Soft Tissue Special Issue: Perivascular and Vascular Tumors of the Head and Neck
Perivascular and vascular neoplasms of the head and neck are a rare group of tumors comprising a spectrum of clinical/biologic and histological features. They are frequently diagnostically challenging, due to their morphologic and immunohistochemical overlap. In this review, we summarize the pathology of these neoplasms, discussing morphology, immunohistochemistry, associated genetic findings, and the differential diagnoses.
KeywordsPerivascular neoplasms Hemangioma Vascular malformations Angiosarcoma Hemangioendothelioma
Perivascular tumors in the head and neck region are benign, and comprise myofibroma/myopericytoma, angioleiomyoma, nasopharyngeal angiofibroma, sinonasal glomangiopericytoma/sinonasal-type hemangiopericytoma and more rarely glomus tumor.
Although the differential diagnosis includes other myofibroblastic lesions (e.g. desmoid-type fibromatosis, nodular fasciitis, infantile fibrosarcoma) and deep benign fibrous histiocytoma/cellular dermatofibroma, the typical biphasic pattern and the myxohyaline matrix of myofibromas is not observed in these lesions and genetic changes are different (desmoid: beta-catenin mutations; nodular fasciitis: USP6-rearrangements, infantile fibrosarcoma: ETV6-NTRK3 fusion) .
Angioleiomyoma is a relatively uncommon benign lesion consisting of prominent mainly thick-walled vessels intermingled with surrounding smooth muscle cells. It forms a morphological spectrum with myofibroma and myopericytoma and arises usually in skin and subcutis. Occurrence in the head and neck is rare with an incidence of up to 13% with variable sites, e.g. intraoral, salivary glands and sinonasal. Adults are mainly affected. Lesions can be painless, tender or painful. Grossly, they are polypoid, nodular and sharply demarcated with a whitish trabecular cut surface with sponge-like areas with blood. Histologically, well-differentiated smooth muscle cells are intimately associated with a prominent thick-walled vascular component with a concentric layer of smooth muscle. The lumina can be collapsed or dilated. Mitotic figures are usually absent. Nuclear atypia, myxoid changes, calcification, ossification and fatty metaplasia can be present in longstanding regressive lesions [7, 8, 9, 10]. One peculiar angioleiomyoma in the lymph node hilus usually occurs in the neck . Immunohistochemical expression of smooth muscle markers as SMA, desmin and caldesmon is typically observed. Simple excision is the adequate therapy [7, 8, 9, 10]. Myopericytoma could be a differential diagnosis but belongs to the same spectrum. EBV-associated smooth muscle tumors may, as common smooth muscle tumors, mimic angioleiomyoma but these rare lesions are characteristically multifocal and affect patients with immunodeficiency. A prominent vasculature is not expected. Ebstein-Barr Virus is detectable by in situ hybridization. Lesions with adipocytic metaplasia could be confused with the very rare angiomyolipomas belonging to the PEComa group. Melanocytic markers as HMB45 and Melan A can help to make a distinction .
Nasopharyngeal Angiofibroma (JNA)
(Juvenile) nasopharyngeal angiofibroma (JNA) is an uncommon benign fibrovascular lesion originating in the nasopharyngeal region of mainly male adolescents and young adults aged between 14 and 25 years. Women and older patients are rarely affected [11, 12, 13]. JNA involves the nasopharynx and dorsolateral aspect of the nasal cavity. Although morphologically benign it can cause destructive involvement of the paranasal sinuses, orbit and skull base with intracranial extension [12, 13]. Symptoms are commonly obstruction and epistaxis. Individual cases have been associated with familial adenomatous polyposis [12, 14]. Recurrences after surgery are reported in up to 57% of cases .
Sinonasal Glomangiopericytoma/Sinonasal-Type Hemangiopericytoma (s-HPC)
These mesenchymal lesions of low-biologic potential occur exclusively in the nasal cavity and paranasal sinuses. Middle-aged adults of either sex are mainly affected. Patients typically present with nasal obstruction and epistaxis [2, 15, 16]. Surgery is the treatment of choice, with recurrences reported in a small number of patients .
A variety of neoplasms enter the morphological differential diagnoses: solitary fibrous tumor can be discriminated by its random or patternless architecture, more tapered nuclei and a variable collagenous background. Nuclear expression of STAT6 due to a NAB2-STAT6 fusion gene is a consistent finding of SFT. Monophasic synovial sarcoma typically shows higher cellularity, with cells disposed in long fascicles. A staghorn-like vasculature may also be present. Synovial sarcoma focally expresses a range of keratins and/or epithelial membrane antigen (EMA) and harbor a specific fusion gene (SS18-SSX1/2). Malignant peripheral nerve sheath tumor (MPNST) has a variety of morphological appearances, but many are typically also arranged in long fascicles, classically with perivascular cuffs. The cells of MPNST typically show at least focal variable pleomorphism and atypia. Focal positivity for SOX10, S100 and GFAP may help in the diagnosis . Loss of H3K27me3 is substantial in high-grade MPNST, and is therefore useful in the diagnostic work-up . Low-grade biphenotypic sinonasal sarcoma shows rather elongated overlapping nuclei, and neural (S100) and myogenic (SMA, desmin, myogenin, myoD1) immunohistochemical features. Nuclear positivity for PAX3 reflects the presence of a fusion gene involving typically PAX3 [20, 21].
Glomus tumors are rare lesions that occur only exceptionally in the head and neck region, and should not to be confused with paraganglioma, which is often located in the carotid, vagus or middle ear region, for which the term glomus tumor was previously used. The age distribution of glomus tumor is broad, although adults are mainly affected. Presenting symptoms depend on the anatomic site, which includes the oral cavity, larynx and neck [22, 23, 24].
Most glomus tumors behave in a benign fashion, and simple excision is the treatment of choice, with only rare recurrences described .
Histologically, these nodular lesions typically comprise uniform glomus cells arranged in sheets surrounding small capillaries. The glomus cells are rounded with a centrally placed nucleus, abundant amphophilic cytoplasm and distinct cell borders. Symplastic glomus tumors show marked atypia without mitotic activity (ancient features), while very rare malignant cases additionally show mitotic figures. SMA is strongly expressed, with accentuation of cell borders [24, 25]. Approximately 50% of glomus tumors harbor a MIR143-NOTCH gen fusion .
Glomus tumors are quite distinctive. Epithelial lesions can be excluded by keratin immunohistochemistry.
Benign Vascular Lesions (Vascular Anomalies)
Distinction between angiomas and vascular malformations as defined by the ISSVA (International Society for the Study of Vascular Anomalies) is encouraged to enable better understanding of lesions etiology, biology and clinical behavior with the aim of improving therapy and patient outcome .
Vascular tumors arise by clonal cellular proliferation of vessels showing a disproportionate growth. In contrast, vascular malformations develop in utero as a result of mosaic mutations leading to erroneous development of (mostly heterogeneous) vessels with proportionate growth [27, 28].
The term (capillary) hemangioma does not function well as a stand-alone diagnosis. Instead, pathologists and clinicians should modify this interpretation, indicating specific entities (e.g. infantile hemangioma, non-involuting congenital hemangioma, epithelioid hemangioma, tufted hemangioma) .
Infantile Hemangioma (IH) (Juvenile Hemangioma, Cellular Hemangioma)
These are the most common tumor of infancy, affecting approximately 4% of children with most lesions arising in the skin of the head and neck [27, 28, 30]. Females are more commonly affected. Lesions are not present at birth, but a small purple area is often a precursor lesion [28, 30] Lesions become apparent at 3 to 7 weeks of age proliferating for an average of 3 to 5 months. Involution then occurs over several years, with a variable fibrofatty residuum. IH can arise superficially and/or deeply. Whereas superficial lesions are elevated, those that are deep seated form a mass. There are three distinct morphological patterns: solitary, segmental/diffuse, or multifocal with a considerable variation in size. A biopsy is rarely required due to a clear clinical diagnosis in most cases [28, 30]. Although all IH involute spontaneously over a period of years, significant cosmetic and, in some cases, functional sequelae may occur as ulceration, bleeding, infection, airway obstruction, amblyopia, disfigurement and rarely congestive heart failure [28, 31]. Treatment options are propranolol (first-line), and less common corticosteroids (intralesional or systemic) or surgery [26, 30, 31].
Congenital Hemangioma (CH): Rapidly Involuting (RICH), Partially Involuting (PICH), or Non-involuting (NICH)
Congenital hemangiomas are rare. Although they resemble classic infantile hemangioma, they are now recognized as a pathogenetically distinct lesion. CH manifests in utero/at birth and can affect the head and neck region. They can regress rapidly (more rapidly than IH) usually within a year, with a lipatrophic end-stage or they persist (NICH). Their histomorphology is similar to IH. However there are few mitotic figures, and a sclerotic stroma surrounding the lobules. The intraneural infiltration seen in IH is not a feature of CH and is a useful discriminating morphological feature. Additionally GLUT1 is negative [26, 31]. Somatic activating mutations in GNAQ and GNA11 were consistently found . Treatment is only required in case of persistence, for cosmetic reasons .
Pyogenic Granuloma (Lobular Capillary Hemangioma)
This is a common, acquired vascular tumor with an estimated prevalence of 0.5–1% mainly affecting middle-aged adults. It often occurs in the head and neck, most commonly in the lip and oral cavity. These vascular papules or polyps have a diameter of up to 1.5 cm, and ulcerate and bleed due to minor trauma. Histologically, lesions are superficially located. The surface is commonly ulcerated with granulation tissue. The lesions are circumscribed capillary proliferations, with a lobulated architecture, often adjacent to larger vessels. The endothelium shows slightly enlarged, plump nuclei without atypia, and mitotic figures can be seen, and may be numerous. Endothelial cells and a continuous outer layer pericytes are immunohistochemically highlighted by vascular markers (CD31, CD34, ERG) and SMA, respectively. The lobules are surrounded by thick bands of fibrous tissue. Neutrophils are often present. Pedunculated lesions can be ligated, while other forms are best treated surgically [20, 26, 31].
Epithelioid Hemangioma (EH) (Synonym: Angiolymphoid Hyperplasia with Eosinophilia)
Genetically, EH harbor FOS and FOSB rearrangements, although these findings are very rare in the superficially located head and neck cases and analyses are not very helpful in this respect [35, 37, 38].
Spontaneous regression has been documented, however, circa 30% of cases recur locally. The optimal treatment is complete excision .
Epithelioid Angiomatous Nodule (EAN)
EAN is a benign cutaneous lesion in the spectrum of epithelioid vascular proliferations. Middle-aged adults are mainly affected with an age range from 15 to 79 years. Lesions are rarely described in the head and neck region, with most frequent occurrence in the face and nasal mucosa. Histologically, these are well-circumscribed nodular neoplasms typically present intradermally or intramucosally, although extension into subcutis/submucosa is possible. There is a sheet-like proliferation of epithelioid cells containing abundant eosinophilic cytoplasm. Vascular channels are always present and may be very subtle with the presence of intracytoplasmic lumina. The nuclei display vesicular chromatin and prominent nucleoli. Vessels adjacent to the lesion are dilated. There is hemosiderin deposition and an inflammatory reaction. Endothelial markers are expressed immunohistochemically with SMA highlighting the pericytic layer of the vascular channels. EAN may easily be mistaken for a malignant lesion (epithelioid hemangioendothelioma or epithelioid angiosarcoma). However EAN is well-circumscribed, and shows no cytologic atypia in contrast to these malignant neoplasms, particularly angiosarcoma [37, 39]. CAMTA1 immunohistochemistry or detection of the typical fusion genes of EHE can also help to discriminate EAN from EHE . Negativity for FOSB suggest possibly a distinct pathogenesis from epithelioid hemangioma . Simple excision is the treatment of choice [37, 39].
Vascular malformations may contain venous, capillary, lymphatic or arterial components in any combination and are associated with overgrowth syndromes [26, 41]. Due to mosaic somatic mutations that arise during embryogenesis, or more rarely germ-line mutations, developmental errors occur in the vascular system. These lesions grow slowly and proportionately with the overall growth of the child, and persist throughout life. Histopathologic distinction from hemangioma can be difficult without patient history, and reactive changes such as vascular ectasia, recruitment of collateral vessels, organizing thombi, hormonal or angiogenic modulation, neovascularization in response to abnormal hemodynamics and signs of regression can blur the typical features. Additionally, differing terminology can cause confusion . Of note, the endothelium of vascular malformations does not express GLUT1, which is characteristic for infantile hemangioma [26, 42]. WT1 immunohistochemistry can be helpful in discriminating vascular neoplasms from malformations with absence of cytoplasmic staining in lymphatic, venous and capillary malformations . Mutationally affected genes include PIK3CA, TEK (TIE2), AKT, GNAQ, GNA11, KRAS, NRAS, PTEN and RASA .
Cutaneous Capillary/Venulocapillary Malformations (Port-Wine Stains)
These lesions arise in the skin, and can be focal or multifocal, consisting of mature capillaries and venules with sometimes extension into subcutis. The vessels are rounded, and lined by elongated endothelial cells and pericytes. There is no mitotic activity. The vessel walls become fibrous and loosely organized smooth muscle fibers are present .
Venous Malformation (VM)
VMs are characterized by abnormal collections of veins, that are superficial or deep, diffuse or localized, and solitary or multiple. Veins show a variable diameter and a variable thick smooth muscle layer, absence of an internal elastic membrane, and inconspicuous endothelium. Small venules or capillaries may also be present. Thrombi and phleboliths with signs of recanalization (Masson lesions) are relatively common. The latter can be confused with malignancy .
Glomuvenous Malformation (GVM) (Synonym: Glomangioma)
This is a frequently multifocal neoplasm occurring in infants, children and adolescents. It accounts for 10% to 20% of all glomus cell lesions. GVMs are superficially located and often disseminated over a large cutaneous area showing multiple to confluent red-blue nodules. GVMs are less painful when compared with adult-type glomus-tumors. The expansion of the lesion makes surgery less amenable and subtotal resected lesions may progress. Laser and sclerotherapy may be helpful. Histologically it resembles a venous malformation with dilated veins surrounded by layers of glomus cells, and sometimes with organized thrombi .
GVMs are associated with mutations in the GLMN gene, which can be seen in both sporadic or hereditary cases .
Arteriovenous Malformation (AVM)
AVMs are usually present at birth showing a significant arteriovenous shunting with raised skin temperature and pulsation. Hemorrhage and ischemia due to arterial steal are relatively common. Deep-seated lesions may become apparent at later age when shunting is low-grade. The histologic appearance of AVMs often varies, with arterioles, capillaries and venules present within a densely fibrous or fibromyxoid background, intermixed with numerous larger-caliber arteries and thick-walled veins. The arteries are often tortuous and the veins demonstrate intimal and adventitial fibrosis. Occasionally scattered dilated lymphatics may be present. The involved skin may show pseudoangiosarcomatous proliferation of small vessels probably due to arterio-venous shunt-related tissue ischemia .
Lymphatic Malformation (LM) (Lymphangioma)
LMs originate commonly in skin and subcutis, and more rarely in soft tissue or viscera with localized/regional growth or diffuse involvement of many tissue planes or organ systems. Most LMs are present at birth or within the first 2 years of life, commonly when superficially located. They are often associated with significant overgrowth of soft tissue (and bone). Localization of LM in the tongue/oropharynx can cause airway obstruction. LMs can be divided into macro- and microcystic or combined lesions, depending on the cyst diameter with a cut-off of 0.5 cm. Whereas microcystic forms occur anywhere in the body, the macrocystic LMs most frequently arise in the neck, axilla, chest wall or groin. Macrocystic forms rarely regress spontaneously. Surgery, sclero- and lasertherapy are treatment options.
Microscopically, microcystic LMs consist of dilated small angular to rounded vessels, lined by flattened endothelium and rimmed by rare pericytes and little or no smooth muscle. The cysts are filled with clear fluid and small numbers of lymphocytes and in traumatized lesions with blood. LMs can include preexistent structures appearing free-floating. Macrocystic LMs possess valves, show thicker irregular coats of smooth muscle and/or fibrous tissue. Organized thrombi due to vessel wall injury or communication with the venous system may be present; this makes it difficult to distinguish veins from lymphatic structures suggesting a venous LM (see below). D2-40 staining of lymphatics helps to discriminate, while CD34 is mainly negative. Lymphoid aggregates are common .
Venous-Lymphatic Malformation (VLM)
These low-flow malformations occur in Klippel–Trenaunay-Syndrome and sporadically. The histology variably combines features of VM and LM. When superficially located, an angiokeratoma-like lesion may be seen .
Malignant Vascular Tumors
The anastomosing vascular channels are ill-defined and diffusely dissect the dermal collagen when arising in the skin. A sieve-like architecture is a common feature. The atypical endothelial cells are usually multilayered, with enlarged, hyperchromatic nuclei and often prominent nucleoli. High-grade areas contain solid nests or sheets of tumor cells with spindle cell or epithelioid morphology with occasional intracytoplasmic lumina. Blood-filled spaces, high mitotic rate and necrosis are more often seen in less-differentiated tumors . The most reliable immunohistochemical markers are CD31 and ERG with use in combination, while CD34 is variably present. Expression of keratins, partially observed in epithelioid AS should not be confused with carcinomas [48, 49, 50]. Of note, CD31 and ERG (own observation) can exceptionally be positive in atypical fibroxanthoma, which could be a diagnostic pitfall . Genetically, various abnormalities have been described, including complex karyotypes, amplifications, mutations and fusion genes underpinning that AS constitutes a heterogeneous group of neoplasms [38, 52]. MYC amplification with expression of the corresponding protein is predominantly seen in cases secondary to radiation or UV-damage in contrast to primary angiosarcomas being rarely MYC amplified [38, 52, 53].
Epithelioid Hemangioendothelioma (EHE)
EHE is a translocation-associated malignant endothelial neoplasm with a wide age distribution, although children are rarely affected. It may arise at any anatomic site including the head and neck region. Bone may be involved primarily or secondarily. There is a propensity for lymph node metastases and very rarely, a lymph node can be the site of origin [34, 54, 55, 56].
Clinical behavior and prognosis depend on the primary site. Surgery is the treatment of choice in local disease. There is a risk of metastatic disease (synchronic or metachronic) and a significant mortality rate (up to 45%) [58, 59, 60].
Vascular Tumors of Intermediate Malignancy
Pseudomyogenic Hemangioendothelioma (PHE) (Synonym: Epithelioid Sarcoma-Like Hemangioendothelioma)
This distinct vascular tumor rarely occurs in the head and neck region. It mainly develops in young adults with male predominance. Lesions originate superficially and/or deeply with multifocal/multicentric disease in two-thirds of patients, with possible involvement of multiple tissue planes. The lesions recur locally after surgical treatment. Nodal and distant metastases have been rarely reported [50, 61, 62].
Immunohistochemistry shows variable positivity of CD31 and strong expression of ERG. In contrast to epithelioid sarcoma, which also may express ERG, EMA and CD34 are negative. INI1 absent in epithelioid sarcoma is retained in PHE. Keratin AE1/3 is diffusely positive while other keratin-cocktails are negative [50, 61, 62]. Strong and diffuse nuclear staining of FOSB is due to FOSB rearrangement . SERPINE1 and ACTB are the known fusion partners [38, 63, 64, 65]. Rhabdomyoblastic/myoid tumors and inflammatory myofibroblastic tumors do not express vascular markers .
Kaposiform Hemangioendothelioma (KHE)/Tufted Hemangioma (TA)
TAs are composed of lobules of capillaries arranged in a cannonball pattern within the dermis and possibly subcutis variably surrounded by a desmoplastic stroma. The capillaries are tightly packed, similar to the arrangement seen in KHE. Peripherally there are larger thin-walled vessels. Endothelial cells are spindled, as in KHE. Microthrombi may be present .
Vascular markers (CD31, CD34 and ERG) are positive in both lesions, and D2-40 and PROX1 are also expressed .
Reported genetic changes are scarce with GNA14 mutations described in one case each of KHE and TA . However, GNA14 mutations are also reported in congenital hemangioma, hepatic small vessel neoplasm and anastomosing hemangioma which are potential differential diagnoses [72, 73, 74]. The architecture of TH and KHE are unique and hemangiomas have a pericytic layer around the endothelial cells. Whether kaposiform lymphangiomatosis is part of KHE needs further clarification . Spindle cell hemangioma (SCH) shows a vague resemblance to KHE but the prominent cavernous component of SCH is absent in KHE. Furthermore SCH is typically located on the extremities and harbors and IDH1/2 mutation [68, 69, 76].
Treatment with sirolimus has been shown to be successful. Surgery of KHE is often unattainable due to extent of the lesion. Single and combination chemotherapy have been used to treat KHE patients. Local excision of TAs is adequate .
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
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