Multifocal epithelial hyperplasia (Heck disease) in a patient with chronic lymphocytic leukemia

J Cutan Pathol 2014: 41: 694–696doi: 10.1111/cup.12341John Wiley & Sons. Printed in Singapore

© 2014 John Wiley & Sons A/S.Published by John Wiley & Sons Ltd

Journal ofCutaneous Pathology

Letter to the Editor

Multifocal epithelial hyperplasia (Heckdisease) in a patient with chroniclymphocytic leukemia

Keywords: Heck disease, human papilloma virus, immunosuppression, leukemia, multifocal epithelialhyperplasia

To the Editor ,Multifocal epithelial hyperplasia (MEH), also

known as Heck disease, is a benign disease ofthe oral mucosa characterized by proliferativelesions most commonly associated with humanpapillomavirus (HPV) subtypes 13 and 32.1 MEHpresents clinically as numerous asymptomaticpink papules and plaques typically found onthe labial and buccal mucosa. Histopathologicmarkers include broad interconnecting rete andmitosoid figures. While ordinarily self-limited innature, lesions can persist indefinitely and mayrecur in immunocompromised hosts. Herein, wepresent a case of MEH associated with chroniclymphocytic leukemia (CLL).

A 52-year-old white male was referred to der-matology for oral lesions. He had a historyof high-risk CLL for which he was currentlyenrolled in a clinical trial of Ofatumumab(Genmab, Copenhagen, Denmark) (anti-CD20monoclonal antibody) and Dinaciclib (Merck,Whitehouse Station, NJ, USA) (SCH727965,a cyclin-dependent kinase inhibitor). Duringthe course of treatment over several years, hereported a gradual onset of enlarging asymp-tomatic flat-topped white plaques on his buccaland labial mucosa and lateral tongue (Figs. 1 and2). His CD4-positive T-cell count was 374 cells/μlat the time of examination.

Shave biopsy from one of the lesions revealedacanthosis with mild papillomatosis (Fig. 3).Some of the keratinocytes showed perinuclearhalos and shrunken hyperchromatic nuclei,features diagnostic of HPV infection. Scattereddyskeratotic cells were seen without significant

Fig. 1. Multifocal epithelial hyperplasia: a clinical photographshows diffuse plaque formation on the buccal and labialmucosa.

cytological atypia. Broad anastomosing retepegs, superficial koilocytes, few binucleate ker-atinocytes and rare mitosoid figures were noted(Fig. 4), supporting the diagnosis of MEH. Inthis context, HPV typing can be consideredbut is not widely commercially available for theassociated subtypes and may reduce diagnos-tic clarity in some cases by cross-reacting withother HPV strands.1 Imiquimod treatment wasinitiated for our patient, while cryotherapy, CO2laser and interferon have been used in otherstudies with limited success.2

The differential diagnosis includes condylomaacuminatum, another HPV-induced disease

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Fig. 2. Multifocal epithelial hyperplasia: plaque formation isdepicted.

Fig. 3. Multifocal epithelial hyperplasia: a shave biopsy displaysacanthosis with mild papillomatosis and broad anastomosingrete pegs (hematoxylin–eosin stain; original magnification:×100.)

with occasional multifocal presentation in theoral mucosa, although those lesions tend tobe more elevated and have a much rougher,cauliflower-like surface architecture. The diffusenature of MEH lesions varies from squamouspapillomas and verruciform xanthomas, whichare typically solitary.2 Verruca vulgaris rarelyaffects the oral mucosa and generally has a morewhite appearance. Verrucous carcinoma is muchthicker and appears whiter because of surfacekeratin production. White sponge nevus is not

Fig. 4. Multifocal epithelial hyperplasia: at higher magnifica-tion, the biopsy displays characteristic koilocytosis, cellular bin-ucleation and mitosoid figures (hematoxylin–eosin stain; orig-inal magnification: ×400.)

significantly elevated, and the white appearanceof that condition would not be consistent withMEH.2

Understanding of disease susceptibility is stillevolving, but known at-risk groups includechildren, human immunodeficiency virus(HIV)-infected patients and impoverishedpopulations living in close quarters. In addition,increased familial propensity for MEH and thepresence of geographical disease clusters histor-ically in Greenland and Central America mightsuggest a genetic predisposition.1,2 The majorhistocompatibility complexes of MEH patientsstudied in Mexico have exhibited an increasedHLA-DR4 allele frequency of the DRB1*04:04subtype compared with control populations.3Our patient was found to have a DRB1*04:01subtype, albeit one rarely seen in the Mexicanpopulation studied. Nevertheless, this close DR4allele relation may have contributed to ourpatient’s predisposition for infection.

Mechanistically, CLL patients have shown animpaired capacity for immunological synapseformation between antigen-presenting cellsand CD4/CD8 T-cells because of ineffec-tive regulation of actin polymerization andremodeling.4 This intrinsic defect of immuno-logic communication limits antigen recognitionand results in a markedly reduced T-cellresponse which, when combined with the novelofatumumab/dinaciclib combination, likelycontributed to the failure of disease clearance inour patient.4

This case illustrates MEH occurrence ina patient with an immunosuppressed state

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from CLL treatment. This further establishesnon-HIV-related immunosuppression as a riskfactor for this low-grade HPV-induced disease.5

Andrew T. Patterson, BS1

Leslie Andritsos, MD2

Carl M. Allen, DDS, MSD3

Alejandro Gru, MD4

Benjamin H. Kaffenberger, MD5,*

1Ohio State University College of Medicine,Columbus, OH, USA

2Blood and Marrow Transplantation Program,Division of Hematology, Ohio State University

College of Medicine, Columbus, OH, USA3Oral and Maxillofacial Pathology,

Ohio State University College of Dentistry,Columbus, OH, USA

4Department of Pathology, Ohio State UniversityCollege of Medicine, Columbus, OH, USA

5Division of Dermatology, Ohio State UniversityCollege of Medicine, Columbus, OH, USA

e-mail: Benjamin.Kaffenberger@osumc.edu

References1. Bennett LK, Hinshaw M. Heck’s disease:

diagnosis and susceptibility. Pediatr Derma-tol 2009; 26: 87.

2. Said AK, Leao JC, Fedele S, Porter SR. Focalepithelial hyperplasia – an update. J OralPathol Med 2013; 42: 435.

3. García-Corona C, Vega-Memije E,Mosqueda-Taylor A, et al. Association

of HLA-DR4 (DRB1*0404) with humanpapillomavirus infection in patients withfocal epithelial hyperplasia. Arch Dermatol2004; 140: 1227.

4. Ramsay AG, Johnson AJ, Lee AM, et al.Chronic lymphocytic leukemia T cells showimpaired immunological synapse formation

that can be reversed with an immunomodu-lating drug. J Clin Invest 2008; 118: 2427.

5. Mealey BL, Hallmon WW, WaldropTC. Occurrence and resolution of focalepithelial hyperplasia in two siblingswith leukocyte adhesion deficiency.J Periodontol 1993; 64: 149.

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