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several months. Our patient was without hydroxyurea for 2 months and showed no improvement. Only after the hydroxyurea therapy was discontinued permanently was her ulcer finally able to resolve with medical and surgical intervention. Another complicating factor in our patient’s wound healing was the immunosuppressive effects of the prednisone and azathioprine, which likely led to intermittent superinfection and prevented the ulcer from healing on its own. Why does hydroxyurea cause cutaneous ulceration? Almost all patients taking hydroxyurea develop megaloblastic erythrocytes within 24 hours, causing decreased susceptibility to deformation that impairs capillary blood flow to the skin.4,5 The result is cutaneous anoxia followed by ulceration. This mechanism may explain why the malleolus, a frequent site of trauma, is a common location for these ulcers. In our patient, the ulcer developed after cryotherapy, which led to skin breakdown and ultimately ulceration. MTHFR polymorphisms, such as the homozygous C→T substitution at nucleotide 677 found in our patient and in 10% to 13% of the white population, can lead to arterial occlusive disease and ulceration. This results from decreased enzyme activity, which causes an increased total homocysteine level in the presence of suboptimal folate intake.6 The concurrent existence of an MTHFR polymorphism or other thrombophilic genetic mutation in a patient taking hydroxyurea could be the complicating insult that leads to cutaneous ulceration. Therefore, we recommend screening for an array of coagulation abnormalities that predispose to thrombophilia (including MTHFR polymorphisms) in patients with ulcers unresponsive to standard therapy as well as the use of B vitamin supplementation in patients with a MTHFR polymorphism. Future studies looking at MTHFR polymorphisms in patients with hydroxyurea-induced ulcers may solidify this association. Sunita C. Crittenden, MD Juliana E. Gilbert, MD Jeffrey P. Callen, MD

Author Affiliations: Division of Dermatology, University of Louisville, Louisville, Kentucky. Corresponding Author: Sunita C. Crittenden, MD, Division of Dermatology, University of Louisville, Louisville, Kentucky, 310 E Broadway, Floor 2A, Louisville, KY 40202 ([email protected]). Published Online: March 5, 2014. doi:10.1001/jamadermatol.2013.7198. Conflict of Interest Disclosures: None reported. 1. Montefusco E, Alimena G, Gastaldi R, Carlesimo OA, Valesini G, Mandelli F. Unusual dermatologic toxicity of long-term therapy with hydroxyurea in chronic myelogenous leukemia. Tumori. 1986;72(3):317-321. 2. New D, Eaton P, Knable A, Callen JP. The use of B vitamins for cutaneous ulcerations mimicking pyoderma gangrenosum in patients with MTHFR polymorphism. Arch Dermatol. 2011;147(4):450-453. 3. Latagliata R, Spadea A, Cedrone M, et al; Gruppo Laziale SMPC Ph1 neg. Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms: the Mister Hyde face of a safe drug. Cancer. 2012;118(2):404-409. 4. Boyd AS, Neldner KH. Hydroxyurea therapy. J Am Acad Dermatol. 1991;25(3): 518-524. 5. Sirieix ME, Debure C, Baudot N, et al. Leg ulcers and hydroxyurea: forty-one cases. Arch Dermatol. 1999;135(7):818-820.

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6. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet. 1999; 354(9176):407-413.

Agminated Pyogenic Granuloma–Like Growth Arising in a Congenital Hemangioma Pyogenic granulomas (PGs), usually solitary and isolated, have rarely been reported to arise as lesions within preexisting vascular malformations.1 Multiple, distinct, PG-like lesions within capillary or arteriovenous malformations (AVMs) have been described.2 To our knowledge, no cases of solitary or agminated PG-type growths have been reported in congenital hemangiomas (CHs). Report of a Case | A healthy male infant presented with a congenital, unchanged, asymptomatic, 2.5-cm, indurated, violaceous plaque with a surrounding blue to white halo on the right jawline (Figure 1A). No other hemangiomas were present. Ultrasonography showed a lobulated vascular mass with prominent flow, consistent with CH. Findings of a subsequent complete blood cell count were normal. Three months later, the patient returned with bleeding and friable granulation tissue–like changes within the hemangioma (Figure 1B). Agminated PG overlying the preexisting CH was suspected. The superficial friable tissue and a portion of the primary lesion were excised. Ten days after excision, there was partial regrowth of the lesion. Examination revealed an overlying 1.0-cm area of coalescing, erythematous, and friable papules, consistent with recurrent agminated PG (Figure 1C). This was then reexcised in its entirety. Microscopic evaluation showed a lobular proliferation of capillaries in the superficial dermis and a capillary proliferation in the deep dermis and subcutaneous tissue with intervening dermal fibrosis with sparse entrapped capillaries (Figure 2A-C). Endothelial cells were immunoreactive for CD31 and CD34. Staining with Ki-67 demonstrated differentially increased activity in the superficial (ie, PG-like) portion vs the deeper (ie, CH) portion (Figure 2D and E), even when the intermixture of inflammatory cells within the superficial portion was accounted for. Stainings with GLUT-1, VVG, WT1, and OCT4 proved negative throughout the lesion. Smooth-muscle actin demonstrated precapillary sphincters throughout the superficial and deep portions. The patient, 1 year later, remained free from recurrence. Discussion | Agminated PGs arising in association with a preexisting vascular lesion have been reported in 5 previous cases. Two adults developed agminated PGs with underlying AVMs.3 Three children developed agminated PGs within preexisting macular congenital vascular malformations believed to represent AVMs.4 Recently, the microscopic presence of areas of microvascular proliferation (similar to that of PGs) has been described in a subset of excised symptomatic or changing venous malformations and AVMs. Similar to the present case, these areas of microvascular proliferation demonstrated high levels of Ki-67 labeling.5 Of the vascular lesions in which microscopic evidence of microvascular proliferation was present, 90% were AVMs.5 JAMA Dermatology July 2014 Volume 150, Number 7

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Figure 1. Clinical Photographs of Patient B

A

C

A, Violaceous plaque on the right jawline at first presentation. B, Patient presented 3 months later with bleeding and new growth associated with pain at the superior pole of the lesion. C, Recurrence of grouped erythematous nodules was apparent 10 days after partial excision of the lesion.

Figure 2. Microscopic Features

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B

D

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Hematoxylin-eosin (A-C) and Ki-67–stained (D and E) specimens. A and B, Pyogenic granuloma (A) overlying a deep capillary congenital hemangioma proliferation (B) with intervening stroma containing fibrosis with entrapped capillaries (original magnifications ×40). C, Superficial lobular capillary proliferation with a collarette of scale, with dermal fibrosis and entrapped

capillaries; a deeper collection of capillaries is seen in the deep dermis and subcutaneous tissue (original magnification ×4). D and E, Staining with Ki-67 demonstrated an increased mitotic index in the superficial component (D) compared with the deep one (E) (original magnifications ×40 [D] and ×20 [E]).

Microvascular proliferation and PGs may occur commonly in AVMs owing to the high-flow properties of AVMs and subsequent biomechanical effects on angiogenesis, which may activate the FLT4 and nitric oxide pathway, a proposed mechanism of angiogenic growth in the development of PG-like lesions.5,6 Both CHs and infantile hemangiomas (IHs) are also high-flow vascular tumors, but despite the common occurrence of IHs, PGs have not been reported to occur in association, possibly owing to the inherent properties of IHs to gradually involute with time.

Given our observation of dermal fibrosis and entrapped capillaries in the tissue between the deeper CH and the superficial PG-like proliferation, this may have represented a single neoplasm. Specifically, the deep capillary proliferation may have tracked up to the superficial dermis, perhaps due to angiogenesis growth factor release in the local microenvironment or in response to minor trauma. The differential Ki-67 labeling does not necessarily indicate that the 2 processes are entirely distinct. In conclusion, we present the novel observation of agminated PG arising in association with a CH. Recognition of this

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type of proliferative vascular growth within noninvoluting, high-flow anomalies may prompt earlier treatment. Further study may provide clues regarding the pathogenesis and treatment of high-flow vascular growths and of proliferative lesions arising in this context. Benjamin Barrick, DO Julia Lehman, MD Megha Tollefson, MD

Author Affiliations: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota (Barrick); Department of Dermatology, Mayo Clinic, Rochester, Minnesota (Lehman, Tollefson). Corresponding Author: Megha Tollefson, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (Tollefson.megha@mayo .edu). Published Online: March 19, 2014. doi:10.1001/jamadermatol.2013.7530. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported financially by the Department of Dermatology at Mayo Clinic. Role of the Sponsors: The Department of Dermatology at Mayo Clinic had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

surrounded by a dense infiltrate composed of small round lymphocytes, histiocytes, mature plasma cells, eosinophils, and a smaller percentage of larger centrocyte-like cells (Figure 2). Most of the cells in the infiltrate were positive for the pan-B cell markers CD20 and CD79a. The cells in the germinal centers were also positive for CD10 and BCL6 and negative for BCL2. The small lymphocytes in the infiltrate were positive for CD3. On the basis of the overall histologic findings, a working diagnosis of primary cutaneous B-cell lymphoma of marginal zone was initially considered, but the histologic specimens were subsequently referred for a second opinion to an expert dermatopathologist. The histologic review suggested a possible differential diagnosis of cutaneous pseudolymphoma mimicking a marginal zone lymphoma, further supported by the absence of light-chain restriction by in situ hybridization. Questioning the patient again revealed that 5 or 6 weeks prior to the onset of the skin eruption, she had undergone a course of natural therapy for chronic fibromyalgia that involved applying medicinal leeches (Hirudo medicinalis). Therefore, a favored diagnosis of pseudolymphoma secondary to the application of leeches was made.

Figure 1. Clinical Photograph of Pruritic Skin Eruption

1. Chen D, Hu XJ, Lin XX, et al. Nodules arising within port-wine stains: a clinicopathologic study of 31 cases. Am J Dermatopathol. 2011;33(2):144-151. 2. Garzon MC, Enjolras O, Frieden IJ. Vascular tumors and vascular malformations: evidence for an association. J Am Acad Dermatol. 2000;42(2 Pt 1):275-279. 3. Kim DH, Kim MY, Park YM, Kim HO. Agminated lobular capillary hemangiomas presumably associated with an acquired arteriovenous malformation. J Dermatol. 2006;33(9):646-648. 4. Baselga E, Wassef M, Lopez S, Hoffman W, Cordisco M, Frieden IJ. Agminated, eruptive pyogenic granuloma-like lesions developing over congenital vascular stains. Pediatr Dermatol. 2012;29(2):186-190. 5. Meijer-Jorna LB, van der Loos CM, de Boer OJ, et al. Microvascular proliferations in arteriovenous malformations relate to high-flow characteristics, inflammation, and previous therapeutic embolization of the lesion. J Am Acad Dermatol. 2013;68(4):638-646.

The image shows the presence of multiple firm and excoriated papules and nodules on the back (arrowheads).

6. Godfraind C, Calicchio ML, Kozakewich H. Pyogenic granuloma, an impaired wound healing process, linked to vascular growth driven by FLT4 and the nitric oxide pathway. Mod Pathol. 2013;26(2):247-255.

Figure 2. Histopathologic Findings of a Punch Biopsy Taken From an Excoriated Nodule on the Back

Diffuse Cutaneous Pseudolymphoma Due to Therapy With Medicinal Leeches Primary cutaneous B-cell lymphoma and B-cell pseudolymphoma may show similar clinical and microscopic presentations and sometimes represent a real diagnostic challenge for both clinician and pathologist.1 Report of a Case | A woman on her 50s presented with a 6-month history of multiple, firm, reddish, pruritic and excoriated papules and nodules extensively distributed on the back (Figure 1). The patient was otherwise healthy, with a medical history of only fibromyalgia, and both clinical examination and blood test findings were unremarkable. Histologic examination of 2 punch biopsy specimens taken from the nodules on the back showed a prominent dermal nodular lymphoid infiltrate with germinal centers jamadermatology.com

The image shows the presence of a dense, nodular, and diffuse infiltrate in the dermis. Note the presence of germinal centers (hematoxylin-eosin, original magnification ×20).

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Agminated pyogenic granuloma-like growth arising in a congenital hemangioma.

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