Clinical Review & Education

JAMA Dermatology Clinicopathological Challenge

Painful Mucosal Ulcerations in a Patient With HIV

Ayan Kusari, MD; Ursula E. Lang, MD, PhD; Aileen Y. Chang, MD

A Inferior lip B External anal mucosa C Original magnification ×40 D Original magnification ×40

Figure. A, Healing oval punched-out ulceration of inferior lip and white plaques on tongue consistent with thrush. B, Two ovoid, punched-out ulcerations of the
external anal mucosa. C, Hematoxylin-eosin staining of perianal lesion showed mixed infiltrate of histiocytes, neutrophils, lymphocytes, and eosinophils, with
prominent admixed large and atypical cells at high power. D, Epstein-Barr virus–encoded RNA staining showed scattered positivity in some cells.

A man in his 40s with a long-standing history of poorly controlled HIV (multiple treatment
lapses, viral load of 22 871 copies/mL 8 months prior to presentation but now undetect- WHAT IS YOUR DIAGNOSIS?
able with use of highly active antiretroviral therapy, with a CD4 count of 40 cells/mm3) pre-
sented to the emergency department with nausea, abdominal pain, bloody stools, odyno- A. Chronic ulcerative herpes simplex
phagia, and recurrent oral and perianal ulcers and was found to have pancytopenia and septic virus
shock. During admission in the intensive care unit, treatment with broad-spectrum oral an-
tibiotics for presumed infection and oral fluconazole for thrush led to improvement in the
B. Epstein-Barr virus–positive
patient’s medical condition, but the ulcers persisted. Dermatology was consulted for input
mucocutaneous ulcers
on the cause of the ulcers, which had been ongoing for approximately 6 months prior; in-
dividual lesions lasted 1 to 3 weeks before self-resolving. Biopsy of an oral mucosal lesion
performed 1 month earlier had shown nonspecific inflammation. Examination revealed ex- C. Crohn disease associated with
quisitely tender, ovoid, punched-out ulcerations of the inferior lip and scrapeable white pyostomatitis vegetans
plaques on the tongue (Figure, A), right buccal mucosa, and external anal mucosa (Figure,
B). A punch biopsy from 1 of the perianal ulcers was performed (Figure, C and D). D. Ulcers secondary to fungal
infection

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Diagnosis
B. Epstein-Barr virus–positive mucocutaneous ulcers
Discussion
Histopathologic evaluation showed ulcerated squamous epithe-
lium with prominent mixed infiltrate of histiocytes, neutrophils,
lymphocytes, and eosinophils, with prominent admixed large and
atypical cells, some of which contained larger, atypical nuclei. Gram,
acid-fast bacilli, and periodic acid–Schiff diastase results were all nega-
tive for organisms, as were herpes simplex virus type 1 (HSV-1) and
HSV-2 stains. An Epstein-Barr virus (EBV)–encoded RNA (EBER) in
situ hybridization study was performed and demonstrated positiv-
ity in scattered lymphocytes that raised concern for EBV-positive mu-
cocutaneous ulcers. Bone marrow biopsy was performed and did not
show concerning abnormalities. The patient continued treatment
with highly active antiretroviral therapy for HIV with some improve-
ment in CD4 count to 62 cells/mm3 1 month following discharge, and
the thrush resolved with oral fluconazole. The ulcers resolved
without reoccurrence between discharge and follow-up 3 months
later.
Epstein-Barr virus–positive mucocutaneous ulceration
(EBVMCU) is a low-grade B-cell lymphoproliferative disorder driven
by EBV infection in the setting of diminished adaptive immune func-
tion. It is most common in patients taking immunosuppressants, par-
ticularly cyclosporine A, azathioprine, and tacrolimus, because these
suppress cytotoxic (CD8+) T-cell function.1 Methotrexate directly in-
duces EBV replication by activating early viral promoters, and its use
was an early identified risk factor for EBVMCU.2 Infection with HIV,
particularly poorly controlled infection that results in decreased CD4+
T-cell count, is also strongly associated with EBVMCU.3 In contrast
with more aggressive forms of posttransplant lymphoproliferative
disorder (PTLD), EBVMCU has an indolent course and is generally
associated with less profound immunosuppression.4 Serum EBV
DNA load is often, though not always, undetectable in EBVMCU,

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 Clinical Review & Education JAMA Dermatology Clinicopathological Challenge

whereas it is usually elevated in more aggressive forms of PTLD.4
These distinguishing features can be helpful because the lympho-
cytes in EBVMCU often demonstrate aggressive-appearing cyto-
morphologic characteristics.4
Well circumscribed, discrete, round ulcerations of the mouth
and perianal mucosa are characteristic; involvement of the trunk,
arms, and other cutaneous locations has also been described. In
some cases, as with the current patient, the morphologic charac-
teristics can be reminiscent of a Lipschütz ulcer, which is typically
seen in young, otherwise healthy female individuals and is also
driven by EBV infection but not indicative of a lymphoproliferative
disorder.5
Biopsy is needed to establish the diagnosis of EBVMCU and
shows large, atypical lymphocytes, immunoblasts, and/or Reed
Sternberg–like cells within a polymorphous infiltrate.1,4 Staining with
EBER, when performed, is invariably positive and may help to es-
tablish the diagnosis.1,6 Treatment depends on the size of the le-
sion and the clinical context; smaller lesions may resolve spontane-
ously within 4 to 12 weeks. 1,6,7 When feasible, reduction of
immunosuppression aids clearance. More extensive lesions associ-
ated with pain or frequent bleeding should be treated; in such cases,
cyclophosphamide, doxorubicin, vinblastine, and prednisone, as well
as radiation therapy, have been successfully used.6,7
The differential diagnosis for this patient’s ulcers includes chronic
ulcerative HSV infection, Crohn disease associated with pyostoma-
titis vegetans, cutaneous T-cell lymphoma, and ulcers secondary to
fungal infection. Chronic ulcerative HSV infection does not typi-
cally spontaneously resolve, and while histopathology may show a
prominent lymphocytic infiltrate, atypical lymphocytes are not a
common histopathologic feature. Pyostomatitis vegetans is asso-
ciated with inflammatory bowel disease, and perianal ulcers and fis-
tulas are often a feature of Crohn disease. However, in pyostoma-
titis vegetans, mucosal microabscesses and pustules coalesce on an
erythematous base to form a “snail track” morphologic appearance8
that may erupt, creating an ulcer; these features were not seen in
this patient. Furthermore, large, atypical lymphocytes as seen in this
case would not be expected in pyostomatitis vegetans. Isolated mu-
cosal ulceration is an uncommon presentation of cutaneous T-cell
lymphoma, though oral mycosis fungoides may present as ulcers,
erythematous plaques, or tumors.9 However, histopathology for my-
cosis fungoides (including oral mycosis fungoides) shows an infil-
trate of atypical lymphocytes at the dermoepidermal interface. Lastly,
invasive fungal infections, including cryptococcosis and histoplas-
mosis, can present with mucosal ulcerations but histopathology
often shows suppurative and granulomatous inflammation in the
presence of fungal organisms.

ARTICLE INFORMATION
Author Affiliations: Department of Dermatology,
University of California, San Francisco School of
Medicine (Kusari, Lang, Chang); Department of
Anatomic Pathology, University of California, San
Francisco (Lang); Zuckerberg San Francisco General
Hospital and Trauma Center, Department of
Dermatology, University of California, San Francisco
(Chang).
Corresponding Author: Ayan Kusari, MD,
Department of Dermatology, University of
California, San Francisco School of Medicine, 1701
Divisadero St, 4th Floor, San Francisco, CA 94115
(ayan.kusari@ucsf.edu).
Published Online: June 8, 2022.
doi:10.1001/jamadermatol.2022.2034
Conflict of Interest Disclosures: None reported.
Disclaimer: Dr Chang is Viewpoint Editor of JAMA
Dermatology but was not involved in any of the
decisions regarding review of the manuscript or its
acceptance.
Additional Contributions: We thank the patient for
granting permission to publish this information. We
also thank Hadley Pearson, MD (University of
California, San Francisco), for involvement in the
clinical care of this patient. Dr Pearson was not
compensated for her contribution.
Self-assessment Credit: This article is eligible for
journal-based self-assessment (1 credit) for
Maintenance of Certification (MOC) from the
American Board of Dermatology (ABD). After
completion of an activity, please log on to the ABD
website at www.abderm.org to register your
credits. This may be done after each exercise or
after accumulating many credits.
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