Are You Confident of the Diagnosis?
What you should be alert for in the history
Glomeruloid hemangioma is a rare benign cutaneous vascular proliferation that typically arises in patients with a history of POEMS syndrome, a paraneoplastic syndrome associated with a plasma cell proliferative disorder. The POEMS acronym stands for polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. Patients with POEMS typically present with a progressive symmetric sensorimotor peripheral neuropathy that progresses proximally and may become debilitating if left untreated. There are often multiple endocrinopathies. Hypogonadism, hypothyroidism, and abnormal glucose metabolism are frequently seen.
Other common non-cutaneous features of POEMS include complications of extra-vascular volume overload, pulmonary hypertension or restrictive lung disease, papilledema, arterial and venous thrombotic events, fatigue, weight loss, and thrombocytosis.
The M protein in POEMS is most characteristically due to boney lesions of osteosclerotic myeloma or a small clonal plasma cell population in the marrow. Patients may present with a history of monoclonal gammopathy of undetermined significance (MGUS). In contrast to multiple myeloma, nearly all patients with POEMS have a lambda paraprotein, with only a small percent (<10%) plasma cells on bone marrow biopsy.
Many patients with glomeruloid hemangioma and POEMS have multicentric Castleman’s disease (angiolymphoid hyperplasia in the lymph nodes) a multisystem disorder, with much overlap with POEMS. These patients may also have a history of renal disease, anemia, thrombocytopenia, and consititutional symptoms. There may be a history of HIV, Kaposi sarcoma, or lymphoma, if glomeruloid hemangioma is associated with Castleman’s disease. Up to at least a quarter of patients with POEMS have multicentric Castleman’s disease, and a higher percentage of POEMS patients with glomeruloid hemangiomas have Castleman’s disease.
Patients will report progressive development of asymptomatic vascular lesions, which are an admixture of glomeruloid hemangiomas and cherry angioma-like papules (
Cherry angioma-like vascular lesions and glomeruloid hemangiomas in patient with POEMS syndrome (courtesy of Dr Franco Rongioletti).
Characteristic findings on physical examination
Patients will often have multiple vascular papules or papulonodules, representing a mixture of both glomeruloid hemangiomas and cherry-like angiomas. It may not be possible to distinguish these clinically. In addition, some lesions may show histologic features of both entities.
The vascular lesions are red to plum-colored dermal papules and small nodules located predominantly on the chest and proximal extremities; upper extremities more so than lower extremities. These range in size from 0.5 to 15mm, but may occasionally be larger. They may be dome-shaped, polypoid, or sessile. Subcutaneous bluish compressible nodules and papules with a mammillated or cerebriform surface have been reported. Before the term glomeruloid hemangioma was coined and the lesion specifically associated with POEMS, the vascular papules were described in Japanese series as cutaneous angiomatous verrucae, however in general, the surface tends to be smooth-topped, and not verruciform. Ulceration is not a feature.
Other POEMS-related cutaneous abnormalities that may be seen in patients presenting with glomeruloid hemangiomas include hypertrichosis, hyperpigmentation, sclerodermoid skin thickening, acrocyanosis, leukonychia, and flushing.
Non-cutaneous findings that may be seen in patients with POEMS-related glomeruloid hemangiomas include ascities, pedal edema, papilledema, and neurologic consequences of a sensorimotor peripheral neuropathy.
Expected results of diagnostic studies
Glomeruloid hemangiomas are diagnosed by light microscopic features. There may be lesions in various stages of evolution. Changes of glomeruloid hemangioma may be seen focally in cherry angioma-like papules. Rare cases in which there is immature vasculature similar to tufted angiomas have been reported.
In fully developed lesions of glomeruloid hemangioma, the dermis contains numerous discrete conglomerates of small anastomosing vessels, residing and often nearly occluding ectatic vascular spaces (
Scanning power view of glomeruloid hemangioma. There are numerous aggregates of an endothelial cell proliferation occupying vascular spaces throughout the dermis. The epidermis is uninvolved and unaltered (H&E 4x).
Medium power view of glomeruloid hemangioma demonstrating glomeruloid collections of endothelial cells, many of which differentiate into well-formed vascular spaces (H&E 10x).
High power view of glomeruloid hemangioma demonstrating well-formed capillaries, admixed with stromal cells. The vascular space is almost fully occupied by the glomeruloid structure (H&E 40x)
Less well developed area showing aggregate of endothelial cells that have morphology similar to renal glomeruli (H&E 20x).
Early lesions may show ectatic vascular spaces only partially occupied by the capillary aggregates (
Early developing glomeruloid cluster of endothelial cells. Endothelial cells with larger nuclei line small well-formed capillaries. Cells with slightly smaller hyperchromatic nuclei line the outside of the capillary stalks and protrude into sinusoid-like spaces (H&E 40x).
High power view of glomeruloid aggregate demonstrating well-formed capillaries, with stromal cells containing abundant pale-staining cytoplasm. Eosinophilic globules are also noted in the stromal cells (H&E 40x).
Glomeruloid hemangioma. Well developed glomeruloid vascular aggregate with well-formed capillaries and sinusoidal spaces (H&E 20x).
High power view of glomeruloid aggregate with architecture that simulates papillary projections. The stalks contain well-formed capillaries containing erythrocytes. Eosinophilic globules are present in some of the cells lining the sinusoidal spaces (H&E 40x).
There are two types of endothelial cells. Those lining the capillaries have ample cytoplasm and large vesicular nuclei with an open chromatin pattern. The second type, which protrudes into the sinusoidal spaces, are smaller, with scant cytoplasm and dense chromatin.
Interspersed between the capillaries within the stroma are cells with vaculolated nuclei and abundant pale to clear cytoplasm. Some of these cells contain eosinophilic hyaline-like globules within their cytoplasm. The globules are PAS-positive, diastase-resistant. These homogenous eosinophilic globules may also be seen in cells lining the vascular luminae. There is a layer of pericytes surrounding the capillaries. In some areas, the capillary lumina may be less apparent, and the cluster may show a collection of variable nuclear morphologies, representing endothelial cells, macrophage-like cells, and pericytes (
High power view of a glomeruloid hemangioma showing variable nuclear morphologies. These represent an admixture of capillary and sinusoidal endothelial cells, pericytes, and stromal macrophage-like cells. There are scattered eosinphilic globules in the stroma and in cells lining the sinusoidal space (H&E 40x).
Mitotic activity should be less than one per high power field. Inflammatory cells, cytologic atypia, and necrosis should be absent.
Immunohistochemical staining demonstrates that the endothelial cells lining the capillaries are positive for CD31, CD34, factor VIII-related antigen, von Willebrand factor (VWF), Ulex Europaeus-I (UEA1), and CD105. Factor VIII-related antigen may stain some of the stromal cells. The sinusoidal endothelial cells are positive for CD31 and CD68, and negative for CD34, UEA-1, and VWF. The cells with globules are CD68 positive. Pericytes surrounding the capillaries are positive for alpha smooth muscle actin (SMA). The globules show polytypic immunoglobulin staining in the rim.
Electron microscopy demonstrates endothelial cells forming the capillaries and cells with intracytoplasmic lumens. Sinusoidal-lining cells showed changes of a macrophage-like cell with varying degrees of differentiation. The globules showed features of immunoglobulin; ultrastructural features of erythrosomes have not been identified.
The main differential diagnosis of glomeruloid hemangioma is papillary hemangioma. In fact, a slide from one of the case reports of glomeruloid hemangioma in a patient without POEMS has been re-reviewed by the author that described papillary hemangioma, who felt instead that it represented this latter entity.
Papillary hemangiomas are cutaneous vascular lesions that arise on the head and neck, in contrast to the trunk and extremities, as is seen with glomeruloid hemangioma. Both are intravascular capillary proliferations associated wtih cells containing PAS (+) hyaline globules, but in glomeruloid hemangiomas the capillaries are well formed and packed into smaller glomeruli-like clusters, whereas in papillary hemangioma, the vascular aggregates are larger, composed of papillary stalks with more pericytes and stromal cells, and fewer capillaries. The globule-containing endothelial cells in papillary hemangiomas line the papillary stalks.
Papillary hemangiomas are so histologically similar to glomeruloid hemangiomas that without close inspection of the vascular architecture, one can easily misinterpret the changes to represent glomeruloid hemangioma, especially if one is not aware of the existence of the entity papillary hemangioma. Immunohistochemical staining may help differentiate papillary hemangioma from glomeruloid hemangioma. Collagen IV will highlight the papillary architecture and thick mantles of pericytes enveloped by prominent basement membrane in the former. In contrast, in glomeruloid hemangioma, collagen IV highlights discrete capillaries and only few pericytes.
Clinically, a solitary lesion arising on the head should prompt a diagnosis of papillary hemangioma, whereas multiple lesions on the trunk or proximal extremities favor glomeruloid hemangioma.
Intravascular lobular capillary hemangioma also presents histologically as a solitary intravascular proliferation of anastomosing capillaries, but the vascular proliferation resides in a fibromyxoid stroma, within a larger caliber vessel. Absence of hyaline globules also helps to distinguish this from glomeruloid hemangioma.
Tufted angioma may have a similar histologic picture at scanning magnification. It presents with discrete tufts of capillaries in the dermis, imparting a canonball-like pattern. The tufts, composed of capillaries and pericytes, proliferate around vessels in contrast to the intravascular location of capillaries in glomeruloid hemangioma. Clinically, these are easily distinguished as tufted angioma typically present as patches on the neck and upper trunk of children. Rare patients with POEMS have had tufted angioma-like histology in the hemangiomas, but these are accompanied by the typical clinical morphology.
Masson’s intravascular papillary endothelial hyperplasia may simulate the intravascular glomeruloid-like structure but is characterized by endothelial cells lining papillary cores of fibrin in clusters, in contrast to well formed capillaries.
Reactive angioendotheliomatosis will show changes similar to glomeruloid hemangioma, but there should be less well-formed glomeruloid aggregates within vessels. The lesions likely have similar pathogenesis; thus, will have overlapping histologic features. The clinical presentation of numerous vascular papules helps to confirm glomeruloid hemangioma.
Who is at Risk for Developing this Disease?
Patients with POEMS syndrome are at risk of developing glomeruloid hemangiomas, and in fact, these lesions are one of the minor criteria required to make a diagnosis of POEMS. Glomeruloid hemangiomas are seen in around 26% to 44% of patients with POEMS.
Patients with Castleman’s disease associated with POEMS are at higher risk of having glomeruloid hemangiomas than those without Castleman’s. Review of the literature has revealed that a third of the patients with POEMS and glomeruloid hemangioma have had multicentric Castleman’s disease.
Glomeruloid hemangiomas have only been reported in the adult population, with an age range of 36 to 68 years, median 49 years, with a nearly equal gender distribution.
What is the Cause of the Disease?
Glomeruloid hemangiomas are considered to be reactive vascular proliferations and not a neoplastic process.
The neovascularizing process has been proposed to be due to angiogenesis, developing from pre-existing vessels, and/or vasculogenesis, developing from in situ differentiating endothelial cells. CD34-positive bone marrow-derived endothelial progenitor mononuclear cells, which can differentiate into endothelial cells, may contribute to vasculogenesis.
Patients with POEMS characteristically have markedly elevated levels of vascular endothelial growth factor (VEGF), which also likely contributes to the angiogenesis and vasculogenesis. VEGF expression and its receptor, VEGFR-1 (Flt1) have been reported in glomeruloid hemangioma.
Systemic Implications and Complications
Glomeruloid hemangiomas are cutaneous markers for POEMS syndrome. Thus, if one encounters this diagnosis, pursuit of an M protein and other features of POEMS should ensue. It was initially felt to be a specific marker of POEMS, but because of rare reports of this vascular lesion arising in isolation or without complete criteria of POEMS, some authors believe that it is not specific. Review of the literature and images of the non-POEMS related glomeruloid hemangioma has led some to conclude that the follow-up must be sufficient, as patients may continue to develop the features of POEMS for months to years after their initial presentation.
Glomeruloid hemangiomas are benign, and do not demonstrate widespread metastases.
There are no known systemic consequences of glomeruloid hemangioma; however, there have been reports of vascular proliferations in non-cutaneous locations, including intracranial hemangiomas with glomeruloid changes. In the original report of glomeruloid hemangioma, glomeruloid vascular proliferations were found in retroperitoneal adipose tissue at autopsy.
Due to the association of glomeruloid hemangioma with POEMS and Castleman’s disease, patients with glomeruloid hemangiomas may develop a variety of systemic complications, but these are not directly related to the vascular lesions.
--Systemic treatment with prednisone, alkylating agents, and other systemic therapy used to treat POEMS syndrome
--Although there are no reports in the literature about using lasers for glomerluar hemanigomas, one might expect a similar response as seen for other hemangiomas treated with those lasers utilized for vascular lesions such as tufted angiomas (the pulsed dye laser).
Optimal Therapeutic Approach for this Disease
Glomeruloid hemangoimas are benign, reactive vascular proliferations that will not progress to malignancy, and therefore, do not require treatment. Glomeruloid hemangiomas and the other vascular proliferations associated with POEMS are cutaneous manifestations of a paraneoplastic syndrome, so therapy should target the plasma cell dyscrasia.
Data on therapy and therapeutic responses for glomeruloid hemangiomas are scant to absent. Most case reports indicate that the symptoms resolved with prednisone, melphalan, cyclophosphamide, or other typical systemic regimens used for POEMS, but specific reference to the response of the vascular lesions is difficult to find in the reported cases of glomeruloid hemangiomas. In the POEMS literature, improvement of the skin findings often precedes that of the neurologic symptoms; however, there can be a 3- to 6-month lag in treatment response of some of the symptoms of POEMS.
In one case in which numerous smaller lesions shrunk in response to prednisone, a 3cm lesion persisted and intralesional triamcinolone and sclerotherapy were attempted without success.
Cosmetically undesirable glomeruloid hemangiomas that do not respond to therapy can be surgically excised.
Patients with glomeruloid hemangiomas associated with POEMS may have resolution of their lesions upon successful systemic treatment or irradiation of the plasma cell dyscrasia. Patients should know that there is no need for specific treatment of the glomeruloid hemangiomas, as these lesions are benign.
If there is no known history of POEMS, patients diagnosed with glomeruloid hemangioma, especially when arising in the context of progressive or eruptive truncal and upper extremity angiomas, should have a detailed physical examination and clinical history, with review of systems that includes symptoms of impotence or menstrual irregularities. Strong consideration should also be given to performing serum protein electropheresis and, if negative, serum immunofixation to exclude an M protein, imaging studies to exclude osteosclerotic myeloma, bone marrow biopsy to evaluate for clonal plasma cells (as little as 5% to 10%), VEGF levels, endocrinologic laboratory work-up, and pulmonary function testing to exclude asymptomatic features of POEMS.
Long-term follow-up (including repeat of some diagnostic studies) of patients with negative or incomplete criteria for a POEMS diagnosis is important, since patients with POEMS may acquire additional diagnostic features years after the original presenting symptoms or signs.
Unusual Clinical Scenarios to Consider in Patient Management
Patients diagnosed with a solitary glomeruloid hemangioma may, in fact, have a papillary hemangioma, and vice versa. A handful of these patients have been reported in the literature to have isolated lesions not associated with POEMS. The pathology should be reviewed by someone familiar with both of these entities, to confirm the diagnosis.
For solitary glomeruloid hemangiomas, one should consider a work-up for POEMS, as outlined above; however, it is worth discussing with the patient that such isolated lesions have been reported to be free of the POEMS-associated paraneoplastic association.
What is the Evidence?
Dispenzieri, A. "POEMS syndrome". Blood Rev. vol. 21. 2007. pp. 285-99.(This article reviews the clinical and laboratory features of POEMS syndrome. The author outlines criteria for making this diagnosis, which includes glomeruloid hemangiomas as one of the minor criteria, among other cutaneous and extracutaneous features. The author discusses the relationship of Castleman’s disease to POEMS and the role of VEGF, interleukin (IL)-1 beta, IL-6, and TNF-alpha in the pathogenesis of this syndrome.)
Chan, JKC, Fletcher, CDM, Hicken, GA, Rosai, J. "Glomeruloid hemangioma. A distinctive cutaneous lesion of multicentric Castleman’s disease associated with POEMS syndrome". Am J Surg Pathol. vol. 14. 1990. pp. 1036-46.(This is the first article to apply the term glomeruloid hemangioma to the vascular lesions seen in POEMS, and to establish these lesions as markers of this syndrome. The authors report two patients with multiple vascular lesions with glomeruli-like morphology of the capillary aggregates and multicentric Castleman’s disease associated with POEMS syndrome. One of the patients underwent an autopsy, where glomeruloid foci were identified in the retroperitoneal fat. The histologic features were described in detail, accompanied by several histologic images to illustrate their findings.A differential diagnosis of similar histologic entities is also provided. They credit Zak et al for reporting the first description of glomeruloid hemangioma in a 1996 paper published in the Journal of Pathology. Additional review of the literature was discussed, and they concluded that the angiomas of POEMS represent both cherry-type and glomeruloid hemangiomas, or a combination thereof, sometimes with additional changes of lobular capillary hemangioma. They stressed the need to recognize glomeruloid hemangioma as a distinct lesion that may precede a full-blown presentation of POEMS, and to follow-up and evaluate these patients for other features of POEMS.)
Rongioletti, F, Gambini, C, Lerza, R. "Glomeruloid hemangioma. A cutaneous marker of POEMS syndrome". Am J Dermatopathol. vol. 16. 1994. pp. 175-8.(This article appears to be the first to apply the term glomeruloid hemangioma to the vascular lesions of POEMS, after the term was coined by Chan et al. They report a man with around 40 angiomas ranging from 0.5 to 1.5cm. Biopsy from one showed typical changes of glomeruloid hemangioma. They also describe two masses in the deeper dermis composed of immature, variously sized polygonal cells surrounding an irregular lumen lined by flat endothelium, changes of which they believed were suggestive of a tufted angioma. An image of these additional findings is not provided. They speculate that the glomeruloid hemangioma may have different stages of development, with tufted angioma being an immature form.)
Pina-Oviedo, S, Lopez-Patino, S, Ortiz-Hidalgo, C. "Glomeruloid hemangiomas localized to the skin of the trunk with no clinical features of POEMS syndrome". Int J Dermatol. vol. 45. 2006. pp. 1449-50.(The patient described has lesions that clinically and histopathologically meet criteria for glomeruloid hemangiomas, yet the patient did not have POEMS. The details of the work-up are not included, nor was the follow-up of 6 months sufficient to completely exclude POEMS, since patients may acquire additional features years after initial presentation of POEMS symptoms.)
Phllips, JA, Dixon, JE, Richardson, JB, Fabre, VC, Callen, JP. "Glomeruloid hemagioma leading to a diagnosis of POEMS syndrome". J Am Acad Dermatol. vol. 55. 2006. pp. 149-52.(The authors report a case of a patient with a 6-month history of progressive onset of vascular lesions, including a 3cm vascular lesion on his face. This was not biopsied, but a lesion from the scalp showed a glomeruloid hemangioma, leading to a diagnosis of POEMS. They describe shrinkage of numerous vascular lesions elsewhere in response to dexamethasone, but his large facial hemangioma did not respond. Intralesional triamcinolone and sclerotherapy were unsuccessful. The authors report this as the first known attempt to treat GH with sclerotherapy. The results favor surgical therapy for such large, resistant vascular lesions.This article demonstrates the range in size of the hemangiomas that can be seen in POEMS, and it also illustrates the important role that dermatologists and dermatopathologists may play in making a diagnosis of POEMS.)
Chan, PT, Lee, KC, Chong, LY, Lo, KK, Cheung, YF. "Glomeruloid haemangioma with cerebriform morphology in POEMS syndrome". Clin Exp Dermatol. vol. 31. 2006. pp. 775-7.(The authors describe a glomeruloid hemangioma with a mammillated surface, imparting a cerebriform appearance. In a brief literature review, they discuss other morphologies of glomeruloid hemangioma that have been reported in the literature, other skin findings in POEMS, and proposed pathogenesis of glomeruloid hemangiomas. Their patients’ hypertrichosis and other extracutaneous features of POEMS responded to cyclophosphamide and prednisone, but the hemangiomas did not.)
Yuri, T, Yamazaki, F, Takasu, K, Shikata, N, Tsubura, A. "Glomeruloid hemangioma". Pathol International. vol. 58. 2008. pp. 390-5.(The authors report a case of glomeruloid hemangiomas associated with POEMS, Castleman’s disease, and Sjögren’s syndrome. The patient was said to have had minimal residual symptoms after prednisolone therapy, but it was not specified if the hemangiomas resolved. The authors evaluated the glomeruloid hemangioma with immunohistochemistry, demonstrating a CD31+/CD34+/CD105+/UEA-1+/CD68- immunophenotype of the cells within the capillary loops, and a CD31+/CD34-/CD68-/+/CD105-/UEA1- immunophenotype in the cells lining the surface of the loops within the glomeruloid structures. These endothelial cells were separated by SMA + pericytes. The article includes nice images demonstrating their findings.)
Suurmeijer, AJH, Fletcher, CDM. "Papillary haemangioma. A distinctive cutaneous haemangioma of the head and neck area containing eosinophilic hyaline globules". Histopathology. vol. 51. 2007. pp. 638-48.(The authors report 11 patients with ages ranging from 1 to 77 years, median 57, with a solitary bluish nodule [median size 10mm, range 3 to 20mm] with a male predominance (male:female=7:4) arising on the head (face) and neck region that had distinctive histologic features, characterized by intravascular papillary growths of vessels in the dermis. There were similarities to glomeruloid hemangioma, but the capillary loops were not arranged in an organoid fashion. Instead, the papilla had cellular cores containing several layers of pericytes and stromal cells, arranged around small capillaries.Simlar to glomeruloid hemangioma, were hyalin globules, but these lined the papillary projections, and showed ultrastructural features of giant lysosomes containing organelle debris and fat vacuoles [thanatosomes]. The patients did not have any evidence of POEMS; thus, papillary hemangioma was felt to represent a distinct new entity.)
Suurmeijer, AJH. "Papillary hemangiomas and glomeruloid hemangiomas are distinct clinicopathologic entities". Int J Surg Pathol. vol. 18. 2010. pp. 48-54.(The author, who reported the original case series of papillary hemangiomas, compares and contrasts this entity with glomeruloid hemangioma. The author reviews the literature of glomeruloid hemangioma, and in addition, reviews slides from some of these cases, as well as one case reported as glomeruloid hemangioma unassociated with POEMS. It was determined that the latter [reported as a 7mm lip lesion in article by Velez D, Delgado-Jimenez Y, Fraga J. Solitary glomeruloid hemangioma without POEMS syndrome. J Cutan Pathol 2005;32:449-52] instead was a papillary hemangioma.Collagen IV was found to be helpful in distinguishing the two vascular lesions. The article includes nice side-by-side images of the two vascular lesions, as well as a table contrasting the clinical and pathologic differences between them. He also provides a composite analysis of cases of glomeruloid hemangiomas associated with POEMS.)
Forman, SB, Tyler, WB, Ferringer, TC, Elston, DM. "Glomeruloid hemangiomas without POEMS syndrome: series of three cases". J Cutan Pathol. vol. 34. 2007. pp. 956-7.(In a brief letter to the editor the authors state that they diagnosed three patients with solitary glomeruloid hemangiomas, but they do not provide images of all three lesions to allow validation of the diagnosis. The letter includes routine histologic images and images of light chain stains, documenting kappa and lambda staining of the globule-containing cells in one of the cases. Anatomic sites of the lesions are not provided to exclude the possiblity that the lesions may represent papillary hemangiomas. POEMS was excluded by a negative SPEP, but this is frequently negative in POEMS, so without more follow-up or work-up, it is unclear if the possiblity of POEMS-related vascular lesions is definitively excluded.The authors conclude that glomeruloid hemangioma should not be considered specific for POEMS. The need for POEMS evaluation when encountering a diagnosis of glomeruloid hemangioma was acknowledged.)
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