Multinucleate cell angiohistiocytoma in the setting of polycythemia vera: Serendipity or an angiogenic trail?

INTRODUCTION

Multinucleate cell angiohistiocytoma (MCAH) is a rare, benign fibrohistiocytic and vascular proliferation of unclear cause, typically appearing as asymptomatic red-to-violaceous papules that slowly emerge and persist over time without regression.^[1] It shows a marked female predilection and often involves the face and extremities.^[2] Clinically, MCAH may mimic other benign vascular, fibrohistiocytic, inflammatory, or granulomatous dermatoses, making its recognition challenging.^[3] Histologically, some consider it within the spectrum of dermatofibromas.^[1,3] We report a unique case of MCAH in a young male with polycythemia vera (PV), manifesting as persistent papules and plaques. Initially mistaken for dermatofibroma or hypertrophic scars, the diagnosis was confirmed through histopathology and immunohistochemistry (IHC). To our knowledge, this is among the few reported instances linking MCAH with PV, raising the possibility of a vascular endothelial growth factor (VEGF)-mediated pathogenic link.

CASE REPORT

A 38-year-old man presented with multiple asymptomatic, skin-colored to brown papules and plaques over his abdomen, back, and forearms for 5 years. These lesions had a gradual onset and progressed in a metachronous fashion. Initially appearing as lentiform papules on the trunk, they gradually enlarged and developed a reddish-brown hue. More recent lesions on the forearm were static for 6 months. The patient reported cosmetic concerns but no symptoms such as pruritus, pain, or trauma. He had been diagnosed with PV 6 years prior, initially managed with phlebotomy (baseline hemoglobin – 21 g/deciliter [g/dL]), and currently maintained on aspirin 150 mg per day for thromboprophylaxis. His hematological parameters have remained stable for the past 1 year. On cutaneous examination, a solitary, non-tender, hyperpigmented plaque of size 2 cm in greatest dimension was present over the right side of the abdomen [Figure 1a]. A shiny, skin-colored, firm papule of size 5 mm was present over the left forearm [Figure 1b]. In addition, there were scattered lesions over the back in an asymmetric fashion. The abdominal lesion did not show the dimple sign. Dermoscopy of the abdominal plaque revealed pigment globules, peripheral pigment network, white fibrotic lines, and minimal scaling [Figure 2a] while that of the forearm lesion displayed dotted vessels on a light pink background [Figure 2b]. Based on these clinical and dermoscopic findings, differentials considered for the abdominal lesion included dermatofibroma, hypertrophic scar, and benign adnexal tumor, while for the forearm lesion, dermatofibroma, papular granuloma annulare, and papular xanthoma were considered. Laboratory investigations were within normal limits: Hemoglobin 13 g/dL, total leukocyte count of 6500 cells/mm³, and platelet count of 2.9 lakh/μL. Renal and hepatic functions, as well as lipid and glucose profiles, were unremarkable. Serological tests for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus were negative. Punch biopsies were obtained from both the abdominal plaque and forearm papule. Hematoxylin and eosin staining of the abdominal lesion revealed a mid-to-deep dermal tumor with multifocal angioplasia, proliferating endothelial cells and fibro-histiocytic cells, and numerous multinucleated giant cells with amphophilic cytoplasm and cleaved nuclei, all embedded in dense collagenous stroma [Figure 3a-c]. The forearm biopsy showed upper dermal lobules of proliferating capillaries and proliferating endothelial cords [Figure 4a and b].

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Figure 1:

Clinical image showing (a): hyperpigmented, firm, non-tender plaque over abdomen (green arrow); (a): Skin colored, shiny, firm, non-tender papule over left forearm (red circle).

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Figure 2:

Dermoscopy of abdominal plaque showing (a): pigment globules (green star), white fibrotic areas (red stars), and scaling (red arrow); (b): Dermoscopy of forearm papule showing light pink background (green circle) (Dinolite, polarized mode, 50x).

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Figure 3:

Abdominal plaque biopsy. (a): Photomicrograph showing deep dermal tumor with fibro-histiocytic proliferation (green solid arrow), (H&E, 4x]; (b): Higher magnification unveils fibro-histiocytic proliferation and multinucleated cells with amphophilic cytoplasm and cleaved contours (green arrow), embedded in thick collagenous stroma (yellow star), (H&E,40x); (c): Vascular proliferation (yellow arrow) is remarkable (H&E, 40x). H&E: Hematoxylin and eosin.

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Figure 4:

Histopathology of the papule on the forearm. (a): Photomicrograph showing upper dermal lobulated proliferation of vascular structures with attenuated overlying epidermis (yellow circle) (H&E, 10x); (b): Proliferation of capillary sized vessels with large, edematous endothelial cells (green arrows) (H&E, 40x). H&E: Hematoxylin and eosin.

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IHC of the abdominal lesion showed cluster of differentiation (CD) 68 positivity in histiocytes and multinucleated cells and CD31 positivity in endothelial cells [Figure 5a and b]. Factor XIIIa staining was negative [Figure 5c]. These findings confirmed the diagnosis of MCAH. Surgical excision was the chosen modality of treatment: Elliptical excision for the larger abdominal lesion and punch excision for the smaller lesions. Given that the patient is in the low-risk category of PV at present (age <60 years, no prior thrombotic phenomena), management consisted of periodic hematological monitoring and maintenance aspirin thromboprophylaxis.

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Figure 5:

(a): Immunohistochemistry showing CD68 positive histiocytes and multinucleate giant cells (yellow arrows); (b): CD31 positivity is depicted by endothelial cells of proliferating vessels (green arrows); (c): Staining for factor XIIIa is negative [DAB (3,3’-diaminobenzidine), 40x].

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DISCUSSION

First described by Smith and Wilson-Jones in 1985, MCAH is a rare fibro-histiocytic vascular proliferation, more frequently observed in middle-aged to elderly women.^[1,4] Costa et al. identified 140 cases in PubMed/MEDLINE; Frew listed 142 cases (including 8 newer ones); Roy et al. analyzed 62 cases, supporting its classification as a distinct histopathological entity; while Edgerton et al. estimated fewer than 150 cases.^[1-3,5]

The pathogenesis remains unclear. Some categorize MCAH as a dermatofibroma variant, while others view it as a reactive lesion with fibro-histiocytic and vascular components.^[1,3,5] Estrogen receptor-alpha (ER-α) positivity in some studies has suggested hormonal influence, possibly explaining female preponderance, although ER expression has been inconsistent.^[1] Other proposed mechanisms include macrophage-mediated inflammation, increased dermal vascularity, and subsequent fibrosis or atrophy.^[2,3] Clinically, MCAH typically presents as grouped, asymptomatic papules which are erythematous, violaceous, or brown, ranging from 2 mm to 15 mm in size, with a dome-shaped or flat surface.^[1] Lesions commonly affect the face and extremities, though truncal, mucosal, or generalized variants exist.^[1,2,6] Triggers such as pregnancy have been reported in eruptive cases.^[1,6] Some associations, such as hepatitis B and cutaneous plasmacytosis have been deemed to be fortuitous, while others, such as post-hip implant have been reported to be causal.^[7,8]

Dermoscopy reveals three key features: Blurry reddish zones (suggesting vascular proliferation), scattered white areas (indicative of collagen thickening), and fine peripheral reticulations (due to rete ridge melanin).^[9] Notwithstanding the presence of a few overlapping dermoscopic features (white fibrotic structures and peripheral reticulations) between MCAH and dermatofibroma, the former can be reliably distinguished from Kaposi’s sarcoma (Rainbow pattern) and lichen planus (Wickham’s striae) with the aid of dermoscopy.^[9] Our case depicted brown pigment globules, white fibrotic lines, and a peripheral pigment network. Reflectance confocal microscopy has furthered MCAH’s diagnostic distinction. It shows a honeycomb epidermal pattern with bizarre, large, isolated reflective structures in the dermis, unlike epidermal streaming, hyper-reflective rings of monomorphic cells, and the organized vascular pattern of dermatofibroma.^[9]

There is a plethora of clinical differentials of MCAH, including lichen planus, angiolymphoid hyperplasia with eosinophilia (ALHE), insect bite reaction, cutaneous lymphoid hyperplasia, dermatofibroma, angiofibroma, and Kaposi’s sarcoma.^[1,2,9] They can be differentiated on histological grounds as follows: Lichen planus shows hypergranulosis, saw toothing of rete pegs, and band-like lymphohistiocytic infiltrate in the upper dermis; ALHE shows angioplasia with epithelioid endothelial cells, prominent lymphoid, and eosinophil-rich infiltrate; insect bite reaction shows wedge-shaped perivascular lymphocytic and eosinophilic infiltrate; whereas cutaneous lymphoid hyperplasia shows dense lymphoid polyclonal infiltrate with eosinophils and few histiocytes with or without germinal center formation. Histopathological differentials are summarized in Table 1.^[1,2,9]

Given its benign nature, MCAH typically requires no intervention unless cosmetically concerning. Treatment options include surgical excision, intralesional corticosteroids, cryotherapy, argon laser, carbon dioxide laser, and pulsed dye lasers.^[1] Potassium titanium phosphate laser shows good results in lighter skin types.^[1,2] Our patient underwent excisional therapy with a good outcome.

The novelty in this case lies in the association of MCAH with PV, a relationship scarcely documented. PV is known for elevated serum VEGF, a pivotal mediator of angiogenesis.^[10] We propose that chronic VEGF elevation in PV may trigger reactive vascular proliferation, contributing to MCAH development. Although the association might be incidental, the plausible VEGF-mediated link warrants deeper investigation. Unfortunately, due to a lack of awareness about the curious connection between VEGF levels and PV, at the time of diagnosis of MCAH, the serum testing of VEGF could not be performed. Future large-scale studies could elucidate whether patients with myeloproliferative disorders are predisposed to vascular proliferative dermatoses such as MCAH.

In our patient, cytoreductive therapy was not initiated as he fulfilled criteria for a low-risk PV category, defined by age <60 years and absence of prior thrombosis.^[11] His hematocrit and hemoglobin levels remained consistently controlled with phlebotomy in the past and maintenance aspirin thromboprophylaxis. Although elevated VEGF in PV may theoretically contribute to angiomatous proliferations such as MCAH, the current treatment guidelines do not mandate cytoreductive agents in otherwise low-risk, hematologically well-controlled cases.^[11] Cytoreductive therapy with hydroxyurea is generally preferred in high-risk patients, as it is considered the least leukemogenic among available options.^[11] Hydroxyurea is also known for its anti-angiogenic properties (both in vivo and in vitro) due to inhibition of hypoxia inducible factor and VEGF.^[12]

However, in our case, such intervention was not required, given the stable hematological parameters and the benign nature of MCAH, which presented with only a limited number of lesions. Therefore, the addition of hydroxyurea would not have been necessary in this context. Nonetheless, in cases with progressive vascular proliferations with inadequate hematologic control, cytoreductive therapy could be contemplated to potentially mitigate the angiogenic drive. Further studies would be valuable to delineate whether such interventions influence the clinical course of MCAH in PV patients.

CONCLUSION

This report adds to the limited literature on MCAH and emphasizes the diagnostic role of histopathology and IHC. Identification of multinucleated CD68-positive cells and vascular CD31 positivity remains central to the diagnosis. While the coexistence of MCAH with PV may be fortuitous, a potential VEGF-driven pathophysiological connection is worth exploring. Recognizing such patterns could improve our understanding of cutaneous manifestations in hematologic disorders.