence rate of about 0.5 new cases per 1,000,000 persons per year in the United States according to the Surveillance, Epidemiology, and End Results (SEER) Program database, accounting for less than 1% of all cutaneous sarcomas [4]. Currently the incidence rate seems to be increased in people over the age of 70 years, supposedly due to the relatively wide application of radiation-based therapies and the longstanding solar exposure in

Cutaneous AS molecular landscape: peculiarities with respect to visceral AS

Overall, the genetic profile of cAS is complex and not well defined, but the current knowledge suggests that ASs harbour biological differences by the site and that cAS may have biological peculiarities. The most commonly mutated genes in cAS include TP53, KRAS, PTPRB and PLCG1 [9]. Primary cAS frequently shows alterations of NTSR-1, ANKRD1 and CDKN2C, while upregulation of MYC, KIT, FLT4, RET, UNC5A, CTLA4, ISLR2, ICOS, RAB17, FLT4 and RASGRP3 has been reported in secondary cAS [10,11].

Primary versus secondary cASs: two different biomolecular profiles

The etiology and pathogenesis of cAS are still poorly understood. According to evidences accumulated during the last decades, two types of cAS can be defined on a pathogenetic basis: primary cAS, arising de-novo in a chronically sun-damaged skin, and secondary cAS, occurring mainly in a context of chronic lymphedema or in irradiated skin [3]. Although lymphedema and ionizing radiations are the most frequent and well-characterized clinical conditions associated with the development of secondary

Clinical findings and dermoscopy

Clinical features of cASs are extremely variable, since the neoplasm may mimic both other cutaneous neoplasms and non-neoplastic skin diseases. For example, cases of cASs clinically simulating rosacea, eczema, haemangioma, xanthelasma, cellulitis, and facial and eyelid angioedema, squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, atypical fibroxanthoma and malignant melanoma have been reported in literature [[27], [28], [29]]. However, at least in early stages, the most common

Histological findings

Histologically, cASs are quite heterogenous, depending on the degree of differentiation. Well-differentiated cASs display readily apparent vascular formation, while poorly differentiated cASs may show only limited – if any – morphological evidence of vascular differentiation. The diagnosis of cAS may be challenging, as well-differentiated forms can be hard to distinguish from benign and low-grade vascular neoplasms, while high-grade cASs can be easily confounded with other non-vascular poorly

Prognosis

cASs are aggressive neoplasms with poor outcome and high rate of metastases, mainly to lungs, bones, liver and lymph-nodes [49]. The reported 5-year survival rates ranged from 10% to 40% in the largest published series [49,50]. Tumour histologic grade does not seem to be a good predictor of prognosis in cASs [51]. On the other hand, adverse prognostic factors in cAS include age > 70 years, poor performance stadium, large tumour size (>5 cm), greater tumour depth, multifocality, presence of

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