Glomeruloid Hemangioma

Etiology

The exact pathogenesis of glomeruloid hemangiomas is uncertain, though several theories have been proposed.[7] Many investigators suggest that the development of these lesions may be driven by the overproduction of angiogenic cytokines and signaling molecules, such as vascular endothelial growth factor (VEGF), interleukins 6 and 1β, and tumor necrosis factor α.[8][9] Other theories propose roles for increased immunoglobulin (Ig) deposition within endothelial cells, elevated estrogen levels, and human herpes virus 8 infection, with this virus being associated with MCD.[10] The eosinophilic granules observed in the endothelial cells of glomeruloid hemangiomas may be abundant Ig deposits that stimulate endothelial cell proliferation in a glomeruloid pattern.

Epidemiology

Glomeruloid hemangiomas are rare benign lesions that may clinically resemble common benign cherry angiomas. These lesions are infrequently investigated, and little is known about their prevalence. Cases of glomeruloid hemangiomas are typically reported in the context of POEMS syndrome, a systemic condition observed more often in men compared to women in their 50s and 60s. POEMS syndrome tends to occur more commonly in individuals of Japanese descent.[11][12] A 2003 national survey conducted in Japan estimated the prevalence of POEMS syndrome to be approximately 0.3 per 100,000 people.[13]

Histopathology

The histopathological findings of glomeruloid hemangiomas include a dilated central vessel with a sinusoidal appearance, surrounded by small capillaries (see Image. Glomeruloid Hemangioma on Histopathology). The central vessel is lined with sinusoidal endothelial cells, which stain positively for CD31 and CD68 but are negative for CD34. The capillary endothelial cells stain positively for CD31, CD68, and CD34. These structures are located within the dermis and resemble renal glomeruli, hence the tumor's name.[14] In addition, the granules within the endothelial cells exhibit positive staining with periodic acid-Schiff and demonstrate resistance to diastase digestion

History and Physical

Glomeruloid hemangiomas appear as small, firm or compressible, dome-shaped papules that may be red, blue, or violaceous in color. The lesions are most commonly located on the trunk or proximal extremities, but they may occasionally be found on the face or other parts of the body. Glomeruloid hemangiomas may be papulonodular, sessile, pedunculated, or cerebriform and can range from a few millimeters to a few centimeters. Dermoscopy of the lesions reveals linear irregular blood vessels, red lacunae, or red-white backgrounds, whereas cherry angiomas only show red lacunae.[15]

Evaluation

Glomeruloid hemangiomas are most closely associated with POEMS syndrome. The occurrence of these lesions is less commonly observed in MCD.

The major diagnostic criteria for POEMS syndrome include polyneuropathy and monoclonal plasma cell dyscrasia. In addition, the diagnosis requires at least one other major criterion and one minor criterion. Major criteria include Castleman disease, bone lesions, and elevated VEGF levels. Minor criteria consist of organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, and hematologic abnormalities.[16]

POEMS syndrome typically presents with progressive polyneuropathy and motor disability, starting distally and progressing proximally. Associated plasma cell dyscrasias may present as monoclonal gammopathy of undetermined significance, solitary osseous or extramedullary plasmacytoma, or multiple myeloma, often characterized by IgA or IgG monoclonal gammopathy and sclerotic bone lesions.

Hepatomegaly is present in 50% of individuals with POEMS syndrome and is more common than splenomegaly or lymphadenopathy. Endocrinopathies, such as diabetes mellitus or hypothyroidism, are reported in up to 67% of patients, along with conditions such as hypogonadism, gynecomastia, hyperprolactinemia, galactorrhea, and hyperparathyroidism. Both POEMS syndrome and MCD can manifest with hypergammaglobulinemia; however, POEMS syndrome is characterized by M-protein monoclonal gammopathy, while MCD typically involves polyclonal gammopathy.

The cutaneous manifestations of POEMS syndrome are diverse and numerous, including hyperpigmentation, hypertrichosis, acrocyanosis, plethora, sclerodermoid changes, hyperhidrosis, leukonychia, scarring alopecia, flushing, clubbing, and various vascular lesions. Glomeruloid hemangiomas are considered to be specific to POEMS syndrome, occurring in 26% to 44% of cases.[17]

The presence of glomeruloid hemangiomas may also serve as a diagnostic clue for another rare systemic disease—thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome, a variant of MCD. Glomeruloid hemangiomas have been reported in various locations, such as the breast, abdominal wall, chest wall, shoulder, upper arm, face, and oral mucosa.

Studies show that glomeruloid hemangiomas may precede the diagnosis of POEMS syndrome by up to 10 years. Therefore, patients without evidence of POEMS syndrome at the time of diagnosis of glomeruloid hemangiomas should continue to be monitored for the development of such systemic disease for several years.

Treatment / Management

Glomeruloid hemangiomas are benign vascular lesions that behave indolently and do not require further treatment. Individuals with glomeruloid hemangiomas should be assessed for signs and symptoms of undiagnosed POEMS syndrome at the time of diagnosis and monitored for several years for the development of POEMS syndrome.

Managing POEMS syndrome necessitates a comprehensive, interprofessional approach. The healthcare team may include members from various specialties, such as, but not limited to, dermatologists, neurologists, hematologists or oncologists, and endocrinologists. Early diagnosis and prompt intervention can minimize the risk of complications, particularly thrombotic diatheses, such as embolism, vascular dissection or necrosis, and volume overload-related issues, such as ascites, pericardial effusion, and pleural effusion.

Treatment protocols for POEMS syndrome include radiation therapy, systemic corticosteroids, and alkylating agents. In addition, therapeutic options include immunomodulatory drugs such as lenalidomide, the VEGF inhibitor bevacizumab, autologous hematopoietic stem cell transplantation, and all-trans retinoic acid.[18][19] Notably, the neuropathy associated with POEMS syndrome typically exhibits a slower response to treatment compared to the cutaneous findings and other systemic manifestations.

Differential Diagnosis

Various vascular lesions, including papillary hemangioma, pyogenic granuloma (also known as lobular capillary hemangioma), tufted angioma, Kaposi sarcoma, and intravascular papillary endothelial hyperplasia (also known as Masson tumor or Masson hemangioma), can mimic glomeruloid hemangiomas morphologically.

Papillary hemangioma is both a morphologic and histopathologic mimic of glomeruloid hemangiomas. Although papillary hemangiomas typically manifest on the head and neck, especially the face, glomeruloid hemangiomas can occur on the extremities and trunk. Papillary hemangiomas are typically solitary lesions and tend to be larger than the multiple lesions characteristic of glomeruloid hemangiomas. In addition, although glomeruloid hemangiomas are commonly observed in young and old adults, papillary hemangiomas are prevalent in children. Unlike glomeruloid hemangiomas, papillary hemangiomas are not linked to POEMS syndrome.

Histologically, papillary hemangiomas are characterized by papillary proliferations lined by plump endothelial cells containing pericytes with abundant basement membrane-like material. In contrast, glomeruloid hemangiomas display a conglomerate of capillaries resembling a renal glomerulus, with thin pericyte-lined endothelial cells and polygonal stromal cells separating the capillaries.[20]

The architectural differences between papillary hemangiomas and glomeruloid hemangiomas are best discerned through immunohistochemistry staining for type IV collagen, which highlights the glomeruloid structure and thin basement membrane in glomeruloid hemangiomas and the papillary configuration with a thick basement membrane-like matrix in papillary hemangiomas. In addition, positive staining for smooth muscle actin and muscle-specific actin is observed around capillaries in glomeruloid hemangiomas and within papillary structures in papillary hemangiomas.

Pyogenic granuloma lacks the glomerulus-like capillary conglomerate observed in glomeruloid hemangiomas on histopathology. In intravascular papillary endothelial hyperplasia, tufts are formed by a fibrous core covered by endothelial cells, in contrast to the anastomosing capillary loops observed in glomeruloid hemangiomas. Histopathological examination of tufted angioma reveals a lobular or cannonball pattern comprising small capillaries surrounded by lymphatic vessels that stain positively for podoplanin. Kaposi sarcoma histopathology may reveal spindle cell proliferation with slit-like vascular spaces, distinguishing it from glomeruloid hemangiomas.

Prognosis

Glomeruloid hemangiomas are benign vascular lesions that behave indolently and are associated with a good prognosis. The development of these lesions may precede an eventual diagnosis of POEMS syndrome, the prognosis of which generally depends on the clinical progression of cachexia, polyneuropathy, and bone marrow involvement. A 2003 study involving 99 patients with POEMS syndrome at the Mayo Clinic found that the median survival from this systemic disorder after diagnosis was 165 months. Fatal outcomes in individuals with POEMS syndrome are mainly attributed to conditions such as congestive heart failure, respiratory failure, renal failure, and infection.

Complications

Glomeruloid hemangiomas are strongly associated with POEMS syndrome and can precede its diagnosis by several years. Patients should be assessed for signs and symptoms of POEMS syndrome at the time of diagnosis and monitored for several years afterward. Symptoms to watch for include polyneuropathy or motor dysfunction, bone pain, abdominal pain, weight changes, and fatigue.