Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.

Heterogeneity of kinase inhibitor resistance mechanisms in GIST.

Most GIST patients develop clinical resistance to KIT/PDGFRA tyrosine kinase inhibitors (TKI). However, it is unclear whether clinical resistance results from single or multiple molecular mechanisms in each patient. KIT and PDGFRA mutations were evaluated in 53 GIST metastases obtained from 14 patients who underwent surgical debulking after progression on imatinib or sunitinib. To interrogate possible resistance mechanisms across a broad biological spectrum of GISTs, inter- and intra-lesional heterogeneity of molecular drug-resistance mechanisms were evaluated in the following: conventional KIT (CD117)-positive GISTs with KIT mutations in exon 9, 11 or 13; KIT-negative GISTs; GISTs with unusual morphology; and KIT/PDGFRA wild-type GISTs. Genomic KIT and PDGFRA mutations were characterized systematically, using complementary techniques including D-HPLC for KIT exons 9, 11-18 and PDGFRA exons 12, 14, 18, and mutation-specific PCR (V654A, D820G, N822K, Y823D). Primary KIT oncogenic mutations were found in 11/14 patients (79%). Of these, 9/11 (83%), had secondary drug-resistant KIT mutations, including six (67%) with two to five different secondary mutations in separate metastases, and three (34%) with two secondary KIT mutations in the same metastasis. The secondary mutations clustered in the KIT ATP binding pocket and kinase catalytic regions. FISH analyses revealed KIT amplicons in 2/10 metastases lacking secondary KIT mutations. This study demonstrates extensive intra- and inter-lesional heterogeneity of resistance mutations and gene amplification in patients with clinically progressing GIST. KIT kinase resistance mutations were not found in KIT/PDGFRA wild-type GISTs or in KIT-mutant GISTs showing unusual morphology and/or loss of KIT expression by IHC, indicating that resistance mechanisms are fundamentally different in these tumours. Our observations underscore the heterogeneity of clinical TKI resistance, and highlight the therapeutic challenges involved in salvaging patients after clinical progression on TKI monotherapies.

Protein kinase C-theta regulates KIT expression and proliferation in gastrointestinal stromal tumors.

Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GISTs), and the KIT/PDGFRA kinase inhibitor, imatinib, is standard of care for patients with metastatic GIST. However, most of these patients eventually develop clinical resistance to imatinib and other KIT/PDGFRA kinase inhibitors and there is an urgent need to identify novel therapeutic strategies. We reported previously that protein kinase C-theta (PKCtheta) is activated in GIST, irrespective of KIT or PDGFRA mutational status, and is expressed at levels unprecedented in other mesenchymal tumors, therefore serving as a diagnostic marker of GIST. Herein, we characterize biological functions of PKCtheta in imatinib-sensitive and imatinib-resistant GISTs, showing that lentivirus-mediated PKCtheta knockdown is accompanied by inhibition of KIT expression in three KIT+/PKCtheta+ GIST cell lines, but not in a comparator KIT+/PKCtheta- Ewing's sarcoma cell line. PKCtheta knockdown in the KIT+ GISTs was associated with inhibition of the phosphatidylinositol-3-kinase/AKT signaling pathway, upregulation of the cyclin-dependent kinase inhibitors p21 and p27, antiproliferative effects due to G(1) arrest and induction of apoptosis, comparable to the effects seen after direct knockdown of KIT expression by KIT short-hairpin RNA. These novel findings highlight that PKCtheta warrants clinical evaluation as a potential therapeutic target in GISTs, including those cases containing mutations that confer resistance to KIT/PDGFRA kinase inhibitors.

Papillary haemangioma. A distinctive cutaneous haemangioma of the head and neck area containing eosinophilic hyaline globules.

AIMS: To investigate and define a morphologically distinctive group of cutaneous papillary haemangiomas. METHODS AND RESULTS: Eleven patients (seven male, four female, age range 1-77 years, median 57) were identified with a solitary bluish cutaneous papule (median size 11 mm) arising in the head and neck region. Most lesions had been present for several years. None of the patients had associated systemic disease or polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome. Only one lesion recurred locally. The lesions showed predominantly intravascular papillary growth within multiple ectatic dermal vessels. The papillae had cellular cores containing pericytes and stromal cells, arranged around normal small capillaries. The surfaces of the papillae were covered by focally swollen endothelial cells containing numerous hyaline globules, ultrastructurally representing giant lysosomes containing organelle debris and fat vacuoles (so-called thanatosomes). These endothelial cells were immunopositive for CD31 and CD34 but negative for D2-40 (podoplanin). CONCLUSIONS: Papillary haemangioma is a distinctive benign cutaneous lesion containing eosinophilic hyaline globules consistent with dysfunction of the autophagocytic-lysosomal pathway.

Immunohistochemistry for beta-catenin in the differential diagnosis of spindle cell lesions: analysis of a series and review of the literature.

AIMS: Nuclear staining for beta-catenin by immunohistochemistry is being used increasingly to diagnose desmoid tumours (deep fibromatoses), especially where the differential diagnosis includes other abdominal spindle cell neoplasms. This study aimed to define the prevalence of beta-catenin positivity in desmoid tumours and other morphologically similar spindle cell neoplasms. METHOD AND RESULTS: Nuclear beta-catenin expression was evaluated by immunohistochemistry in 270 soft tissue tumours. Nuclear immunopositivity was detected in 80% of cases of sporadic desmoid fibromatosis (24/30) and in 67% of tumours in patients with familial adenomatous polyposis (8/12). Nuclear positivity was also present in 14/25 superficial fibromatoses (56%), 3/10 low-grade myofibroblastic sarcomas (30%), 5/23 solitary fibrous tumours (22%), 1/5 infantile fibrosarcomas (20%), 1/18 desmoplastic fibroblastomas (6%) and 1/21 gastrointestinal stromal tumours (5%). No nuclear immunoreactivity was present in neurofibromas (0/26), schwannomas (0/25), nodular fasciitis (0/19), leiomyosarcomas (0/16), inflammatory myofibroblastic tumours (0/12), fibromas of tendon sheath (0/9), lipofibromatoses (0/5), Gardner fibromas (0/4), calcifying aponeurotic fibromas (0/4) or fibromatosis colli (0/1). CONCLUSION: Nuclear staining for beta-catenin is supportive, but not definitive, of the diagnosis of desmoid fibromatosis. No significant difference in immunoreactivity was observed between sporadic and familial desmoid fibromatoses. beta-Catenin negativity does not preclude the diagnosis of fibromatosis.

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance.

Most gastrointestinal stromal tumors (GISTs) express oncogenic and constitutively active forms of the KIT or platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase proteins, and these kinase oncoproteins serve as targets for effective therapies. Given that mutant KIT oncoproteins serve crucial transforming roles in GISTs, we evaluated interactions with the KIT oncoproteins and determined signaling pathways that are dependent on KIT oncogenic activation in GISTs. Tyrosine-phosphorylated KIT oncoproteins interacted with PDGFRA, PDGFRB, phosphatidylinositol 3-kinase (PI3-K) and PKCtheta in GIST cells, and these interactions were abolished by KIT inhibition with imatinib or PKC412 or KIT RNAi. Notably, tyrosine-phosphorylated PDGFRA was prominent in frozen GIST tumors expressing KIT oncoproteins, suggesting that KIT-mediated PDGFRA phosphorylation is an efficient and biologically consequential mechanism in GISTs. Activated signaling intermediates were identified by immunoaffinity purification of tyrosine-phosphorylated proteins in GIST cells before and after treatment with KIT inhibitors, and these analyses show that GRB2, SHC, CBL and MAPK activation are largely KIT dependent in GISTs, whereas PI3-K, STAT1 and STAT3 activation are partially KIT dependent. In addition, we found that phosphorylation of several tyrosine kinase proteins - including JAK1 and EPHA4 - did not depend on KIT activation. Likewise, paxillin activation was independent of the KIT oncogenic signal. These studies identify signaling pathways that can provide both KIT-dependent and KIT-independent therapeutic synergies in GIST, and thereby highlight clinical strategies that might consolidate GIST therapeutic response to KIT/PDGFRA inhibition.

EGFR amplification and lack of activating mutations in metaplastic breast carcinomas.

Metaplastic breast carcinomas are reported to harbour epidermal growth factor receptor (EGFR) overexpression in up to 80% of the cases, but EGFR gene amplification is the underlying genetic mechanism in around one-third of these. In this study, EGFR gene amplification as defined by chromogenic in situ hybridization and protein overexpression was examined in a cohort of 47 metaplastic breast carcinomas. Furthermore, the presence of activating EGFR mutations in exons 18, 19, 20, and 21 was investigated. Thirty-two cases showed EGFR overexpression and of these, 11 (34%) harboured EGFR gene amplification. In addition, EGFR amplification showed a statistically significant association with EGFR overexpression (p < 0.0094) and was restricted to carcinomas with homologous metaplasia. Ten cases, five with and five without EGFR amplification, were subjected to microarray-based CGH, which demonstrated that EGFR copy number gain may occur by amplification of a discrete genomic region or by gains of the short arm of chromosome 7 with a breakpoint near the EGFR gene locus, the minimal region of amplification mapping to EGFR, LANCL2, and SEC61G. No activating EGFR mutations were identified, suggesting that this is unlikely to be a common alternative underlying genetic mechanism for EGFR expression in metaplastic breast carcinomas. Given that metaplastic breast carcinomas are resistant to conventional chemotherapy or hormone therapy regimens and that tumours with EGFR amplification are reported to be sensitive to EGFR tyrosine kinase inhibitors, these findings indicate that further studies are warranted to explore EGFR tyrosine kinase inhibitors as potential therapeutic agents for metaplastic breast carcinomas harbouring amplification of 7p11.2.

ALK expression in pseudosarcomatous myofibroblastic proliferations of the genitourinary tract.

AIMS: Pseudosarcomatous myofibroblastic proliferation of the genitourinary tract is rare and may develop after trauma or spontaneously. The aim of this study was to characterize further the clinicopathological features of these lesions and to examine their relationship to inflammatory myofibroblastic tumour (IMT). METHODS AND RESULTS: Twenty-seven cases of pseudosarcomatous myofibroblastic proliferation were analysed. There were seven males and 20 females; median age was 37 years (range 16-88). Most lesions were from the bladder (n = 21), while others were in the urethra, vulva, vagina, rectum and retrovesical space. Median tumour size was 30 mm (range 6-120 mm). Seven cases (25%) had a history of prior trauma or surgery. Three cases recurred locally but not destructively. The tumours had fasciitis-like features including bland spindle cells with evenly distributed chromatin, admixed inflammatory cells (mainly lymphocytes) and often a myxoid stroma. Immunohistochemistry showed positivity for smooth muscle actin in 14/20 cases, keratin in 8/19, desmin in 7/20 and anaplastic lymphoma kinase (ALK) in 10/21 cases. Fluorescent in situ hybridization was performed in six ALK+ cases; all were negative for ALK gene rearrangement. CONCLUSIONS: Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract may show ALK immunopositivity but do not show consistent ALK rearrangement. Given subtle morphological differences and more consistently benign behaviour, their relationship to inflammatory myofibroblastic tumour at other sites remains uncertain.

Haemosiderotic fibrolipomatous tumour (so-called haemosiderotic fibrohistiocytic lipomatous tumour): analysis of 13 new cases in support of a distinct entity.

AIMS: To describe 13 new cases of a rare soft tissue neoplasm currently known as haemosiderotic fibrohistiocytic lipomatous tumour (HFHLL) and to further its characterization. METHODS AND RESULTS: Patients were eight females and five males, aged 8 months to 74 years. Lesions ranged in size from 10 to 130 mm (median 45). Twelve of 13 lesions were located in the ankle/foot region; one involved the hand. Grossly the lesions were fatty/gelatinous or lipoma-like. They were characterized by varying proportions of mature adipocytes and fibroblastic spindle cells, associated with haemosiderin pigment present predominantly in macrophages within the spindle cell component. Dissecting between adipocytic lobules were septa containing short spindle cells with streaming, swirling or honeycomb growth patterns. Most tumours contained scattered osteoclast-like giant cells. Mitoses were rare and only one case showed mild atypia. Immunohistochemistry in 10 cases showed 7/9 CD34+; all were negative for smooth muscle actin, CD68, S100 and desmin. Follow-up in nine cases ranging from 1 to 130 months (median 12) showed local recurrence in three but no metastasis. CONCLUSIONS: So-called HFHLL, better termed haemosiderotic fibrolipomatous tumour, is a distinct lesion characterized by an admixture of fibroblastic spindle cells, mature adipocytes and haemosiderin pigmentation, shows a predilection for the distal extremities and quite often recurs locally.

The evolving classification of soft tissue tumours: an update based on the new WHO classification.

Tumour classifications have become an integral part of modern oncology and, for pathologists, they provide guidelines which facilitate diagnostic and prognostic reproducibility. In many organ systems and most especially over the past decade or so, the World Health Organization (WHO) classifications have become pre-eminent, partly enabled by the timely publication of new "blue books" which now incorporate detailed text and copious illustrations. The new WHO classification of soft tissue tumours was introduced in late 2002 and, because it represents a broad consensus view, it has gained widespread acceptance. This review summarizes the changes, both major and minor, which were introduced and briefly describes the significant number of tumour types which have been first recognized or properly characterized during the past decade. Arguably the four most significant conceptual advances have been: (i) the formal recognition that morphologically benign lesions (such as cutaneous fibrous histiocytoma) may very rarely metastasize; (ii) the general acceptance that most pleomorphic sarcomas can be meaningfully subclassified and that so-called malignant fibrous histiocytoma is not a definable entity, but instead represents a wastebasket of undifferentiated pleomorphic sarcomas, accounting for no more than 5% of adult soft tissue sarcomas; (iii) the acknowledgement that most lesions formerly known as haemangiopericytoma show no evidence of pericytic differentiation and, instead, are fibroblastic in nature and form a morphological continuum with solitary fibrous tumour; and (iv) the increasing appreciation that not only do we not know from which cell type(s) most soft tissue tumours originate (histogenesis) but, for many, we do not recognize their line of differentiation or lineage--hence an increasing number of tumours are placed in the "uncertain differentiation" category.

PEComa: what do we know so far?

PEComas (tumours showing perivascular epithelioid cell differentiation) are a family of related mesenchymal neoplasms that include angiomyolipoma, lymphangiomyomatosis, clear cell "sugar" tumour of the lung, and a group of rare, morphologically and immunophenotypically similar lesions arising at a variety of visceral and soft tissue sites. These tumours all share a distinctive cell type, the perivascular epithelioid cell or "PEC' (which has no known normal tissue counterpart). PEComas show a marked female predominance and are composed of nests and sheets of usually epithelioid but occasionally spindled cells with clear to granular eosinophilic cytoplasm and a focal association with blood vessel walls. PEComas appear to arise most commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, and abdominopelvic sites, with a subset occurring in somatic soft tissue and skin. Nearly all PEComas show immunoreactivity for both melanocytic (HMB-45 and/or melan-A) and smooth muscle (actin and/or desmin) markers. A subset of PEComas behave in a malignant fashion. This review examines the members of the PEComa family, with an emphasis on lesions arising outside of the kidney, lung and liver, and discusses preliminary evidence for pathological features that might predict malignant behaviour.

Postradiation vascular proliferations: an increasing problem.

The occurrence of cutaneous vascular lesions is a rare but well-documented complication of radiation treatment and may be associated with significant morbidity as well as mortality. The overall incidence is low but appears to be rising due to a change in the prevailing treatment of breast carcinoma with increased use of radiation in the setting of breast-conserving therapy for stage 1 and 2 disease. The spectrum of postradiation vascular lesions is wide and ranges from atypical vascular lesions with reportedly benign clinical behaviour to frank cutaneous angiosarcoma. There is, however, significant clinical as well as histological overlap. It is frequently difficult to classify these postradiation vascular lesions accurately and they create an emerging diagnostic and therapeutic challenge to both pathologists and clinicians. Experience with these vascular lesions is very limited, and this article aims to provide an overview of our current understanding and concept of radiation-associated vascular lesions with focus on their clinical and histological presentation as well as behaviour and treatment.

Prognostic information in soft tissue sarcoma using tumour size, vascular invasion and microscopic tumour necrosis-the SIN-system.

We have earlier devised a system for soft tissue sarcoma (STS), based on three negative prognostic features: large tumour size, vascular invasion, and microscopic tumour necrosis, the SIN-system. Tumours which exhibit 2 or 3 of these features are categorised as high-risk, the others as low-risk. We have now tested this system for reproducibility both as regards recognition of its components, and as regards prognostic strength in patients from another institution. We have also compared it with the American Joint Committee on Cancer (AJCC) system. 200 patients with STS were analysed, all had been treated by surgery, in 97 patients combined with radiotherapy. The median follow-up for the 117 survivors was 10 (1.5-27) years. Without knowledge of the clinical data, three groups of pathologists independently reviewed original slides from all of the tumours. Based on the factors, the tumours were classified as high-risk or low-risk. The prognostic strength was compared using the results obtained by the different observers. Concordance in recognition of vascular invasion, tumour necrosis, and overall grading was seen in 156 (78%), 154 (77%), and 167 (84%) of the 200 tumours, respectively. Based on the different observers' grading, the cumulative 5-year metastasis-free survival rate (MFSR) varied for patients with low-risk tumours between 0.85 and 0.80, and for patients with high-risk tumours between 0.48 and 0.43. The Kappa-value for grading between all three groups of observers was 0.77. The SIN-system gave more clinically useful prognostic information than the AJCC system. Useful prognostic information in STS can be obtained by using tumour size, vascular invasion and microscopic tumour necrosis. This system provides two distinct prognostic groups, and has a high reproducibility.

Synovial sarcoma in older patients: clinicopathological analysis of 32 cases with emphasis on unusual histological features.

AIMS: To analyse the clinicopathological features of synovial sarcoma presenting in patients over 60 years of age, an uncommon subset which have not been specifically studied. METHODS AND RESULTS: Thirty-two cases of primary synovial sarcoma in patients aged > or =60 years were retrieved from the authors' consultation files. These were analysed histologically and immunohistochemically and clinical follow-up was obtained in 26 cases (median duration 41 months). Mean age at diagnosis was 71.6 years (range 60-84) with 19 females and 13 males. Anatomical sites were lower limb (n = 13), upper limb (n = 5), lung/pleura (n = 5), trunk (n = 4), head/neck (n = 3), mediastinum (n = 1) and scrotum (n = 1). Histologically, 23 were monophasic and nine were biphasic; 14 were poorly differentiated, of which five showed focally marked pleomorphism. Unusual features in two cases each included organoid nodules, granular cell change, squamous metaplasia and papillary architecture. Ten patients developed local recurrence and 11 developed metastases, of whom seven died. Large tumour size, poorly differentiated morphology and high mitotic rate correlated with poor outcome. CONCLUSIONS: Less than 10% of synovial sarcomas occur in patients over 60, in which age group this diagnosis is often not considered. Despite inevitable bias in consultation material, it seems that these cases, when compared with younger age groups, more often show poorly differentiated histology and more often develop at unusual locations.

Malignant myopericytoma: expanding the spectrum of tumours with myopericytic differentiation.

AIMS: The spectrum of tumours showing myopericytic differentiation is increasingly being defined and includes lesions such as myofibroma and infantile haemangiopericytoma. Here we seek to describe for the first time and clinicopathologically characterize examples of malignant myopericytoma. METHODS AND RESULTS: Five cases of malignant myopericytoma were identified in the authors' consultation files. Immunostains were performed and clinical information was obtained. Tumours arose in three females and two males (median age 67 years, range 19-81 years) on the neck, arm, thigh and foot. One patient presented with disseminated metastases. One patient had a prior history of multiple benign myopericytomas in the same location. Four patients developed metastases and three died within 1 year. Tumours were composed of highly mitotic myoid-appearing ovoid-to-spindle cells showing at least focally striking perivascular orientation resembling that seen in benign myopericytoma; three cases were focally fascicular and three showed thin-walled branching vessels. All tumours showed at least focally prominent positivity for smooth muscle actin. One case showed dot-like desmin positivity. CONCLUSIONS: In reporting examples of malignant myopericytoma, we further characterize and broaden the morphological spectrum of myopericytic neoplasms. Available data indicate that malignant myopericytomas are associated with aggressive clinical behaviour.