Eruptive Cutaneous Epithelioid Angiomatous Nodules

The patient was a young man in his early thirties who initially presented with a single nodular lesion on his left shoulder when traveling to a metropolitan area in Southeast Asia in November 2014. The lesion was hemorrhagic and ulcerated. An attempt was made to ablate the lesion using a laser procedure; however, it subsequently recurred in January 2015. Shortly thereafter, additional smaller lesions developed in the same area (Figure 1). Intralesional steroids and minocycline were ineffective. He felt that burning the lesions limited their spread and bleeding.

The patient’s past medical history was remarkable for hypothyroidism and also low testosterone. The patient was on testosterone supplement and daily men’s vitamins. The patient engaged in contact sports and was an avid avocational wrestler. The patient denied experiencing any constitutional symptoms prior to or since developing the eruption. Three biopsies were taken from the affected areas including the left scapula and forearm.

Light Microscopic Findings
The biopsy in specimen A showed a well-circumscribed, superficially disposed nodular distortion of the dermis by closely apposed vessels and singly disposed cells amidst a somewhat fibrotic dermis (Figure 2A).^1,2 The vessels were lined by atypical plump endothelial cells (Figure 2B). The endothelia were prominent with conspicuous nucleolation and some degree of nuclear hyperchromasia. In addition, similar cells were found in a single cell array amidst the well-formed vessels (Figure 2C). Human herpesvirus 8 (HHV8), Epstein-Barr virus, and cytomegalovirus preparations were negative. A Warthin-Starry preparation to assess for possible parasitization of the abnormal endothelial cells by Bartonella bacilliformis and other species³ was negative. 

The biopsy in specimen B demonstrated a very atypical vascular proliferation with foci of glomeruloid neovascularization reminiscent of the pattern seen in the A specimen, but there was an additional significant pattern of infiltrative vascular proliferation (Figure 2D). A number of bizarre cells scaffolding in a single cell fashion along collagen and elastic fibers were observed defining a pattern reminiscent of an angiosarcoma given the extent of cellular atypia and the distinct infiltrative growth pattern along the collagen and elastic fibers. The endothelial cells were remarkable for their large size and abundant amphophilic cytoplasm and bizarre nuclear features. The cytoplasm ranged in quality from being eosinophilic to amphophilic in quality. Several of the very atypical cells exhibited large cytoplasmic vacuoles. The atypical vascular channels and singly disposed cells without any vasoformative tendency were highlighted by clusters of differentiation (CD) 34. The cytomegalovirus, HHV8, and Epstein-Barr virus stains (LMP1) were negative. Immunohistochemical and molecular assays were negative for all Bartonella species examined, including Bartonella quintana, Bartonella henselae, and Bartonella vinsonii.  

Discussion
The case represents an atypical cutaneous eruptive angiomatous process occurring in a healthy young man. The eruption was of sudden onset without any obvious inciting trigger. It was regionally confined and was histomorphologically characterized by an atypical vascular proliferation lined by abnormal enlarged endothelial cells, which also appeared to assume a nonvasoformative single-cell growth pattern in the dermis. The cells had a distinctly epithelioid appearance manifesting nuclear hyperchromasia and nuclear enlargement, and cytoplasms were abundant and amphophilic to eosinophilic and somewhat vacuolated in quality as well. While the proliferation was very abnormal cytomorphologically and architecturally, the overall cutaneous presentation was not consistent with an epithelioid angiosarcoma, which has been reported to arise in association with reactive angioendotheliomatosis.^4,5 The differential diagnosis encompassed multicentric cutaneous angiosarcomatous mimics. There are four main diagnostic considerations, and each will be considered separately. 

The first consideration is Kaposi sarcoma. However, the negative HHV8 stain would not be consistent with this diagnosis given the relatively ubiquitous association of HHV8 with Kaposi sarcoma.⁶

The next is infective angioendotheliomatosis attributable to a Bartonella species. Verruga peruana, a cutaneous manifestation of B bacilliformis, is characterized by an eruption of red to purple papules or nodules on the face and extremities. Histologically, these lesions show proliferation of endothelial cells with cytologic atypia that can range in morphology from an epithelioid hemangioma-like appearance to more solid and spindled appearance that can mimic sarcomas.⁷ While certain aspects of the histopathology in this case are reminiscent of verruga peruana, the clinical features and basic epidemiology are not consistent with the diagnosis. First, B bacilliformis has exclusively been reported in the South American countries of Colombia, Ecuador, and Peru in the Andes mountains.^8,9 This patient traveled to Southeast Asia before the lesion manifested, where B bacilliformis has not been reported.^10,11 Next, verruga peruana can be preceded by Oroya fever, which causes symptoms of fever, headaches, and muscle aches.¹² This patient denied experiencing any of such symptoms. Bacillary angiomatosis, a related infective angioendotheliomatosis syndrome caused by B henselae that is most often associated with HIV/AIDS, was also considered. Bacillary angiomatosis is characterized by vascular proliferation with lobules composed of rounded edematous vessels lined by protuberant endothelial cells and neutrophilic clusters. Many organisms parasitizing pericytes are typically seen on Warthin-Starry stain, unlike in this case.¹³  One might further consider a species of Bartonella, distinct from the three most common, that have been found in mammalian reservoirs in Southeast Asia.^10,11 Nevertheless, the molecular and immunohistochemical investigation were negative.  

The mechanism of Bartonella infection involves invasion and colonization of human erythrocytes, the steps of which differ between species.¹⁴ For instance, B bacilliformis contains a unipolar flagella and is very motile, and antibodies against a component of this flagella have shown to inhibit the organism’s binding to the erythrocytes.¹⁵ In addition, this particular species uses deformin, a virulence factor that causes invaginations in the membranes of erythrocytes and allows for further success in invasion.¹⁶ This process of entry causes the Oroya fever phase in B bacilliformis infection but has no hemolytic effect in other Bartonella cases.¹⁷ Additionally, Bartonella target host endothelial cells, manifesting in angiogenesis and/or proinflammatory responses seen in B bacilliformis and bacillary angiomatosis.^7,13  

The third diagnostic consideration is an atypical variant of angiolymphoid hyperplasia with eosinophilia (ALHE), a very plausible diagnosis in this case. Kimura disease and ALHE are conditions that involve the head and neck region, tend to recur despite treatment, and share certain histopathologic features, such as lymphoeosinophilic infiltrates of the involved tissue and vascular proliferation.^18,19 Although there have been several reports of both entities occurring in a single patient,^20,21 most authors view ALHE and Kimura disease as two distinct disorders.²² 

ALHE occurs in young to middle-aged women and presents with multiple small (<2 cm) erythematous dermal papules or nodules.¹⁸ The lesions are commonly superficial, localizing to the dermis or subcutis. Eosinophilia occurs in approximately 20% of patients, but other systemic manifestations are absent. Histologic examination shows a diffuse lymphoid infiltrate of diverse intensity, with a variable eosinophilic component. The vascular proliferation in ALHE is characterized by thick-walled blood vessels lined by plump epithelioid endothelial cells with vacuolated cytoplasm and vesicular nuclei, which protrude into and sometimes occlude the vascular lumens.²³ In rare cases, variants of ALHE can present with worrisome histologic features suggesting angiosarcoma, including infiltrative networks of vascular channels lined by hyperchromatic atypical endothelial cells, and careful consideration must be made to differentiate this entity from angiosarcoma.²⁴ In this case, the morphologic semblance of the well-formed vessels to those seen in ALHE would certainly suggest that this case could potentially be categorized as an atypical variant of ALHE. The main differentiating point that ultimately lead us to not render this diagnosis was the degree of single cell nonvasoformative atypical endothelial cell growth within the dermis. Due to the vascular aspect of this entity being very conspicuous, some authors have considered therapeutic intervention with β blockers. One report described a favorable treatment response with propranolol 40 mg daily.²⁵

Kimura disease occurs mainly in young Asian men and presents with large (>2 cm) masses.¹⁹ The lesions are deep and involve subcutaneous tissue, muscle, and salivary glands. There are frequent systemic manifestations, such as lymph node enlargement, eosinophilia, and elevated serum IgE. Histopathologically, Kimura disease show a significant pattern of reactive lymphoid hyperplasia including conspicuous germinal centers and tissue eosinsophilia.²⁶ A vascular proliferation may be present, but the characteristic cytomorphologic alterations of the endothelium seen in ALHE are not identified.

Serologic findings in these closely related conditions include high IgE levels and peripheral blood eosinophilia. Given the findings of clonality in some cases, certain phenotypic abnormalities, such as a loss of CD7 (personal observations), the lack of an antigenic trigger, recalcitrance to sustained remission with standard lympholytic therapy (eg, steroids) along with synchronous and or metachronous T-cell lymphoma, it is reasonable to suggest that this condition, especially when presenting with marked and intractable facial infiltration (ie, Kimura disease) might be considered under the rubric of a form of low-grade T-cell dyscrasia.^27-29 

The final consideration and favored diagnosis are in the context of eruptive angiomatous nodule. The cutaneous angiomatous epithelioid nodule is an important entity to recognize because the extent of endothelial cell atypia can at times be significant, and if one is not cognizant of the entity, one can potentially misdiagnose such cases as representing epithelioid angiosarcoma.³⁰ In the original paper, the authors reviewed all of their consultation files over a 13-year period, demonstrating 15 examples of an entity that appeared to have a uniform clinical and histopathologic presentation.³⁰ The medium age of presentation was 37 years (range, 15-79 years), hence involving a demographic population different than the tufted angioma, the Dabska tumor, and the Kaposiform hemangioendothelioma, all of which can show significant areas of solid epithelioid endothelial cell growth. The lesions developed over time and mostly presented as a solitary bluish nodule or papule that rarely exceeded 1.0 cm in size. In fact, the median diameter was 0.5 cm. The lesions could be distributed over the trunk, extremities, and face.  The most commonly affected sites, however, were trunk and extremities. Of the 15 cases,³⁰ one patient developed multiple lesions but confined to the same geographic site. The fact that this patient was taking exogenous testosterones and engaged in rigorous contact sports could be a pathophysiologic trigger in the evolution of this benign eruptive vasoformative process. In particular, rat studies have shown that exogenous testosterone is associated with increased levels of vascular endothelial cell growth factor and increased numbers of endothelial progenitor cells,^31,32 with one study showing that testosterone and voluntary exercise promoted angiogenesis in the hearts of rats by enhancing expression of vascular endothelial cell growth factor.³³

The histopathology of the cutaneous epithelioid angiomatous nodule is highly distinctive with all of the salient features being summarized by the original index paper by Brenn and Fletcher.³⁰ The lesions are typically well circumscribed and show a nodular appearance; the nodule is usually unilobular as opposed to multinodular and is composed predominantly of a solid, sheet-like proliferation of large polygonal epithelioid cells containing abundant eosinophilic to clear cytoplasm with vesicular nuclei and prominent nucleoli. However, there can be a well-defined vasoformative component that resembles the vascular channels found in ALHE. As with ALHE, endothelial cells exhibit intracytoplasmic vacuoles that are quite numerous. Mitotic figures can be seen, but they are not atypical and high-grade nuclear atypia is not present. 

While these lesions are typically solitary, there have been several papers published that describe multicentric forms of cutaneous epithelioid angiomatous nodules.^34-38 In these cases, multiple metachronous epithelioid angiomatous nodules developed over a 1- to 2-year period. The locations of these lesions include the scalp, neck, chest, and forearms. In one case of multiple cutaneous epithelioid angiomatous nodules of the forearm, treatment with a combination of cryotherapy and excision resulted in resolution without recurrence after 3 months’ follow-up.³⁸ 

Conclusion
In summation, we have presented an unusual case of an atypical but benign eruptive angiomatous process in a young man. While there were certain features of ALHE, ultimately, we felt that the best clinical pathologic correlative diagnosis was one of eruptive angiomatous nodules, recognizing that there is likely a very fine line of distinction between atypical variants of ALHE and eruptive angiomatous nodules. The role of exogenous testosterone coupled with vigorous exercise as a trigger is worthy of further exploration.

Dr Kubiak is with the department of pathology and laboratory medicine at Weill Cornell Medicine in New York City, NY. Dr Kyriakides is a physician in the department of dermatology at St. Barnabas Hospital in Bronx, NY. Dr Jacobs is in private practice in dermatology and laser surgery in New York City. Dr Magro is a distinguished professor of pathology and laboratory medicine in the department of pathology at Weill Cornell Medicine in New York, NY, and section editor of The Dermatopathologist in The Dermatologist.

Disclosures: The authors report no relevant financial relationships.

References
1. Requena L, Sangueza OP. Cutaneous vascular proliferations. Part III. Malignant neoplasms, other cutaneous neoplasms with significant vascular component, and disorders erroneously considered as vascular neoplasms. J Am Acad Dermatol. 1998;38(2 Pt 1):143-175. doi:10.1016/s0190-9622(98)70237-3

2. Berger TG, Dawson NA. Angioendotheliomatosis. J Am Acad Dermatol 1988;18(2 Pt 2):407-412. doi:10.1016/S0190-9622(88)70058-4

3. Anderson BE, Neuman MA. Bartonella spp. as emerging human pathogens. Clin Microbiol Rev. 1997;10(2):203-219. 

4 . Hart J, Mandavilli S. Epithelioid angiosarcoma: a brief diagnostic review and differential diagnosis. Arch Pathol Lab Med. 2011;135(2):268-272. doi:10.1043/1543-2165-135.2.268

5. Clarke LE, Julian KG, Clarke JT, Ioffreda MD. Reactive angioendotheliomatosis in association with a well-diffferentiated angiosarcoma. Am J Dermatopathol. 2005;27(5):422-427. doi:10.1097/01.dad.0000159214.70183.0d

6. Cheuk W, Wong KOY, Wong CSC, Dinkel JE, Ben-Dor D, Chan JKC. Immunostaining for human herpesvirus 8 latent nuclear antigen-1 helps distinguish kaposi sarcoma from its mimickers. Am J Clin Pathol. 2004;121(3):335-342. doi:10.1309/B8TC-0LBV-H8XY-5MFV

7. Garcia FU, Wojta J, Broadley KN, Davidson JM, Hoover RL. Bartonella bacilliformis stimulates endothelial cells in vitro and is angiogenic in vivo. Am J Pathol. 1990;136(5):1125-1135. 

8. Sanchez Clemente N, Ugarte-Gil CA, Solórzano N, Maguiña C, et al. Bartonella bacilliformis: a systematic review of the literature to guide the research agenda for elimination. PLoS Negl Trop Dis. 2012;6(10):e1819. doi:10.1371/journal.pntd.0001819.

9. Minnick MF, Anderson BE, Lima A, Battisti JM, Lawyer PG, Birtles RJ. Oroya fever and verruga peruana: bartonelloses unique to South America. PLoS Negl Trop Dis. 2014;8(7):e2919. doi:10.1371/journal.pntd.0002919.

10. Neves ES, Mendenhall IH, Borthwick SA, Su YCF, Smith GJD. Detection and genetic characterization of diverse Bartonella genotypes in the small mammals of Singapore. Zoonoses Public Health. 2018;65(1):e207-e215.

11. Kosoy M, Bai Y. Bartonella bacteria in urban rats: a movement from the jungles of Southeast Asia to metropoles around the globe. Front Ecol Evol. 2019;7:88. doi:10.3389/fevo.2019.00088

12. Kosek M, Lavarello R, Gilman RH, et al. Natural history of infection with Bartonella bacilliformis in a nonendemic population. J Infect Dis. 2000;182(3):865-872. doi:10.1086/315797

13. LeBoit PE, Berger TG, Egbert BM, Beckstead JH, Yen TSB, Stoler MH. Bacillary angiomatosis: the histopathology and differential diagnosis of a pseudoneoplastic infection in patients with human immunodeficiency virus disease. Am J Surg Pathol. 1989;13(11):909-920. 

14. Harms A, Dehio C. Intruders below the radar: molecular pathogenesis of Bartonella spp. Clin Microbiol Rev. 2012;25(1):42-78. doi:10.1128/CMR.05009-11

15. Scherer DC, Deburon-Connors I, Minnick MF. Characterization of Bartonella bacilliformis flagella and effect of antiflagellin antibodies on invasion of human erythrocytes. Infect Immun. 1993;61(12):4962-4971. doi:10.1128/IAI.61.12.4962-4971.1993

16. Mernaugh G, Ihler GM. Deformation factor: an extracellular protein synthesized by the Bartonella bacilliformis that deforms erythrocyte membranes. Infect Immun. 1992;60(3):937-943. 

17. Xu Y-H, Lu Z-Y, Ihler GM. Purification of deformin, an extracellular protein synthesized by Bartonella bacilliformis which causes deformation of erythrocyte membranes. Biochim Biophys Act. 1995;1234(2):173-183. doi:10.1016/0005-2736(94)00271-p

18. Chitrapu P, Patel M, Readinger A, Menter A. Angiolymphoid hyperplasia with eosinophilia. Proc (Bayl Univ Med Cent). 2014;27(4):336-337. doi:10.1080/08998280.2014.11929150

19. Dhingra H, Nagpal R, Baliyan A, Alva SR. Kimura disease: case report and brief review of literature. Med Pharm Reports. 2018;92(2):195-199. doi:10.15386/cjmed-1030

20. Reddy PKS, Prasad ALS, Sumathy TK, Shivaswamy KN, Ranganathan C. An overlap of angiolymphoid hyperplasia with eosinophilia and Kimura’s disease: successful treatment of skin lesions with cryotherapy. Indian J Dermatol. 2015;60(2):216. doi:10.4103/0019-5154.152574

21. Chong WS, Thomas A, Goh CL. Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: two disease entities in the same patient: case report and review of the literature. Int J Dermatol. 2006;45(2):139-145. doi:10.1111/j.1365-4632.2004.02361.x

22. Helander SD, Peters MS, Kuo TT, Su WP. Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: new observations from immunohistochemical studies of lymphocyte markers, endothelial antigens, and granulocyte proteins. J Cutan Pathol. 1995;22(4):319-326. doi:10.1111/j.1600-0560.1995.tb01414.x

23. Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia: a clinicopathologic study of 116 patients. J Am Acad Dermatol. 1985;12:781-796. doi:10.1016/s0190-9622(85)70098-9

24. Zeitouni NC, Hanna S, Loree TR, Brooks J, Cheney RT. Angiolymphoid hyperplasia with eosinophilia: a classic clinical presentation with histologic features of angiosarcoma. Dermatologic Surg. 2002;28(8):772-775. doi:10.1046/j.1524-4725.2002.02006.x

25. Horst C, Kapur N. Propranolol: a novel treatment for angiolymphoid hyperplasia with eosinophilia. Clin Exp Dermatol. 2014;39(7):810-812. doi:10.1111/ced.12412

26. Chen H, Thompson LDR, Aguilera NSI, Abbondanzo SL. Kimura disease: a clinicopathologic study of 21 cases. Am J Surg Pathol. 2004;28(4):505-513. doi:10.1097/00000478-200404000-00010

27. Andreae J, Galle C, Magdorf K, et al. Severe atherosclerosis of the aorta and development of peripheral T-cell lymphoma in an adolescent with angiolymphoid hyperplasia with eosinophilia. Br J Dermatol. 2005;152(5):1033-1038. doi:10.1111/j.1365-2133.2005.06421.x

28. Chen JF, Gao HW, Wu BY, Tsai WC, Chiang CP. Angiolymphoid hyperplasia with eosinophilia affecting the scrotum: a rare case report with molecular evidence of T-cell clonality. J Dermatol 2010;37(4):355-359. doi:10.1111/j.1346-8138.2010.00818.x

29. Gonzalez-Cuyar LF, Tavora F, Zhao XF, et al. Angiolymphoid hyperplasia with eosinophilia developing in a patient with history of peripheral T-cell lymphoma: evidence for multicentric T-cell lymphoproliferative process. Diagn Pathol. 2008;3:22. doi:10.1186/1746-1596-3-22

30. Brenn T, Flencher CDM. Cutaneous Epithelioid angiomatous nodule: a distinct lesion in the morphologic spectrum of epithelioid vascular tumors. Am J Dermatopathol. 2004;26(1):14-21. doi:10.1097/00000372-200402000-00003

31. Lam YT, Hsu C-J, Simpson PJL, et al. Androgens stimulate EPC-mediated neovascularization and are associated with increased coronary collateralization. Endocrinology. 2020;161(5):1-13. doi:10.1210/endocr/bqaa043

32. Motamer M, Javanmard SH, Mortazavi ZS, Bahrani S. Evaluation of the effect of testosterone on the number of endothelial progenitor cells and amount of SDF-1a, PDGF, bFGF, and NO. Int J Prev Med. 2019;10:214. doi:10.4103/ijpvm.IJPVM_79_18

33. Chodari L, Mohammadi M, Ghorbanzadeh V, Dariushnejad H, Mohaddes G. Testosterone and voluntary exercise promote angiogenesis in hearts of rats with diabetes by enhancing expression of VEGF-A and SDF-1a. Can J Diabetes. 2016;40(5):436-441. doi:10.1016/j.jcjd.2016.03.004

34. Blackwood L, Chapman I, Lyon M, Hernandez C. Multifocal eruptive cutaneous epithelioid angiomatous nodules. JAAD Case Reports. 2016;2(6):454-456. doi:10.1016/j.jdcr.2016.09.013.

35. Luzar B, Calonje E. Update on cutaneous epithelioid vascular tumours. Diagnostic Histopathol. 2018;24(8):273-287. doi:10.1016/j.mpdhp.2018.06.002

36. Pavlidakey PG, Burroughs C, Karrs T, Somach SC. Cutaneous epithelioid angiomatous nodule: a case with metachronous lesions. Am J Dermatopathol. 2011;33(8):831-834. doi:10.1097/DAD.0b013e3181fef12c

37. Labbène I, Rammeh S, Znaidi N, Fazaa B, Zermani R. A case of multiple epithelioid angiomatous nodules. Dermatol Online J. 2012;18(8):8.

38. Dastgheib L, Aslani FS, Sepaskhak M, Saki N, Motevalli D. A young woman with multiple cutaneous epithelioid angiomatous nodules (CEAN) on her forearm: a case report and follow-up of therapeutic intervention. Dermatol Online J. 2013;19(3):1.