Agminated Pyogenic Granuloma–Like Growth

Letters

several months. Our patient was without hydroxyurea for 2 6. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet. 1999; months and showed no improvement. Only after the hydroxy- 354(9176):407-413. urea therapy was discontinued permanently was her ulcer fi- nally able to resolve with medical and surgical intervention. An- Agminated Pyogenic Granuloma–Like Growth other complicating factor in our patient’s wound healing was Arising in a Congenital Hemangioma the immunosuppressive effects of the prednisone and azathio- Pyogenic granulomas (PGs), usually solitary and isolated, have prine, which likely led to intermittent superinfection and pre- rarely been reported to arise as lesions within preexisting vas- vented the ulcer from healing on its own. cular malformations.1 Multiple, distinct, PG-like lesions within Why does hydroxyurea cause cutaneous ulceration? Al- capillary or arteriovenous malformations (AVMs) have been most all patients taking hydroxyurea develop megaloblastic described.2 To our knowledge, no cases of solitary or agmi- erythrocytes within 24 hours, causing decreased susceptibil- nated PG-type growths have been reported in congenital hem- ity to deformation that impairs capillary blood flow to the angiomas (CHs). skin.4,5 The result is cutaneous anoxia followed by ulceration. This mechanism may explain why the malleolus, a fre- Report of a Case | A healthy male infant presented with a con- quent site of trauma, is a common location for these ulcers. genital, unchanged, asymptomatic, 2.5-cm, indurated, viola- In our patient, the ulcer developed after cryotherapy, which ceous plaque with a surrounding blue to white halo on the right led to skin breakdown and ultimately ulceration. jawline (Figure 1A). No other hemangiomas were present. Ul- MTHFR polymorphisms, such as the homozygous C→T trasonography showed a lobulated vascular mass with promi- substitution at nucleotide 677 found in our patient and in 10% nent flow, consistent with CH. to 13% of the white population, can lead to arterial occlusive Findings of a subsequent complete blood cell count were disease and ulceration. This results from decreased enzyme normal. Three months later, the patient returned with bleed- activity, which causes an increased total homocysteine level ing and friable granulation tissue–like changes within the he- in the presence of suboptimal folate intake.6 mangioma (Figure 1B). Agminated PG overlying the preexist- The concurrent existence of an MTHFR polymorphism or ing CH was suspected. The superficial friable tissue and a other thrombophilic genetic mutation in a patient taking hydroxy- portion of the primary lesion were excised. urea could be the complicating insult that leads to cutaneous Ten days after excision, there was partial regrowth of the ulceration. Therefore, we recommend screening for an array of lesion. Examination revealed an overlying 1.0-cm area of co- coagulation abnormalities that predispose to thrombophilia alescing, erythematous, and friable papules, consistent with (including MTHFR polymorphisms) in patients with ulcers un- recurrent agminated PG (Figure 1C). This was then reexcised responsive to standard therapy as well as the use of B vitamin in its entirety. supplementation in patients with a MTHFR polymorphism. Fu- Microscopic evaluation showed a lobular proliferation of cap- ture studies looking at MTHFR polymorphisms in patients with illaries in the superficial dermis and a capillary proliferation in hydroxyurea-induced ulcers may solidify this association. the deep dermis and subcutaneous tissue with intervening dermal fibrosis with sparse entrapped capillaries (Figure 2A-C). En- Sunita C. Crittenden, MD dothelial cells were immunoreactive for CD31 and CD34. Stain- Juliana E. Gilbert, MD ing with Ki-67 demonstrated differentially increased activity in Jeffrey P. Callen, MD 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 Author Affiliations: Division of Dermatology, University of Louisville, Louisville, Kentucky. with GLUT-1, VVG, WT1, and OCT4 proved negative throughout Corresponding Author: Sunita C. Crittenden, MD, Division of Dermatology, the lesion. Smooth-muscle actin demonstrated precapillary University of Louisville, Louisville, Kentucky, 310 E Broadway, Floor 2A, sphincters throughout the superficial and deep portions. The pa- Louisville, KY 40202 ([email protected]). tient, 1 year later, remained free from recurrence. Published Online: March 5, 2014. doi:10.1001/jamadermatol.2013.7198. Discussion | Agminated PGs arising in association with a preex- Conflict of Interest Disclosures: None reported. isting vascular lesion have been reported in 5 previous cases. 1. Montefusco E, Alimena G, Gastaldi R, Carlesimo OA, Valesini G, Mandelli F. Two adults developed agminated PGs with underlying AVMs.3 Unusual dermatologic toxicity of long-term therapy with hydroxyurea in chronic myelogenous leukemia. Tumori. 1986;72(3):317-321. Three children developed agminated PGs within preexisting macular congenital vascular malformations believed to rep- 2. New D, Eaton P, Knable A, Callen JP. The use of B vitamins for cutaneous 4 ulcerations mimicking pyoderma gangrenosum in patients with MTHFR resent AVMs. polymorphism. Arch Dermatol. 2011;147(4):450-453. Recently, the microscopic presence of areas of microvas- 3. Latagliata R, Spadea A, Cedrone M, et al; Gruppo Laziale SMPC Ph1 neg. cular proliferation (similar to that of PGs) has been described Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia in a subset of excised symptomatic or changing venous mal- chromosome-negative myeloproliferative neoplasms: the Mister Hyde face of a safe drug. Cancer. 2012;118(2):404-409. formations and AVMs. Similar to the present case, these areas of microvascular proliferation demonstrated high levels of 4. Boyd AS, Neldner KH. Hydroxyurea therapy. J Am Acad Dermatol. 1991;25(3): 5 518-524. Ki-67 labeling. Of the vascular lesions in which microscopic 5. Sirieix ME, Debure C, Baudot N, et al. Leg ulcers and hydroxyurea: forty-one evidence of microvascular proliferation was present, 90% were cases. Arch Dermatol. 1999;135(7):818-820. AVMs.5

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Figure 1. Clinical Photographs of Patient

A B 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

A B C

D E

Hematoxylin-eosin (A-C) and Ki-67–stained (D and E) specimens. A and B, capillaries; a deeper collection of capillaries is seen in the deep dermis and Pyogenic granuloma (A) overlying a deep capillary congenital hemangioma subcutaneous tissue (original magnification ×4). D and E, Staining with Ki-67 proliferation (B) with intervening stroma containing fibrosis with entrapped demonstrated an increased mitotic index in the superficial component (D) capillaries (original magnifications ×40). C, Superficial lobular capillary compared with the deep one (E) (original magnifications ×40 [D] and ×20 [E]). proliferation with a collarette of scale, with dermal fibrosis and entrapped

Microvascular proliferation and PGs may occur com- Given our observation of dermal fibrosis and entrapped cap- monly in AVMs owing to the high-flow properties of AVMs and illaries in the tissue between the deeper CH and the superficial subsequent biomechanical effects on angiogenesis, which may PG-like proliferation, this may have represented a single neo- activate the FLT4 and nitric oxide pathway, a proposed mecha- plasm. Specifically, the deep capillary proliferation may have nism of angiogenic growth in the development of PG-like tracked up to the superficial dermis, perhaps due to angiogen- lesions.5,6 Both CHs and infantile hemangiomas (IHs) are also esis growth factor release in the local microenvironment or in re- high-flow vascular tumors, but despite the common occur- sponse to minor trauma. The differential Ki-67 labeling does not rence of IHs, PGs have not been reported to occur in associa- necessarily indicate that the 2 processes are entirely distinct. tion, possibly owing to the inherent properties of IHs to gradu- In conclusion, we present the novel observation of agmi- ally involute with time. nated PG arising in association with a CH. Recognition of this

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type of proliferative vascular growth within noninvoluting, surrounded by a dense infiltrate composed of small round high-flow anomalies may prompt earlier treatment. Further lymphocytes, histiocytes, mature plasma cells, eosinophils, study may provide clues regarding the pathogenesis and treat- and a smaller percentage of larger centrocyte-like cells ment of high-flow vascular growths and of proliferative le- (Figure 2). Most of the cells in the infiltrate were positive for sions arising in this context. the pan-B cell markers CD20 and CD79a. The cells in the germinal centers were also positive for CD10 and BCL6 and Benjamin Barrick, DO negative for BCL2. The small lymphocytes in the infiltrate Julia Lehman, MD were positive for CD3. On the basis of the overall histologic Megha Tollefson, MD 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 Author Affiliations: Department of Internal Medicine, Mayo Clinic, Rochester, second opinion to an expert dermatopathologist. The histo- Minnesota (Barrick); Department of Dermatology, Mayo Clinic, Rochester, logic review suggested a possible differential diagnosis of Minnesota (Lehman, Tollefson). cutaneous pseudolymphoma mimicking a marginal zone Corresponding Author: Megha Tollefson, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (Tollefson.megha@mayo lymphoma, further supported by the absence of light-chain .edu). restriction by in situ hybridization. Published Online: March 19, 2014. Questioning the patient again revealed that 5 or 6 weeks doi:10.1001/jamadermatol.2013.7530. prior to the onset of the skin eruption, she had undergone a Conflict of Interest Disclosures: None reported. course of natural therapy for chronic fibromyalgia that in- Funding/Support: This study was supported financially by the Department of volved applying medicinal leeches (Hirudo medicinalis). There- Dermatology at Mayo Clinic. fore, a favored diagnosis of pseudolymphoma secondary to the Role of the Sponsors: The Department of Dermatology at Mayo Clinic had no application of leeches was made. 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. 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 The image shows the presence of multiple firm and excoriated papules and characteristics, inflammation, and previous therapeutic embolization of the nodules on the back (arrowheads). lesion. J Am Acad Dermatol. 2013;68(4):638-646. 6. Godfraind C, Calicchio ML, Kozakewich H. Pyogenic granuloma, an impaired Figure 2. Histopathologic Findings of a Punch Biopsy Taken From wound healing process, linked to vascular growth driven by FLT4 and the nitric oxide pathway. Mod Pathol. 2013;26(2):247-255. 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 presenta- tions 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 The image shows the presence of a dense, nodular, and diffuse infiltrate in the taken from the nodules on the back showed a prominent dermis. Note the presence of germinal centers (hematoxylin-eosin, original magnification ×20). dermal nodular lymphoid infiltrate with germinal centers

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