Vascular Neoplasms and Neoplastic-Like Proliferations

Introduction

Masson first described this process in 1923 in hemorrhoidal veins, terming it hemangio-endotheliome vegetant intravasculaire , and interpreted it as a neoplastic process mimicking angiosarcoma. In 1932, Henschen re-interpreted the process as reactive, and in 1971 Kauffman and Stout noted its occurrence not only in thrombosed vessels but also in a hematoma, further demonstrating the potential for confusion with soft tissue angiosarcoma. A lymphatic vessel counterpart of Masson's lesion was reported in 1979 in a cystic lymphatic malformation .

Epidemiology

Papillary endothelial hyperplasia (PEH) shows a slight female predominance, most pronounced for the rare extravascular examples . Although lesions can occur at any age, most are in adults, with an average age of 34 years. A history of trauma is elicited in a small minority of patients .

Pathogenesis

Areas of papillary endothelial hyperplasia can, in most cases, be seen to merge with definitive thrombus material, in support of the notion that they represent an unusual form of thrombus organization.

Clinical features

Primary lesions of superficial tissues appear as solitary, firm masses, often with red or blue discoloration of the overlying skin or mucosa. The history is typically one of slow growth over a period of several months or years. These occur most commonly within veins of the head and neck and, interestingly, the fingers, but they may also arise elsewhere . In a study of 314 cases, 56% were of the primary form, 40% were associated with other vascular lesions, and 4% appeared extravascularly . Clinical features of the secondary forms are those of the underlying vascular anomaly.

Pathology

Intravascular examples may be limited to the confines of a single thin-walled vein or may arise, often multifocally, within pre-existing vascular lesions such as venous malformations, glomuvenous malformations, spindle cell hemangiomas, and pyogenic granulomas ( Fig. 114.2 ). Foci of intravascular PEH are extremely common in venous malformations and serve to distinguish these low-flow lesions from high-flow arteriovenous malformations. Rarely, the involved vessel wall is ruptured, allowing the proliferative vascular process to spill out into the adjacent stroma. Extravascular examples that on serial sectioning show no evidence of a surrounding blood vessel wall may have arisen within an organizing hematoma .

Early lesions show growth of endothelial sprouts into fibrinous thrombus material, dividing it into papillary fronds lined by a single layer of plump endothelial cells with minimal mitotic activity and no significant cytologic atypia ( Fig. 114.2 , inset). The early fibrin cores of the papillae become collagenized and hyalinized with time, and the endothelial lining becomes thin and attenuated. Lesional papillae may fuse to form an anastomosing meshwork of vessels separated by connective tissue stroma that mimics angiosarcoma. However, the relatively high mitotic rate, striking pleomorphism, and necrosis that characterize angiosarcoma are lacking .

Differential diagnosis

The clinical appearance of these lesions is nonspecific, and diagnosis relies on microscopic examination. The most important consideration for the pathologist is well-differentiated angiosarcoma.

Treatment

Surgical excision is usually curative. Local recurrences may occur when the lesion is superimposed on a vascular malformation that may generate new foci of endothelial hyperplasia.

Introduction

Angioendotheliomatosis has historically been considered to be a single disease entity, divided into benign and malignant variants. As such, the large pleomorphic cells found within blood vessels in malignant angioendotheliomatosis were thought to be transformed endothelial cells. However, immunohistochemical studies have convincingly demonstrated that these cells are neoplastic lymphocytes. Accordingly, malignant angioendotheliomatosis has been renamed intravascular large cell lymphoma (B or NK/T) (see Ch. 119 ). The benign form is a true angioendotheliomatosis and is considered reactive.

Epidemiology

Reactive angioendotheliomatosis is rare and although it can occur at any age, the age of onset often reflects that of any associated systemic disorder. While many cases are idiopathic, this vascular proliferation is associated with systemic disorders such as bacterial endocarditis, monoclonal gammopathies (including type I cryoglobulinemia), antiphospholipid syndrome, renal transplantation, hepatic disease, and rheumatoid arthritis. The diffuse dermal angiomatosis variant occurs most commonly on the leg or the breast and is associated with atherosclerosis, cigarette smoking, and large pendulous breasts.

Pathogenesis

Reactive angioendotheliomatosis is a benign self-limited process. Its frequent association with various systemic conditions has led some investigators to propose that the capillary proliferation may be caused by a circulating angiogenic factor . However, the fact that many of the disorders associated with this process cause vascular occlusion or tissue ischemia suggests that a local, hypoxia-induced increase in vascular endothelial growth factor (VEGF) may be playing a role. In addition, immunological factors may contribute to the proliferative process.

Clinical features

Although erythematous nodules or plaques, often with superimposed petechiae or ecchymoses, are the characteristic primary lesions, the spectrum ranges from erythematous macules to tumor-like masses. Sites of involvement can vary, but the most common is the lower extremities. Focal ulceration may be evident, especially in the diffuse dermal angiomatosis variant (see Fig. 105.20 ).

Pathology

In this predominantly dermal, but also occasionally subcutaneous, process, there is a poorly marginated proliferation of closely packed capillaries lined by plump endothelial cells rimmed by small numbers of pericytes. The pattern of proliferation is highly variable both within and between lesions and is typically described as diffuse and/or lobular . Focally, more dilated capillaries may be present and foci of hemosiderin deposition, fibrin microthrombi, and/or mild chronic inflammation are relatively common. Immunohistochemical positivity for endothelial markers such as CD31 and von Willebrand factor, and focally for pericyte/smooth muscle-associated actins, confirms the cellular composition. Cytologic atypia is absent and mitotic figures are rare to absent.

The capillary lumina are small and may be occluded by fibrin thrombi and bulging endothelial cells ( Fig. 114.3A ). In many cases, the proliferating capillaries appear to be contained within a larger, pre-existing vessel, obliterating its lumen, but sometimes the proliferation extends directly between collagen bundles ( Fig. 114.3B ). Cases associated with cryoglobulinemia typically show intraluminal and intracellular eosinophilic globules, but this finding can also be seen in the absence of cryoglobulinemia.

Differential diagnosis

The clinical differential diagnosis includes vascular tumors (e.g. Kaposi sarcoma, angiosarcoma) as well as other causes of ulceration (see Fig. 105.1 ). Histologically, one must consider other forms of intravascular endothelial proliferation, including intravascular pyogenic granuloma, papillary intralymphatic angioendothelioma, and intravascular PEH. Intralymphatic histiocytosis can be distinguished by the presence of CD68-positive histiocytes within dilated lymphatic vessels.

Treatment

Evaluation for known associated systemic disorders is important because lesions may regress upon resolution of the underlying condition, e.g. revascularization of an ischemic limb. In case reports, oral isotretinoin has led to improvement, possibly due to its antiangiogenic properties .

Introduction

Angiokeratomas are well-circumscribed vascular lesions consisting of superficial vascular ectasia and hyperkeratosis. Five variants have been recognized. With the exception of angiokeratoma circumscriptum (which represents a capillary–lymphatic or capillary malformation), angiokeratomas result from ectatic dilation of pre-existing vessels in the papillary dermis.

Clinical features

Solitary or multiple angiokeratomas

Most commonly, they present as a small, warty, black papule on the lower extremities, but may occur anywhere on the body ( Fig. 114.4 ). The lesions are thought to result from injury to or chronic irritation of the wall of a venule in the papillary dermis. Solitary lesions may be confused with melanoma due to their dark color. Dermoscopy will readily distinguish between these two entities (see Ch. 0 ).

Angiokeratomas of the scrotum and vulva

Synonym

▪ Angiokeratoma of Fordyce

These angiokeratomas may arise in the second or third decade but are most commonly seen in older age groups. The lesions are red–purple to black in color, may be single or multiple, and arise along superficial vessels ( Fig. 114.5 ). In some patients, they may be associated with thrombophlebitis, varicoceles, and inguinal hernias. Vulvar lesions may be associated with vulvar varicosities, hemorrhoids, oral contraceptive use, or increased venous pressure during pregnancy.

Angiokeratoma circumscriptum

This entity usually develops during infancy or childhood as either a plaque of multiple discrete papules ( Fig. 114.6 ) or hyperkeratotic papules and nodules that often become confluent. They occur on the trunk, arms or legs and are unilateral in most patients. There is a female predominance.

Pathology

Marked dilatation of the papillary dermal vessels is seen in association with an acanthotic, variably hyperkeratotic epidermis. Elongated rete ridges may partially or completely enclose vascular channels, and a collarette may be present at the margin of the lesions. In Fabry disease, vacuoles can be detected within endothelial cells and pericytes. The amount of glycolipid is small and may be difficult to detect in routinely prepared sections. However, the deposits stain positively with PAS and anti-GB3 antibody. They can also be demonstrated by electron microscopy.

Differential diagnosis

Clinically, angiokeratomas should be distinguished from other vascular lesions as well as acral pseudolymphomatous angiokeratomas (see Ch. 121 ). Darkly colored or thrombosed angiokeratomas may resemble cutaneous melanoma.

Treatment

Patients may request removal for cosmetic reasons. This may be achieved by shave excision, diathermy or laser therapy, the choice of which would largely depend on the size of the lesion.

Introduction and history

The original description in 1988 coined the term targetoid hemosiderotic hemangioma to emphasize the targetoid clinical appearance and hemosiderin deposition. Since then it has become apparent that only a minority of these lesions have an ecchymotic halo and hemosiderin deposition is variable. The term hobnail hemangioma was proposed to encompass lesions with the characteristic biphasic growth pattern and marked hobnail endothelial morphology, with or without a targetoid clinical appearance and/or marked hemosiderin deposition . A benign clinical course has been observed in the over 100 cases that have been reported to date . Recently, this “hemangioma” was reclassified as a targetoid hemosiderotic lymphatic malformation (THLM) .

Epidemiology

There is no gender predilection . In a series of 62 patients, their ages ranged from 6 to 72 years (median, 32 years) .

Pathogenesis

This vascular anomaly was thought to represent the benign end of a spectrum of vascular tumors that have hobnail endothelial cells and which includes papillary intralymphatic angioendothelioma (PILA) and retiform hemangioendothelioma (see Table 114.1 ) . However, the endothelial cells of THLM and PILA, but not retiform hemangioendothelioma, stain positively for several markers of lymphatic differentiation . In addition, the endothelial cells of THLM are generally negative for Wilms tumor-1 and have a low Ki-67 proliferation index. The latter explains its reclassification as a vascular malformation based upon International Society for the Study of Vascular Anomalies (ISSVA)-sanctioned restriction of the suffix “angioma” to intrinsically proliferative vascular tumors .

Trauma may stimulate the appearance of a THLM, with microshunts between small lesional blood vessels and adjacent lesional lymphatic vessels explaining the presence of erythrocytes within lymphatic vessels and hemosiderin deposits .

Clinical features

Most lesions are asymptomatic, solitary, well-circumscribed, red–blue to brown papules that are initially 2 to 3 mm in diameter and then slowly increase in size. In some cases, the papule is surrounded by a thin pale ring and then an ecchymotic halo ( Fig. 114.7 ). The ecchymotic ring may fade and eventually disappear over time, and some lesions undergo cycles of spontaneous regression and recurrence. Favored sites, in decreasing order of frequency, are the lower extremities, upper extremities, back, buttock/hip, and chest wall. Lesions have also been reported on the tongue and gingiva .

Pathology

There is a biphasic histologic pattern, consisting of: (1) dilated, thin-walled vessels containing small numbers of red blood cells and lined by prominent hobnail endothelial cells within the superficial dermis ( Fig. 114.8 ); and (2) smaller, more slit-like vessels that dissect between collagen bundles in deeper portions of the dermis. Extravasated red blood cells and hemosiderin deposits are common, but may be absent. Although the superficial vessels occasionally have delicate intraluminal papillary fronds, the more complex, multilayered endothelial tufts of PILA are lacking. The endothelial cells of both the dilated and the slit-like vessels stain positively for the lymphoendothelial markers VEGF-3 and podoplanin (see Ch. 102 ), but show little, if any, reactivity for the blood vascular marker CD34 .

Differential diagnosis

The clinical differential diagnosis includes melanocytic nevus, sclerosing hemangioma, and benign vascular neoplasms and proliferations in Table 114.1 . Histopathologically, it must be distinguished from patch-stage and lymphangioma-like variants of Kaposi sarcoma, well-differentiated angiosarcoma, retiform hemangioendothelioma, PILA, and microcystic lymphatic malformation.

Treatment

Treatment consists of simple excision. Longitudinal evaluation of 35 patients, ranging from 1 to 4 years, revealed no local recurrence or systemic metastasis .

Introduction and history

This rare, but increasingly well-recognized, vascular anomaly was originally thought to be a “hemangioma”, but has since been reclassified as a vascular malformation. The debate arose in part because these lesions may show evidence of cellular proliferation during their evolution . Mulliken and colleagues recommended use of the term verrucous venous malformation while others prefer the designation verrucous venulocapillary malformation, congruent with the predominant component vessels.

Epidemiology

There are no gender, racial or ethnic predilections.

Pathogenesis

Somatic missense mutations in the mitogen-activated protein kinase kinase kinase 3 gene ( MAP3K3 ) were detected in 6 of 10 verrucous venulocapillary malformations . The mutant allele frequencies ranged from 6–19% in affected tissue and these mutations were not found in unaffected tissue or other types of vascular anomalies. Of note, studies in MAP3K3 knockout mice had previously implicated MAP3K3 in vascular development.

Clinical features

Verrucous venulocapillary malformations are congenital and present as isolated, grouped or confluent red-to-purple papules. The vast majority occur on the distal extremities, particularly the leg ( Fig. 114.9A ) ; the trunk is a rare location . They progressively darken and become hyperkeratotic during childhood, often increasingly complicated by ulceration, bleeding, and scarring. They do not regress and are not associated with local tissue hypertrophy or other developmental anomalies.

Pathology

Features can vary with age, in particular the appearance of secondary orthohyperkeratosis and verrucous hyperplasia, but consistently there are dilated capillaries and venules (without a smooth muscle layer) within the papillary dermis and occasionally the investing dermis around adnexae. There is sparing of the reticular dermis, with the dilated blood vessels reappearing in the subcutis, where they are usually smaller in caliber, often grouped, and sometimes have intraluminal thrombi ( Fig. 114.9B ). The superficial dermal vessels are usually the most obviously dilated with expansion of the dermal papillae ( Fig. 114.9C ).

Endothelial cells consistently express markers of blood vascular differentiation, including CD31 and CD34. Focal positivity for lymphatic endothelial markers, e.g. Prox1, podoplanin, has been observed in some, but not all, studies . Mitotic activity is very low. Many verrucous venulocapillary malformations have light, focal immunoreactivity for GLUT1, in contrast to the intense endothelial GLUT1 positivity seen in infantile hemangiomas ; staining for CD15 and indolamine 2,3 deoxygenase is negative (personal observation).

Differential diagnosis and treatment

The differential diagnosis includes other venous malformations (see Ch. 104 ) and infantile hemangiomas. Therapeutic options include surgical excision and treatment of the superficial component with pulsed dye, long-pulsed Nd:YAG, and/or carbon dioxide lasers.

Introduction and history

Poncet and Dor are credited with the initial description in 1897, and they believed the cause was a Botryomyces infection. The term granuloma pyogenicum was coined in 1904 by Hartzell to describe four similar cases that he thought represented a nonspecific granulation tissue-type response to any type of pyogenic agent . Although the etiology of these common lesions remains uncertain, the term pyogenic granuloma is clearly a misnomer. There is no evidence to implicate any infectious agent, and the histologic appearance is not granulomatous.

Epidemiology

Pyogenic granulomas can develop at any age but are more common in children and young adults. There may be a slight male predominance, but no racial or familial predisposition. Gingival lesions are relatively common during pregnancy (see Ch. 27 ).

Pathogenesis

Pyogenic granulomas exhibit a number of clinical features suggestive of reactive neovascularization, including a common association with a pre-existing injury or irritation, limited capacity for growth, and a propensity for multiple eruptions that may be localized or disseminated. The occasional eruption of pyogenic granulomas within existing port-wine stains and other vascular malformations suggests that abnormalities in blood flow may be etiologically important in some cases.

Clinical features

The lesion presents as a solitary red papule or polyp that grows rapidly over the course of several weeks or months, stabilizes, and then may decrease in size ( Fig. 114.10 ). Its final size is rarely >1 cm, and it may persist indefinitely if not removed. Approximately one-third develop following minor trauma. In one series of 289 cases, the most common sites, in decreasing order of frequency, were the gingiva, fingers, lips, face, and tongue . They are extremely friable, frequently ulcerate, and may bleed profusely with minor trauma. Multiple satellite lesions occasionally develop near a primary pyogenic granuloma, usually after destruction of that lesion . Rarely, pyogenic granulomas arise within the subcutis, develop intravascularly, or erupt in a disseminated fashion . Pyogenic granulomas have been reported in association with systemic retinoids , indinavir, and BRAF and EGFR inhibitors, but in some cases this may represent excessive granulation tissue.

Pathology

The quintessential lesion is a well-circumscribed, exophytic, sometimes pedunculated, proliferation of small capillaries, often arranged in a lobular pattern ( Fig. 114.11 ). Lesional capillaries are lined by flattened to slightly plump endothelial cells, rimmed by pericytes, and surrounded by a variably edematous fibromyxoid interstitial stroma containing fibroblasts. Endothelial and stromal cell mitotic activity is highly variable and depends on the stage of growth; a scant infiltrate of lymphocytes, plasma cells, and mast cells may be present. Capillary lumina within the lobules vary from small and angular to branching and ectatic, and foci of thrombosis and intravascular PEH may be present. A few larger vessels with smooth muscle walls, usually venous (but often including a small ascending arterial feeder), are frequently present at the base of the lesion. Thick, intervening bands of dense fibrous tissue sharply define the lobularity and help distinguish pyogenic granuloma from other lobular forms of capillary proliferation such as infantile hemangioma.

The lateral margins are often defined by prominent epithelial “collarettes” resulting from peripheral adnexal hyperplasia or, in some cases, from downward growth of rete ridges, bridged by flattened epidermis. The histology of many early lesions is altered by ulceration and secondary inflammatory changes, leading to an appearance similar to granulation tissue, with radially oriented capillaries, fibrin deposition, and a loss of lobularity. Intravascular and subcutaneous forms demonstrate features similar to superficial lesions, but without the inflammatory complications. Late-stage lesions are characterized by increased intra lobular and inter lobular fibrosis, as well as quiescent, flattened capillary endothelia.

Differential diagnosis

The diagnosis of pyogenic granuloma can be made clinically if the red, bleeding papule is coupled with the characteristic location and history. Otherwise they can be easily confused with amelanotic melanoma and, in the immunosuppressed patient, bacillary angiomatosis or Kaposi sarcoma. Glomus tumors, hemangiomas, and irritated melanocytic nevi and warts can all mimic pyogenic granulomas. Histologic confirmation is always helpful in cases where the diagnosis is in question.

Treatment

Shave excision followed by electrosurgery of the base under local anesthesia is sufficient for most lesions. Patients and parents should be alerted to the possibility of recurrence after removal. Excision with suturing may result in less postoperative bleeding and a lower recurrence rate.

Pulsed dye laser has also been shown to be a safe and effective treatment for small pyogenic granulomas and may be particularly useful in children . There is a report of successful sclerotherapy in nine patients using monoethanolamine oleate, with inconspicuous scar formation and no recurrence .

Introduction and history

Cherry angiomas are the most common of the acquired cutaneous vascular proliferations. They can be unattractive and rarely when eruptive herald an underlying systemic abnormality.

Epidemiology

Both sexes are affected equally. Although they may occasionally develop during adolescence, cherry hemangiomas usually first appear during the third decade of life or later, and then increase in number over time. Most people over 60 years of age have one or more such lesions.

Pathogenesis

An increased number of cherry angiomas often appear during pregnancy and may involute in the postpartum period, suggesting that hormonal factors may be important in their pathogenesis. Two women with hundreds of eruptive cherry hemangiomas, both of whom had increased serum levels of prolactin, have also been reported . Most angiomas that appear in the setting of POEMS syndrome are cherry angiomas, often in association with glomeruloid hemangiomas.

Clinical features

Cherry angiomas are round to oval, bright red to purple, dome-shaped papules ranging in size from barely visible to several millimeters in diameter ( Fig. 114.12 ). Well-developed lesions may be polypoid. They most commonly develop on the trunk and proximal extremities and are rare on the hands, feet, and face. It is not unusual for elderly adults to have 50–100 cherry angiomas on their trunk. Rarely, a segmental distribution pattern, possibly reflecting mosaicism, is seen.

Patients are usually aware of the benign nature of these extremely common lesions and bring them to a physician's attention only when concerned about their appearance. They are generally asymptomatic, but may occasionally bleed when traumatized.

Pathology

Histologically, congested, ectatic capillaries and postcapillary venules are seen within the papillary dermis and superficial reticular dermis ( Fig. 114.12 , inset). Early lesions are characterized by small lumina and plump endothelial cells. With maturation, the vessels dilate and the endothelial cell cytoplasm flattens, often producing slightly hobnailed nuclei. Vessel diameter decreases with descent into the reticular dermis. There is loss of epidermal ridges centrally and peripherally adnexal epithelial collarettes are seen.

Differential diagnosis

The distinctive clinical and dermoscopic findings (see Ch. 0 ) limit other diagnostic considerations. Glomeruloid hemangiomas, although similar in clinical appearance, can be distinguished histologically. Tiny cherry angiomas may resemble petechiae.

Treatment

Patients may request removal of cosmetically undesirable or chronically traumatized cherry angiomas. This can be accomplished by shave excision, electrodesiccation or laser ablation, and recurrences are unusual.