An Overview of Cutaneous Vascular Neoplasms By Konstantinos Linos MD, FCAP, FASDP Bone, Soft Tissue and Dermatopathology Assistant Professor of Pathology Dartmouth-Hitchcock Medical Center Geisel School of Medicine at Dartmouth Hanover, NH, USA
Financial disclosures Book Royalties
Benign Vascular Tumors
Epithelioid Hemangioma Most commonly present on the Head & Neck area Often periauricular Middle-aged adults, female predominance However wide range of cutaneous location Rarely intravascular Also affects bone Can be multifocal in 25%
Microscopic features Circumscribed dermal or subcutaneous lobular proliferations of well-formed capillaries Usually surrounds a large vessel Inflammatory infiltrate Lymphocytes (sometimes germinal centers), eosinophils, histiocytes and plasma cells Involved capillaries retain lumina Lined by epithelioid cells Variably hobnail Mitoses may be seen but not atypical
IHC Positive for vascular markers CD31, CD34, ERG Also positive for D2-40 Pitfall!! Immunoreactivity for EMA and keratins may be seen
Cutaneous Epithelioid Angiomatous Nodule Most cases solitary as small violaceous superficial nodules Occasional multiple or eruptive forms Unilobular dermal and circumscribed Large solid sheets of epithelioid endothelial cells Intracytoplasmic vacuoles No significant pleomorphism Conspicuous mitotic activity but no atypical
Symplastic Hemangioma Degenerative-type pleomorphism of vascular smooth muscle and interstitial cells Pre-existing long-standing vascular neoplasm Probably due to inflammation or hypoxia Extremities or face of young to elderly adults No sex predilection Characteristically bizarre pleomorphic cells within the walls of vascular channels Occasional mitotic figures are seen
Spindle Cell Hemangioma Superficial subcutaneous or dermal erythematous to violaceous nodule Predilection for distal extremities of young adults, especially hands Sometimes multiple small nodules Subset of cases a/w Maffucci Syndrome Multiple spindle cell hemangiomas Enchondromas Increased risk for chondrosarcoma A/w IDH mutations
Microscopic Features Circumscribed subcutaneous or dermal tumors Half partially intravascular Biphasic composition Cavernous vascular spaces Solid spindle cell areas Cavernous vessels may contain phleboliths Spindle cell areas with slit-like spaces and intracytoplasmic lumina Mitotic activity and atypia low
Acquired Tufted Angioma Aka Angioblastoma of Nakagawa Most frequently in early childhood as progressive enlarging macule in head & neck area Cases with Kasabach-Merritt Syndrome have been described Less frequently than kaposiform hemangioendothelioma
Microscopic features In dermis or subcutis with so-called cannonball pattern of spherical welldermacated nodules Dilated lymphatic channels at the periphery Single endothelial cell layer surrounded by SMA positive pericytes Pericytes can be prominent and have a spindled appearance D2-40 positive in lymphatics and partially in capillary network
Vascular Tumors of Intermediate Malignancy
Kaposiform Hemangioendothelioma Vary rare tumor of infancy and childhood Most frequently as multinodular lesions in peripheral soft tissue or skin Followed by retroperitoneum Subset of cases a/w lymphangiomatosis Most patients in the first two years Has been reported in adults
Microscopic features Plexiform mass of lobules separated by fibrous septa Capillary hemangioma-like areas alternating with spindle cells Spindle cells slit-like lumina with mild atypia and few mitoses Glomeruloid structures characteristic Small vessels surrounded by pericytes and hyaline globules At the periphery striking lymphatic proliferation with ectatic vascular spaces
Immunohistochemistry Endothelial cells express CD31, CD34 and ERG SMA highlights the pericytes Lymphatic markers (VEFG3, D2-40, Prox1) are positive both in the lymphatic channels at the lobule periphery and spindle cells GLUT1 is negative
Prognosis May show regional perinodal soft tissue involvement Not been reported to produce distal metastases Can be infiltrative and retroperitoneal cases can extensively infiltrate surrounding organs Can induce Kasabach-Merritt Syndrome Thrombocytopenia and consumption coagulopathy Related to tumor size and location 10% lethal secondary to KMS complications
D2-40
Papillary Intralymphatic Hemangioendothelioma (PILA) Aka Dabska tumor Closely related to retiform hemangioendothelioma Most in infants and children Some cases congenital Up to 25% in adults Single slowly growing nodule or plaque Most cases skin and superficial tissue of head and neck, trunk or extremities
Microscopic features Numerous and dilated, thin-walled lymphatic like spaces line by bland hobnail endothelial cells Intravascular papillae lined by hobnail endothelial cells as well Papillae containing a collagenous core Mononuclear inflammatory component may be present Usually not prominent
IHC Immunophenotype that resembles normal lymphatic endothelium CD31, CD34, ERG VEGFR3, podoplanin Lack of actin-positive cuff of pericytes
Retiform Hemangioendothelioma Superficially located, mainly occurs in adults Elongated-shaped vessels resembling rete testis Similarly to PILA lined by hobnail endothelial cells and a/w lymphocytes Intravascular papillary projections absent or very few Closely related to PILA Hobnail Hemangioendotheliomas
Epithelioid sarcoma-like/pseudomyogenic hemangioendothelioma Typically young adults with marked male (4:1) predilection Rare soft tissue of intermediate biological potential Propensity for local recurrence or frequent (and characteristic) development of additional nodules in the same region Metastasis is rare Conservative management is the mainstay of therapy
Radiologic findings Diagnostic Pathology: Soft Tissue Tumors 2nd Ed 2015, Elsevier
Microscopic findings Histopathology 2016 May;68:776-95
Immunohistochemistry POSITIVE CKAE1/3 ERG CD31 (variable) AE1/AE3 NEGATIVE CD34 INI-1 (SMRCB1) is retained AE1/AE3 INI1 CD31 ERG
Other Differential Diagnosis Spindle cell squamous cell carcinoma Cellular benign fibrous histiocytoma Smooth muscle neoplasms Epithelioid Hemangioendothelioma
Molecular Recurrent balanced translocation t(7;19)(q22;q13) Fusion of SERPINE1 and FOSB genes To date this translocation has not been identified in other soft tissue tumors
WHO 2013 definition Locally aggressive, rarely metastasizing vascular neoplasm, containing an admixture of histologically distinct components Chiefly in adults Composite Hemangioendothelioma Very rare pediatric or congenital cases Predominantly skin and superficial soft tissues High rate of local recurrence (50%) Low risk of lymph node (6%) or distant metastases(1%)
CD31 Synaptophysin
D2-40 Synaptophysin
Malignant Vascular Tumors
Epithelioid Hemangioendothelioma (EHE) and CAMTA1 Rare low-grade, malignant vascular neoplasm that shows endothelial differentiation Less aggressive than angiosarcoma Risk of metastasis in ~ 20-30% of cases Death in approximately 15% of cases
Clinical Features Affects patients of all ages but rare during childhood Typically solitary lesion on the extremities Can involve larger preexisting vessels Multiple cutaneous nodules!!!!metastasizing deep soft tissue or osseous EHE should be ruled out!!!!
Microscopic findings Diagnostic Pathology: Vascular 2016 Elsevier
Immunohistochemistry POSITIVE CD31 CD34 ERG AE1/AE3 in 25% of cases NEGATIVE S100 protein Desmin EMA CD31
Molecular Recurrent translocation t(1;3)(p36;q25) involving WWTR1 (3q25) and CAMTA1 (1p36) Approximately 90% of EHE with classic morphology and not identified in histologic mimics A subset shown to harbor YAP1-TFE3
CAMTA1
TFE3 TFE3 is a member of the microphthalmia (MiT) family of transcription factors, which includes MiTF, TFEB, TFEC, and TFE3 Although TFE3 is ubiquitously expressed in humans, native TFE3 protein is usually not detected by routine immunohistochemical methods
TFE3 Alveolar soft part sarcoma Xp11 translocation renal cell carcinoma melanotic Xp11 translocation renal cell carcinoma A subset of PEComas Epithelioid hemangioendotheliomas
Antonescu et al, Genes, Chromosomes and Cancer 52, 772-784, 2013
CD31 TFE3 CAMTA1
Angiosarcoma Angiosarcoma arises in four typical clinical settings: Chronically sun-damaged skin, particularly the scalp or face Sporadic visceral angiosarcoma In the setting of chronic lymphedema (eg, after mastectomy in Stewart-Treves syndrome) In areas of prior therapeutic radiation, such as for the management of breast carcinoma.
Atypical vascular proliferations, which have been described under various nomenclature designations, occur in areas of prior radiation In some cases may be difficult to distinguish from vasoformative angiosarcoma.
MYC MYC proto-oncogene is a transcription factor located on the long arm of chromosome 8 (8q24.21) Nuclear expression of MYC occurs in the vast majority of secondary angiosarcomas Only very rarely seen in primary angiosarcoma Not detected in atypical or benign vascular lesions occurring in irradiated skin.
Angiosarcoma FISH MYC
Angiosarcomas Case 1 Case 2
Atypical Vascular lesion (AVL)
Conclusion MYC immunohistochemistry is therefore useful in differentiating atypical or benign vascular lesions occurring in irradiated skin from secondary postradiation angiosarcomas.
CD31 ERG
Email: Konstantinos.Linos@hitchcock.org @ @ KonstantinosLin