Clinics in Dermatology (2014) 32, 259–274

Nonspecific genital ulcers

Virendra N. Sehgal, MD ⁎, Deepika Pandhi, MD, Ananta Khurana, MD
Dermato-Venereology (Skin/VD) Centre, Sehgal Nursing Home, Delhi, Department of Dermatology and STD,
University College of Medical Sciences and Guru Teg Bahadur Hospital, University of Delhi, New Delhi, India

Abstract Recent intervention of nonspecific genital ulcers has added refreshing dimensions to genital
ulcer disease. It was considered pertinent to dwell on diverse clinical presentation and diagnostic
strategies. It seems to possess spectrum. It includes infective causes, Epstein Bar Virus, tuberculosis,
Leishmaniasis, HIV/AIDS related ulcers and amoebiasis. Noninfective causes are immunobullous
disorders, aphthosis, Behcet's disease (BD), inflammatory bowel disease, lichen planus and lichen
sclerosis et atrophicus, drug reactions, premalignant and malignant conditions, pyoderma gangrenosum,
and hidradenitis suppurativa. The diagnostic features and treatment option of each disorder are
succinctly outlined for ready reference.
© 2014 Elsevier Inc. All rights reserved.

Introduction Reactive nonsexually related acute genital

The presence of an erosion or ulcer over genitalia usually
takes one's mind toward sexually transmitted infections
(STIs); however, it is important to have a broader approach
and consider non-STI causes, as well. Many of these, in
fact, are diseases, which are more common than STIs.
Wrongly labeling a patient as having a venereal disease can
have great psychosocial implications, apart from the
resultant wrong treatment.
An ulcer/erosion on genitalia can have infective and
noninfective causes.1 Non-STI infective causes include:
Epstein Barr virus, tuberculosis, leishmaniasis, HIV/AIDS
related ulcers and amoebiasis. The list for noninfective
causes is much longer and encompasses drug reactions,
immunobullous disorders, aphthosis, Behcet's disease,
inflammatory bowel disease, erosive forms of lichen planus
and lichen sclerosis et atrophicus, premalignant and
malignant conditions, pyoderma gangrenosum, and hidrade-
nitis suppurativa.1
ulcers (RNSRAGU)/Lipschutz ulcer/ulcus vulvae
acutum/acute genital ulcer 2-6
RNSRAGU is a frequently encountered, often overlooked
entity, affecting adolescent girls and young women. The
development of acute, painful genital ulcer(s), generally
preceded by nonspecific prodromal symptoms, is the usual
presentation in a sexually inactive young girl/woman. The
entity has grave sociocultural consequences, for it may
invariably be diagnosed as a sexually transmitted disease.
Epidemiology
It is an uncommon entity for only a few case series2-7 are
thus far available; hence, its precise incidence is unknown.
Pathogenesis

⁎ Corresponding author. Tel.: + 91 011 27675363; fax: + 91 11 2767 It seems to be an outcome of a reactive process, triggered
0373. by distant infections. Accordingly, several reports describe
E-mail address: drsehgal@ndf.vsnl.net.in (V.N. Sehgal). the association of the reactive lesions with various infective

0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.clindermatol.2013.08.024
260
pathogens. Benjamin Lipschütz (1878-1931) blamed these
lesions on Bacillus grassus in 1912, which was later
identified as Döderlein's bacillus.8 Epstein Barr virus
(EBV), too, has been implicated.9-11 In addition to cytomeg-
alovirus (CMV), Salmonella typhi, Salmonella paratyphi,
the influenza virus, and Mycoplasma.12-17
EBV, with which the condition has been most commonly
associated, is a ubiquitous human herpes virus (HHV-4),
transmitted by saliva. The primary infection caused by this
virus is generally asymptomatic but in a minority results in
infectious mononucleosis.9 It replicates in the oropharynx
and establishes a latent infection within B-lymphocytes. The
incidence of EBV-associated ulcus vulvae acutum (EBV-
AUVA) among acute genital ulcers in adolescent women
was reported to be approximately 30% and 10%, respective-
ly.3,7 Such genital ulcers have been reported to occur with or
without the typical manifestations of the infectious mono-
nucleosis syndrome. EBV infection has been detected in
most reported cases using serology and in a few cases by
detecting EBV from the ulcer base using PCR.9,10,18-21
Genital ulcers are believed to be caused by a systemic
viremia associated with primary infections. Although, both
male and female genital tracts have been shown to harbor
EBV, it is accepted that EBV-AUVA is not a STD.11,20
Various hypotheses have been proposed to explain the cause
of genital ulcers associated with EBV infection.21,22 They
include the formation of immune complexes, leading to
complement activation and subsequent tissue necrosis /direct
cytolytic effect of virus cells multiplication within vulvar
keratinocytes, where they probably are reached via infected
cervico-vaginal secretions.11,21 In paratyphoid fever, the
ulcer may occur due to endotoxins released by the pathogen,
in the same way as ulcers occur in the gastrointestinal tract.15
These lesions may be a form of aphthosis, similar to that
of oral aphthosis, supported by its association with oral
ulcers in up to 70% of patients, and recurrences in a subset
of 33%.2,3,6,7 It may also be related to an exuberant
systemic immune response to an acute infection. 13
Cytotoxic T cells recruited in response to a systemic illness
may mediate the inflammation that results in genital
ulceration.15 Consequently, RNSRAGU may be a reactive
process analogous to erythema nodosum (EN) and other
reactive dermatoses.6
Clinical features
Lipschutz8 in 1913, described the presence of nonvener-
eal, acutely developing, genital ulcers in adolescent women,
the ulcus vulvae acutum, the first of the three types, while the
other two probably now would be classified as Behcet's
disease or Crohn's disease.23
The usual presentation is that of a painful, usually single,
genital ulcer developing acutely. It is frequently preceded by
fever and nonspecific prodromal symptoms.6 Dysuria is
V.N. Sehgal et al.
common. It may be associated with oral aphthae. The ulcer is
mostly located on the inner aspect of the labium, 24
occasionally, it may involve the labium majora, perineum,
and lower portion of the vagina. The ulcer is soft and tender.
It is sharply demarcated and covered by grayish exudates or
an adherent pseudomembrane.15,24 Vivid-red-purple mar-
gins have also been described.11 “Kissing ulcers,” affecting
the opposing mucosal surfaces, may be apparent.3,7 The size
of the ulcer is more than 1 cm, but it may be variable.
Features suggestive of a systemic infection may be present,
and a typical infectious mononucleosis syndrome6,10 may
even be present.
Diagnosis
The diagnosis of RNSRAGU is mainly clinical, which
requires the exclusion of other common causes of genital
ulceration. An acute genital ulcer developing in an otherwise
healthy adolescent woman, without any sexual history and
with a history of preceding fever or acute systemic illness,
suggests the diagnosis.6
Examination of the oral mucosa, lymph nodes, and skin,
plus a systemic evaluation, especially for hepatosplenome-
galy, is essential.
Ruling out herpes progenitalis is prudent, this being the
most common cause of genital ulceration in most countries.
This is ideally done with viral PCR from a lesional swab. If
this is unavailable, HSV serum capsid antibody may be
considered.6
Because EBV and CMV have been demonstrated in a few
cases of ulcus vulvae acutum, their serology may be done, if
available. This includes IgG and IgM antibodies to CMV and
IgM antibodies to EBV capsid antigen.9,12 A systemic screen
for infection may be undertaken with a total leukocyte count,
C-reactive protein, liver function panel, blood culture,
antistreptolysin O (ASLO) levels, and a throat swab.6,15,25
Serological tests for syphilis and HIV may also be considered
as required.6,15
Histopathology is nonspecific and is not indicated for a
single episode of acute genital ulcer.24
Treatment
The ulcer resolves spontaneously within 16-21 days,
usually without any scarring.24 Pain relief and supportive
measures are all that are required in most cases. Analgesics
and topical anesthetics may be prescribed. In moderately
severe disease, potent topical steroids, oral nonsteroidal
anti-inflammatory drugs, and local anesthetics are required.
In those with severe involvement (multiple lesions,
necrotic ulcers), systemic steroids may be required.24
Systemic antibiotics may be given if needed on the basis
of the cultures.
Nonspecific genital ulcers
Prognosis
There may be a recurrence rate of 33%, as revealed in a
series of 20 patients.7 A single episode of acute genital ulcer,
without any evidence of a systemic disease, does not warrant
further extensive evaluation; however, with recurrent oral
and genital ulceration or significant extra-cutaneous involve-
ment, an evaluation for Behcet's disease may be undertaken.
When this has been ruled out, such patients may be deemed
to have complex aphthosis.
Behcet's disease
This is a chronic relapsing systemic vasculitis of unknown
origin. It is a multisystem disease and has a myriad of clinical
features, posing a diagnostic challenge. The lack of an
accepted and standardized laboratory diagnostic method
makes clinical criteria the diagnostic cornerstone.26
Epidemiology
The disease is most prevalent along the “silk route,” with
an incidence of 14-20 per 100,000, and within 100km on
either side; 80-370 per 100,000 in Turkey, and about 0.1-7.5
per 100,000 in Europe and the United States.26-29 It usually
appears in the 3rd decade of life. It rarely develops before
puberty or after the age of 50. The male to female ratio is now
almost equal, although earlier reports had shown a higher
prevalence in men.30 It runs a milder course in women as
compared to men.26
Pathogenesis
Vasculitis is the basic underlying pathology, with
Behcet's being unique with a primary vasculitis and
predominant venous involvement.31
A genetic predisposition, especially HLA-B51 associa-
tion, has been incriminated for producing susceptibility.32,33
The role of infectious agents, especially streptococcus, has
been proposed.34 Antibodies to heat shock protein 60
(HSP60; a streptococcal protein) has been demonstrated.
Increased serum levels of HSP60 occur but do not seem to
correlate with the disease activity.35 Inflammatory mediators
are important in the pathogenesis, including IL-1, 8,12,17
and TNF-alpha.36 A predominant Th1 immune response,
triggered by IL-12 has been demonstrated.37,38
Clinical features
Genital ulcer(s) form a part component of the diagnostic
criteria for Behcet's disease.37 This is the second most
261
common lesion seen in Behcet's disease, occurring in about
57% to 93% of patients.27 It may be the initial sign in 18% of
patients.28 Their severity may range from small asymptom-
atic lesions to severely symptomatic ulcers, leading to
secondary complications, especially in women.39-42 The
ulcers are oval and/or round, well demarcated with a grayish
yellow necrotic base, and an erythematous halo/rim. The
genital ulcers of Behcet's are usually deeper than oral ulcers
and are often preceded by a tender nodule.
Commonly they occur on the scrotum, comprising 90% of
all the ulcers26 and less often on the glans and shaft in men,
while the labia and vaginal mucosa are the most common
sites in women. Occasionally, cervical lesions may occur.26
The perineal and perianal regions may be involved in both
men and women.43,44 The lesions usually last 10-30
days. 45,46 Two-thirds (66.2% in men and 60.7% in
women) of all genital ulcers heal with scarring46; hence,
this is a sign to look for in absence of any active lesions or as
evidence of preceding lesions. Larger lesions have a higher
tendency to scar with an incidence of this sequel in almost
100% of women and about 89% of men.46 The lesions on the
labia minora heal without any evidence of scarring (personal
communication). Occasionally, vulvar ulceration may lead to
labial destruction with lesions in the vagina leading to
urethral/ bladder fistulas.26
Diagnosis
This is based on clinical criteria and relies heavily on
mucocutaneous signs. When a diagnosis of Behcet's is
suspected a detailed systemic evaluation must be undertaken
to look for involvement elsewhere. Other systems commonly
involved include: ocular, articular, neurological, gastrointes-
tinal, urogenital, pulmonary, vascular, and cardiac.
Various clinical criteria have been proposed, for which
the International Study Group criteria include47:
• recurrent oral ulceration
• minor aphthous
• major aphthous
• herpetiform ulceration observed by physician or
patient that has recurred at least 3 times in one 12-
month period
plus two of the following criteria:
• recurrent genital ulceration: aphthous ulceration or
scarring observed by physician or patient
• eye lesions: anterior uveitis, posterior uveitis, or cells in
vitreous on slit-lamp examination; or retinal vasculitis
observed by an ophthalmologist
• skin lesions: erythema nodosum observed by physician
or patient, pseudofolliculitis or papulopustular lesions; or
acneiform nodules observed by physician in postadoles-
cent patients not receiving corticosteroid treatment
262 V.N. Sehgal et al.

• positive pathergy test read by a physician at 24 to

48 hours

Pathergy is a nonspecific skin hyperreactivity test that forms

a part of many clinical diagnostic criteria of Behcet's disease;
however, it is also positive in many other diseases: ie, pyoderma
gangrenosum, Sweet's syndrome, and subcorneal pustular
dermatosis (Sneddon-Wilkerson disease).48 Heavy neutrophilic
infiltrates or leukocytoclastic vasculitis develop at the site after
12 to 48 hours. An erythematous papule of greater than 2mm
size at the site of the prick with a 20- to 22-gauge needle (to a
vascular skin obliquely to the depth of 5mm followed by
intradermal injection of 0.1ml of normal saline).48 The
phenomenon may not predictably correlate with the presence
of clinical symptoms and signs. The positivity of pathergy
varies from region to region. A high positivity (84% to 98%) is
found in Mediterranean and Middle Eastern countries with a
significantly lower positivity in Western countries.49-51 The
phenomenon in Behcet's disease is waxing and waning, like the
majority of other clinical manifestations;52 therefore, it may be
repeated, if necessary, for diagnostic purposes.

Histopathology

It is characterized by vasculitis and thrombosis. Early

mucocutaneous lesions show neutrophilic vascular reaction
with endothelial swelling, red blood cell extravasation, and
leukocytoclasis or a fully developed leukocytoclastic
vasculitis with fibrinoid necrosis of vessel walls.53,54

Fig. 1 Nonspecific genital ulcer, complex aphthos.

Treatment
Topical treatment of genital ulcers of Behcet's disease
includes corticosteroids and anaesthetics.26 Topical sucralfate
may reduce the healing duration and pain.55,56 Intralesional
corticosteroids can be employed in recalcitrant ulcers.26
Severe mucocutaneous disease warrants systemic man-
agement, which predominantly involves the use of varying
combinations of the following: corticosteroids, colchicines,
dapsone, interferon-alpha, thalidomide, azathioprine, cyclo-
sporine A, methotrexate, and anti-TNF agents.55-61
Complex aphthosis
Complex aphthosis (CA), is the presence of almost
constant, multiple (≥ 3) oral or oral and genital aphthae
(Figures 1A and B) in the absence of systemic manifesta-
tions.62 The clinical appearance of oral and genital lesions is
similar to that described in BD.39 This entity is probably a
subset of recurrent aphthous stomatitis, defined as the
recurrence of one or more painful oral ulcers at intervals
ranging from a few days to months.39 It becomes crucial to
distinguish this entity from Behcet's disease, characterized
mainly by the lack of systemic features; however, it is likely
that this may be a forme-fruste' of BD.62
Several factors have been implicated in the pathogenesis
of oral aphthae, but similar details for genital lesions are
lacking. CA can be seen in nutritional deficiencies mainly of
vitamins B1, B2, B6, B12, folate, iron, and zinc, and they
may respond to replacement therapy.63-71 There may be an
underlying associated hematologic abnormality, especially
cyclic neutropenia and agranulocytosis.70,72 Allergies to
various foods, such as cow's milk, gluten, food dyes,
nonsteroidal anti-inflammatory drugs, and preservatives,
have also been implicated.73-79 Stress and the menstrual
cycle abrasion remain controversial as causes.80 Secondary
causes of CA include inflammatory bowel disease, Sweet's
syndrome, and HIV.81-84
It is difficult to predict the evolution to BD in a patient at
risk; nonetheless, human leukocyte antigen-B51 (HLA-B51)
is more prevalent in BD than CA. Its predictive value is
inadequate to make individual therapeutic decisions.85
In one study,86 specific cutaneous manifestations, in the
form of unipolar aphthosis having either oral or genital
Nonspecific genital ulcers
ulcers, were present in 15%, whereas bipolar aphthosis,
having both oral and genital ulcers, were present in 17%. At
least one specific manifestation of BD was present in 43% of
the patients with uni- or bipolar aphthosis, In addition, 10
patients, classified as bipolar aphthosis, had previously
experienced unipolar aphthosis and six BD patients had
experienced bipolar aphthosis86; however, only six patients
(7%) with aphthosis developed the complete signs of BD.
This and other similar studies86,87 point in favor of a
continuous spectrum linking severe aphthosis to BD,
unipolar aphthosis being at one end and BD at the other.
Crohn's disease
Crohn's disease (CD) is a chronic granulomatous
inflammatory bowel disorder that may involve any segment
of the gastrointestinal tract. Mucocutaneous lesions are its
most frequent extra intestinal manifestations, seen in 22% to
75% of patients.88,89 Cutaneous manifestations, on the other
hand, are in the form of granulomatous infiltrations, reactive
dermatoses, and skin changes resulting from nutritional
deficiencies.90 There are direct involvement of the contig-
uous sites such as perianal region, peristomal or perifistular
areas. While metastatic CD (MCD) may involve noncontig-
uous sites.
Epidemiology
CD incidence ranges from 3.1 to 14.6 per 100,000 person-
years in a review of large population-based patient cohorts'
studies91 in North America. Its incidence of perianal
involvement is as low as 3.8%92 and as high as 61% to
80%.93-95 This variation is partly related to different defining
criteria. MCD in adults usually appears long after the initial
diagnosis of CD in 70% of the patients, and it has rarely been
reported as the initial symptom.96 MCD appears at the same
time as CD in almost half of the cases in children.96
Pathogenesis
The etiology of MCD is unknown. It is probable that
antigens or immune complexes get deposited in the skin,
creating microscopic perivascular granulomas in primary
Crohn's disease of the gastrointestinal tract.88 Autoimmune
cross-reactivity has also been proclaimed, where antibodies
specific to antigens in the gastrointestinal tract may react
with skin antigens of similar structure.97 The granulomatous
inflammation may also be due to a type IV hypersensitivity
reaction wherein T cells cross-react with skin antigens,
resulting in an inflammatory response similar to that seen in
the gastrointestinal tract of CD.98
263
Clinical features
Contiguous involvement of the perianal region can
present as cavitating ulcers with or without lymphedema,
polypoid skin-tag like lesions, moist plaques, fissures,
fistulas, sinus tracts, anorectal strictures, and abscesses.99
The characteristic early lesions are small erythematous
papules that may enlarge to become nodular and ulcerate
exuding purulent discharge.96 MCD can present as genital
ulcers in adults; however, more commonly, it presents as
nodules and/or plaques with or without ulceration on arms
and legs. In children, MCD generally manifests as genital
edema with/without erythema.96
Although Crohn's disease typically affects the terminal
ileum more often than the large bowel, cutaneous manifes-
tations of Crohn's disease appear to occur more often in
patients who have involvement of the colon.100 It is believed
that there is no correlation between MCD and the
gastrointestinal activity of CD,100,101 however, Palmaras
et al96 noted associated gastrointestinal CD activity present-
ing as chronic diarrhea and/or vomiting, rectal bleeding,
chronic constipation and abdominal pain/cramps in one third
of the MCD cases in adults and half of the cases in children.
Diagnosis
Presence of CD of the gastrointestinal tract simplifies the
diagnosis; however, difficulty may arise in cases where
gastrointestinal activity is absent or those having a
suggestive sexual history. Histopathology is characterized
by discrete, noncaseating, sarcoidal granulomas with nu-
merous foreign body and Langhan's type multinucleated
giant cells present more commonly in the superficial dermis,
deep dermis and adipose tissue.96 Often, there is perivas-
cular, the granulomatous perivasculitis or perifollicular
accentuation and extravascular neutrophilia102,103 Granulo-
matous inflammation with associated necrobiosis has been
reported104 as a rare feature of MCD. Eosinophils may also
be a histopathological feature.97
Treatment
Evidence for treatment modalities of cutaneous CD is
mainly anecdotal. Oral metronidazole is often effective.
Other treatments include various chemotherapeutic
agents, including oral steroids,105-109 topical steroids,109,110
azathioprine,106,107,111 cyclosporine,112,113 sulfasalazine,113,114
and tetracyclines.115 Patients with perianal CD seem to be
resistant to systemic steroids.116 Topical tacrolimus has been
used successfully in the treatment of perineal CD.117,118 Oral
tacrolimus therapy seems to be associated with short and long-
term benefits and may represent a therapeutic option in CD
when conventional therapies fail.119
264
Infliximab has been used for treatment of extra-intestinal
manifestations of CD with successful treatment reported in
four cases; one of them as a combination with methotrex-
ate.120-126 Finally, surgical treatment by repeated curettage
of the ulcers plus oral zinc sulphate resulted in clearance of
the lesions in a few patients.127
Prognosis
Although spontaneous resolution of MCD has been
described, complete resolution is uncommon and unpredict-
able.128 Surgical removal of the affected bowel does not
necessarily improve MCD.129 Treatment is often unsatisfac-
tory, as adequate evidence-based management is lacking.
When a diagnosis of MCD is made, the likelihood of
subsequent onset of CD is 2 months to 4 years in adults with
a mean of 2.66; median, 2 years and 9 months to 14 years
(mean, 4.6; median, 3.9 years) in children.96
Pyoderma gangrenosum
Pyoderma gangrenosum (PG) is a rare, chronic, often
destructive, inflammatory skin disease130 the incidence of
which is about 3 to10 patients per million population per year.130
Its pathogenesis is not well understood; however,
neutrophil dysfunction does have a role. IgA gammopathies,
impairing neutrophil chemotaxis in vitro, are not uncom-
mon.131 Circulating immunoglobulins affecting neutrophil
functions and monoclonal or polyclonal hyperglobulinemia
is frequent; moreover, interleukin-8 (IL-8), a potent
leucocyte chemotactic agent, has been shown to be over-
expressed in PG ulcers and to induce similar ulceration in
human skin xenografts transfected with recombinant human
IL-8. ‘Pyogenic sterile arthritis, pyoderma gangrenosum, and
acne' (PAPA) syndrome is an autosomal-dominant disorder
that maps to chromosome 15q.132 The IL-16 gene maps to
15q25 and may be overexpressed in this disorder, because
the IL-16 protein is chemotactic to neutrophils.130,133
Clinical variants
• Ulcerative,
• Pustular,
• Bullous
• and Vegetative.
Genital lesions affecting the vulva, penis, and scrotum are
known. An ulcerative variant is common. The ulcer typically
has a raised inflammatory, dusky red/purplish border and a
boggy necrotic base. The primary lesion starts as a deep-
seated, painful nodule or as a superficial hemorrhagic
pustule, either de novo or after minimal trauma. The actively
V.N. Sehgal et al.
advancing ulceration may expand more rapidly in one
direction resulting in a serpiginous pattern.130 The margins
are often surrounded by an intense halo of bright erythema
that extends up to 2 cm from the ulcer border into the
neighboring, apparently normal, skin. Peripheral growth
results from the burrowing extension of the undermined
margin or from fresh hemorrhagic pustules arising on the
border. The base of such an ulcer is partially covered with
necrotic material and studded with small abscesses. Super-
ficial ulcers may be confined to the dermis, but more often
ulcers extend into the fat and even down to the fascia.130
Ulcers may be single or multiple, and can sometimes
coalesce to form multicentric, irregular lesions. Lymphade-
nopathy is generally absent.130 Pustular PG developing over
the penis in a 47 year old134 has been described. Infants show
prominent involvement of the genital and perianal region.
The local destruction associated with this disease can be
crucial in this sensitive region. One patient is known135 to
have had misdiagnosed penile PG treated with skin grafts
leading to deterioration of the disease, resulting in urethral
fistula. Pathergy is positive in up to 25% of cases, and this
may be demonstrated at the biopsy site, as well.130
PG is associated with systemic disorders in about 50% of
patients.136 Noteworthy among these are inflammatory
bowel disease (IBDs; ulcerative colitis and Crohn's disease),
primary biliary cirrhosis, chronic active hepatitis, rheumatoid
arthritis, ankylosing spondylitis, osteoarthritis, leukemias
(acute myeloid, lymphoblastic, chronic myeloid, lymphoid,
hairy cell leukemia), myeloproliferative syndrome, hyperglo-
bulinaemia, thrombocythemia, myelodysplasia, dysglobuline-
mia, congenital hypogammaglobulinemia, monoclonal
hypergammaglobulinemia, myeloma, Waldenström syn-
drome, lymphoma, Takayasu's disease, Wegener's granulo-
matosis, systemic lupus erythematosus, necrotizing vasculitis,
rheumatoid uveitis and scleritis, malignancies (colon, prostate,
breast, bronchus), carcinoid syndrome, diabetes, and diseases
of the lung (pneumonitis, abscess).130
Histopathology is nonspecific, mainly useful in ruling
out other differentials. An ulcer biopsy may reveal edema
and massive neutrophilic inflammation in the dermis. There
may also be engorgement and thrombosis of small- and
medium-sized vessels along with necrosis and hemorrhage.
Lesions further evolve into suppurative granulomatous
dermatitis and regress with prominent fibroplasia.130 The
presence of vasculitis in the histology of PG is controver-
sial: some investigators found no evidence of leucocyto-
clastic vasculitis in the biopsies of PG.137 Although there
are a few reported cases of the two disorders occurring
together,138,139 true vasculitis is now considered to be
unusual.130 Laboratory abnormalities commonly associated
include a high erythrocyte sedimentation rate, leukocytosis,
and an elevated C-reactive protein. Radiographic pro-
cedures may include an upper gastrointestinal series and a
barium enema. Flexible sigmoidoscopy and/or colonoscopy
may also be done with biopsies. 130 Serum protein
electrophoresis, serum immunodiffusion studies, and
Nonspecific genital ulcers 265

serum and urine immunoelectrophoresis can be useful in Drug induced

ruling out monoclonal gammopathy or myeloma.
Diagnosis requires both major criteria and at least two
minor criteria:131
Major criteria include
• Rapid progression of painful, necrolytic cutaneous
ulcers with an irregular, violaceous, and undermined
border
• Other causes of cutaneous ulceration have been
excluded
Minor criteria include
• History suggestive of pathergye or clinical finding of
cribriform scarring systemic diseases associated
with PG
• Histopathologic findings (sterile dermal neutrophilia, ±
mixed inflammation, ± lymphocytic vasculitis)
• Treatment response (rapid response to systemic
steroid treatment)
Erythema multiforme (EM) is rarely associated with genital
lesions, whereas oral lesions are nearly always present.152 The
genitalia is more frequently affected in Stevens–Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), often
with erosions.152,153 In a series154 of 40 patients with TEN, 28
had severe vulvo-vaginal involvement that resulted in
permanent scarring in five of them.
Fixed drug eruptions (FDEs) are peculiar cutaneous
eruptions characterized by solitary/multiple, round and/or
oval, erythematous patches (Figures 2A and B), which are
variable in size and progressively become dusky violaceous
or brown in color.155,156 Some of them develop bulla or
superficial erosions and may be confused with other causes
of genital ulcers. They characteristically appear in the same
site each time when the responsible drug is administered,
although the number of involved sites and the size of the
lesions may increase with repeated exposures. The lesions
usually develop 30 min to 8 h after drug administration with
associated itching and/or burning, and may fade over a

Treatment

Localized, mild disease may be managed with topical

therapy alone, which includes topical corticosteroids, tacroli-
mus, and imiquimod. Severe disease warrants systemic
management. The most promising results are obtained with
systemic corticosteroids and cyclosporine.130 Other drugs that
have shown beneficial results include dapsone, sulfasalazine,
clofazamine, colchicines, minocycline, immunosupressives
(azathioprine, methotrexate, cyclophosphamide), IVIG, and
biological (especially infliximab).140-147 Recurrences are
unpredictable and do not warrant maintenance therapy.

Prognosis

PG is an unpredictable disease. It can have a rapid

dramatic onset and course or may be a slowly developing and
indolent process. When associated with ulcerative colitis, the
disease activity of pyoderma gangrenosum may parallel that
of the bowel disease: the control of the intestinal condition
can resolve the skin problem and recurrences may occur at
periods of exacerbation of IBD. Skin lesions may also have an
evolution that is partially independent of the intestinal activity
of IBD. The relationship between exacerbations of the colitis
and the onset of skin disorder 148,149 has been ques-
tioned.150,151 The disease may come to a spontaneous halt
without apparent reason; sometimes, it remains quiescent for
months and even years and exacerbates again after minimal
trauma, surgery, or no apparent triggering cause.140 Fig. 2 Nonspecific genital ulcer, fixed drug eruption.
266 V.N. Sehgal et al.

period of 1-2 weeks with crusting and scaling followed by

hyperpigmentation that may persist for months.156
These are more common (or more easily recognized) over
the penis as compared to the vulva.157 Male genital FDE are
more frequent over the glans or coronal sulcus but the shaft
or scrotum may also be involved.158 A number of drugs can
induce FDE, but in a male genital case series, the more
commonly implicated drugs were cotrimoxazole, tetracy-
cline, and ampicillin.158 Cases have occurred in men after
contact with sexual partners who have taken the drug to
which they were known to be sensitive: co-trimoxazole,
diclofenac, isosorbide, and aspirin are the drugs cited.159,160
In a recent series of patients with vulval FDE, the most
common clinical presentation was a bilaterally symmetrical
erythematous vulvitis, involving the labia minora and majora
and extending to the perineum and, rarely, the inner thighs
and perianal area. The majority had an erosive mucositis. The
most common drugs implicated were ibuprofen, cyclo-
oxygenase-2 inhibitors, and 3-hydroxy-3-methylglutaryl-
CoA reductase inhibitors.161

Immunobullous disorders Fig. 4 Nonspecific genital ulcer Lichen Planus.

Pemphigus vulgaris (PV) may cause genital erosions
(Figure 3). In one series162 of 34 patients with PV, 21 had
labial involvement, 3 had vaginal lesions, and 10 had labial
and vaginal involvement. Although PV generally does not
lead to scarring, vulvo-vaginal lesions may result in
scarring.163 There is a confirmed case of PV limited only
to the prepuce.164
Cicatricial pemphigoid (CP) may have an exclusive
genital involvement in isolation. In addition to erosions,
vaginal scarring/phimosis may be evident.154,163,165 Linear
immunoglobulin A (IgA) disease commonly involves the
mucosa. Mucosal lesions of bullous pemphigoid are
uncommon, although a few cases of isolated genital
involvement have been reported.166,167
Fig. 3 Nonspecific genital ulcer, Pemphigus vulgaris.
A biopsy for histopathology along with direct immunoflu-
orescence usually confirms the diagnosis.
Lichen planus
Erosive mucosal lichen planus (LP) is a well-established
variant of LP characterized by the formation of ulcerative
lesions predominantly involving the oral and genital mucosa.
In women, it involves the vaginal orifice and often the
labia minora. In men, the disease may involve the glans and
prepuce. The lesions are erythematous, partly erosive and
desquamative, occasionally, surrounded by a pale border
(Figure 4). It causes severe symptoms like burning, pain,
pruritus, and dyspareunia.168 Isolated erosive LP of the glans
has also been described152,169,170 and may result in sequelae,
such as scarring and phimosis. Orogenital lichen planus
affecting the external urinary meatus, masquerading as
sexually transmitted urethritis and erosive genital disease,
has also been reported.171 There are rare reports172-175 of
squamous cell carcinoma eventuating from chronic penile
dermatoses thought to be lichen planus. Such cases need to
be differentiated from other entities, such as plasma cell
balanitis, erythroplasia of Queyrat, fixed drug eruption,
lichen planus, erosive balanitis, and solitary plasmocytoma.
Vulvo-vaginal LP may cause scarring, leading to the
narrowing of the vagina and labia minora.175 A large case
series of vulvar LP revealed development of vulvar
intraepithelial neoplasia in 7 of 114 women and squamous
cell carcinoma in 3 women during a five-year observation
Nonspecific genital ulcers
period.176 In another case series, 1 of 44 women developed
vulvar carcinoma.177
Erosive LP of the genitalia often poses a diagnostic
challenge. Characteristic histopathological findings of LP are
often absent. In addition, bullous and cicatrical pemphigoid
and other bullous diseases may be considered in its
differential diagnosis, because they may also cause scarring
of the outer genitalia.168 Diagnosis may be facilitated if there
are typical changes in other parts of the skin and
immunofluorescence findings.178
Treatment is challenging and often prolonged. Topical
steroids and tacrolimus are effective. Systemic therapy may
be warranted in severe cases and includes systemic steroids,
acitretin, methotrexate, and cyclosporine.168,179,180
Lichen sclerosus et atrophicus
Erosions and ulcerations may develop over genital lichen
sclerosus et atrophicus (LSA).181 Severe itching is a feature.
Extension may occur into the perianal region in a “figure
eight.” There may be dysuria, pain on defecation, and
dyspareunia. Presence of cutaneous lesions and histopathol-
ogy may suggest the diagnosis. Treatment is difficult and
consists mainly of potent topical steroids and calcineurin
inhibitors. There are various reports 182-184 of systemic
treatments, including methotrexate, acitretin, pulsed methyl-
prednisolone with methotrexate and Photo-dynamic therapy.
Dermatitis artefacta
Infections
Amoebiasis
Cutaneous amoebiasis (CA) is an uncommon manifesta-
tion of Entamoeba histolytica even in endemic regions.185
The infection affects the skin when amoebae escape from the
bowel to the contiguous skin or any discharge containing
virulent trophozoites remains in prolonged/repeated contact
with traumatized skin.186 The vulval/perineal region is
highly vulnerable; but involvement of glans is rare and
may occur from direct inoculation by anal /vaginal
intercourse with a person suffering from amoebic dysentery
or a recto-vaginal fistula.
The rapidly spreading necrotizing infection involves the
skin, fat, and muscle. A typical lesion is a granulomatous,
well-demarcated, intensely tender, and painful ulcer. It has a
central slough, raised, purplish-black undermined margin,
outer erythematous zone and purulent exudate.187-190 Acute
illness with fever, malaise and general debility that may
terminate fatally is not uncommon;187,191 however, most
patients suffer a chronic indolent clinical course and
significant morbidity in the absence of a diagnosis. Lesions
are commonly confused with STIs and malignancy. It,
267
therefore, requires a high index of suspicion. Wet preparation
from the ulcer margin may show trophozoites of E histolytica
identified by their characteristic motility, pseudopodia and
phagocytosed intracytoplasmic erythrocytes.185 Serology is
not diagnostic, especially in endemic regions, as it may
remain positive long after treatment and is negative in the
absence of invasive intestinal or hepatic disease.185
Histological findings include epidermal hyperplasia,
spongiosis, ulceration, areas of necrosis, mixed inflammato-
ry infiltrate, and, importantly, the presence of hematopha-
gous amoebic trophozoites (HAT). Occasionally, there may
be vasculitis or thrombosis with luminal HAT.191,192
The lesions generally respond swiftly to a standard course
of metronidazole, 800 mg three times a day for 5 days193;
however, neglected cases have progressed to necrotizing
vulvitis requiring radical vulvectomy.194 Sexual partners
must also be evaluated.195
Leishmaniasis
Genital lesions are rare but have been described in South
America among miners196 and farmers.197 There is also a
report of vulval involvement.198 The diagnosis is confirmed
by demonstrating the presence of Leishmania amastigotes in
smear or biopsy material. Culture and polymerase chain
reaction (PCR) methods can increase detection rates.193
Treatment should be undertaken with expert advice and will
usually be either systemic or local pentavalent antimonial
therapy, depending on the species and clinical picture. Mild
cases caused by certain species, such as L peruviana, may
resolve spontaneously.193
Tuberculosis (TB)
Cutaneous tuberculosis (CTB) assumes significance in
the contemporary HIV era. Ulceration of the vulva and penis
may result in diagnostic difficulties, especially in the absence
of TB foci elsewhere. Tuberculosis cutis orificialis (TCO) is
the most common form of reinfection, as secondary
cutaneous tuberculosis to affect the anogenital region. It is
the orificial TB occurring in patients with advanced
genitourinary and intestinal tuberculosis. Clinically, edem-
atous, reddish or yellowish nodules appear on the anogenital
area. These nodules rapidly break down to form painful,
circular and irregular ulcers with undermined edges. It is soft
in consistency, and often a typical “punched-out” appear-
ance.199 These extremely painful ulcers are always coated
with pseudomembrane and may perforate the underlying
tissue.200 The outcome depends on the course of the
underlying disease. In general, individuals having TCO
have a poor prognosis in view of advanced systemic disease;
however, a few cases have been reported where no internal
involvement was found.201-203
TB chancre, a primary exogenous form of CTB, has been
reported to develop on the glans, following circumcision.204
Primary infection may also be acquired through sexual contact
with an infected partner or contamination from infected
clothing.205 It presents as a painless, well-demarcated ulcer,
268
with an indurated granular base and dusky erythematous or
bluish undermined edges.204 Tuberculids involving genitalia
are rare. Papulonecrotic tuberculids (PNT) presents as large,
deep and painful ulcers, which are often multiple. Only a few
cases have so far been reported.206-208
Diagnosis of the genital tuberculous lesions is made by
demonstration of epithelioid granulomas along with positiv-
ity in Ziehl-Nelson staining. PCR is able to demonstrate the
bacilli from tissue samples; however it may be difficult in
case of PNT. 209 Treatment consists of the standard
antituberculosis regime with four drug intensive phase
(rifampicin, isoniazid, pyrizinamide, and ethambutol) and
continuation phase of four months with two drugs only
(rifampicin and isoniazid ).209
Candidosis
Candidal infection can lead to erosive lesions over the
vulva and glans. It may be a STI, or there may be an
underlying dermatological or medical cause, although the
symptoms and signs of Candida may be more florid than the
underlying predisposing cause. Medical causes include
diabetes mellitus, high-dose oral contraceptive agents,
pregnancy, iatrogenic immunosuppression, and systemic
antibiotic treatment.152
Diagnosis is confirmed by direct microscopy and culture.
Treatment of genital candidiosis requires systemic and
topical azoles.
Varicella-zoster virus
Sacral zoster can affect the vulva, penis, and scrotum. It
may be accompanied by bowel and bladder dysfunction.210,211
Other bacterial etiologies that may present with genital
ulcerations/erosions include streptococcal cellulitis,212 Bur-
uli ulcer due to Mycobacterium ulcerans,213 nonsyphilitic
spirochaetal ulcerative balanoposthitis,214 genital ulceration
associated with disseminated early yaws215 and bullous
necrotic erysipelas of the penis due to Streptococcus
pyogenes.216 Ecthyma gangrenosum and Fournier's gan-
grene may lead to ulceration and gangrene of the anogenital
region.217,218 Among fungal pathogens, there are rare reports
of genital ulceration with Paracoccidioidomycosis, zygomy-
cosis and histoplasmosis.219-222
Chancroidal ulcer
Chancroidal ulcer223 is characterized by a single ulcer that
has well-defined, soft, tender, nonindurated and weakening
edges. It has a longer incubation period of 8 to 11 days.
Absence of lymphadenopathy is a prominent feature. The
V.N. Sehgal et al.
male/female ratio being 27/1. Persons of low socioeconomic
status in the sexually vulnerable age-group are predomi-
nantly affected. The prepuce, coronal sulcus, and glans penis
are common sites, as is the labia minora. Due to the limited
value of gram-stained smears for the detection of H ducreyi
and lack of a good culture media, chancroid and chancroidal
ulcers should be differentiated clinically.
Premalignant lesions and malignancy
Men
About 35% cases of penile carcinoma present as a sore or
ulcer.224 Associated clinical manifestations may include
pain, discharge, bleeding, and foul odor. The ulcer gradually
enlarges and infiltrates deeper in the tissue. Lymph nodes are
affected in later stages. The disease may develop de novo or
be preceded by certain at-risk conditions like LSA, erosive
LP, chronic balanitis, leukoplakia and in-situ carcinomas,
erythroplasia of Queyrat, Bowen's disease, and bowenoid
papulosis.225 Biopsy of suspicious looking lesions entails
early diagnosis of the underlying malignancy.
Erythroplasia of Queyrat (EQ)
It is an in-situ carcinoma that usually presents as single,
reddish, sharply defined, and sometimes eroded and oozing
plaque located on the glans, the inner surface of the prepuce
or the coronal sulcus.225
Chronic lymphocytic leukemia and acute promyelocytic
leukemia may also result in penile ulceration.226-228 All-
transretinoic acid (ATRA) used for the treatment of acute
promyelocytic leukemia has been occasionally reported229,230
to result in scrotal ulceration.
Women
Squamous cell carcinoma is the most frequent malignancy
of the vulva. It may develop from vulvar intraepithelial
neoplasia caused by the human papillomavirus infection or
may develop from vulvar nonneoplastic epithelial disorders
as a result of chronic inflammation.231 The most frequently
reported symptom of vulvar cancer is a long history of
pruritus.231 Less common presenting symptoms include
vulvar bleeding, discharge, dysuria, and pain. The lesion is
usually raised and may be fleshy, ulcerated, leukoplakic, or
warty in appearance.232 Most squamous cell carcinomas are
unifocal and occur on the labia majora. Approximately 5% of
cases are multifocal, and the labia minora, clitoris, or
perineum may be involved as primary sites.231 Malignant
melanoma of the vulva can present with ulcerations, as can
basal cell carcinoma, which is occasionally seen over the
genitalia.233,234
Nonspecific genital ulcers
Miscellaneous conditions
Zoon's balanitis and vulvitis
In 1952, Zoon first described, under the nomenclature of
balanitis chronica circumscripta plasmacellularis, a chronic
inflammation of the glans penis or inner surface of the
foreskin, clinically resembling the erythroplasia of Queyrat,
and histologically characterized by an infiltrate of plasma
cells.235 Garnier, in 1954, described the female equivalent of
it, which is much less common.236
Zoon's balanitis (or plasma cell balanitis or balanitis
circumscripta plasmacellularis) is a disorder typical of
middle-aged and older uncircumcised men.237 It is a chronic,
reactive, irritant mucositis, without precancerous tendencies,
often associated with mild phimosis. Clinically, it is always
asymptomatic, scarcely palpable, and typically as a well-
demarcated, moist, bright red or brown patch, located on the
dorsal portion of the glans and frequently also in the adjacent
prepuce.237,238 Edema, ulcerations, or eschars are usually
absent. Biopsy shows epidermal thinning, absent horny and
granular layers and distinctive lozenge-shaped keratinocytes
with widened intercellular spaces, a dense inflammatory
infiltrate composed largely of plasma cells, dilated blood
vessels and hemosiderin in the dermis.152 Russell bodies and
dermal-epidermal splitting have also been described.239
Therapy of Zoon's balanitis is not standardized. Circumci-
sion is the most useful and curative treatment. Topical
application of corticosteroids can offer improvement of the
disorder, without persistent clinical healing. Some evidence
regarding the beneficial use of carbon dioxide laser, pimecro-
limus, and tacrolimus has been reported in literature.237,240,241
Imiquimod has also been tried with success.237,241
Factitial
Erosions/ulcerations of the genitalia may occur during
sexual intercourse or may be self-induced. Lesions in
dermatitis artefacta are typically geometrical, angulated, and
curvilinear.152,242 Sometimes, they are induced by needles,
knives, or cigarette burns, and extraneous foreign material
may be introduced into the skin (lipogranuloma and silicone
granuloma).243,244 Association with an atypical behavioral
pattern or underlying personality disorder should be
evaluated.242
Others
Ulceration of the penis and scrotum following applica-
tion of tazarotene gel and imiquimod has been de-
scribed. 245,246 Inadvertent subcutaneous injection of
papaverine for the treatment of erectile impotence may
269
result in a genital ulcer(s).247 Foscarnet is a recognized
cause in HIV-infected patients.248,249 Nicorandil250,251 is
another newly implicated cause.
References
1. Bohl TG. Vulvar ulcers and erosions—a dermatologist's viewpoint.
Dermatol Ther. 2004;17:55-67.
2. Rosman IS, Berk DR, Bayliss SJ, et al. Acute genital ulcers in
nonsexually active young girls: Case series, review of the literature,
and evaluation and management recommendations. Pediatr Dermatol.
2012;29:147-153.
3. Farhi D, Wendling J, Molinari E, et al. Nonsexually related acute
genital ulcers in 13 pubertal girls: A clinical and microbiological
study. Arch Dermatol. 2009;145:38-45.
4. Deitch HR, Huppert J, Adams Hillard PJ. Unusual vulvar ulcerations
in young adolescent females. J Pediatr Adolesc Gynecol. 2004;17:
13-16.
5. Cebesoy FB, Balat O, Inaloz S. Premenarchal vulvar ulceration: Is
chronic irritation a causative factor? Pediatr Dermatol. 2009;26:
514-518.
6. Lehman JS, Bruce AJ, Wetter DA, et al. Reactive nonsexually related
acute genital ulcers: Review of cases evaluated at Mayo Clinic. J Am
Acad Dermatol. 2010;63:44-51.
7. Huppert JS, Gerber MA, Deitch HR, et al. Vulvar ulcers in young
females: A manifestation of aphthosis. J Pediatr Adolesc Gynecol.
2006;19:195-204.
8. Lipschutz B. Über eine eigenartige Geschwürsform des weiblichen
Genitales (Ulcus vulvae acutum). Archiv für Dermatologie und
Syphilis (Berlin). 1913;114:363-395.
9. Taylor S, Drake SM, Dedicoat M, et al. Genital ulcers associated
with acute Epstein-Barr virus infection. Sex Transm Infect. 1998;74:
296-297.
10. Halvorsen JA, Brevig T, Aas T, et al. Genital ulcers as initial
manifestation of Epstein-Barr virus infection: two new cases and a
review of the literature. Acta Derm Venereol. 2006;86:439-442.
11. Sárdy M, Wollenberg A, Niedermeier A, et al. Genital ulcers
associated with Epstein-Barr virus infection (ulcus vulvae acutum).
Acta Derm Venereol. 2011;91:55-59.
12. Martin JM, Godoy R, Calduch L, et al. Lipschutz acute vulval ulcers
associated with primary cytomegalovirus infection. Pediatr Dermatol.
2008;25:113-115.
13. Berlin C. The pathogenesis of the so-called ulcus vulvae acutum. Acta
Derm Venereol. 1965;45:221-222.
14. Roberts DW, Barron SL. Typhoid fever with vulvovaginitis. Lancet.
958;1043-1044.
15. Pelletier F, Aubin F, Puzenat E, et al. Lipschütz genital ulceration: A
rare manifestation of paratyphoid fever. Eur J Dermatol. 2003;13:
297-298.
16. Wetter DA, Bruce AJ, MacLaughlin KL, et al. Ulcus vulvae acutum in
a 13-year-old girl after influenza A infection. Skinmed. 2008;7:95-98.
17. Korting GW, Hinterberger G. Ulcus vulvae actum with cold-
agglutinin-positive, Mycoplasma-caused atypical pneumonia.
Hautarzt. 1979;30:550-552.
18. Portnoy J, Ahronheim GA, Ghibu F, et al. Recovery of Epstein-Barr
virus from genital ulcers. N Engl J Med. 1984;311:966-968.
19. Pelleticr F, Leblanc L, Estavoyer J-M, Drobachel TC, Kliayat AN,
Laurent R. Ulcere de Lipschiitz au coursdune primo-infection a virus
Epstein-Barr. Ann Dermatol Venereol. 2002;129:905-907.
20. Näher H, Gissmann L, Freese UK, et al. Subclinical Epstein-Barr virus
infection of both the male and female genital tract indication for sexual
transmission. J Invest Dennatol. 1992;98:791-793.
21. Leigh R, Nyirjesy P. Genitourinary manifestations of Epstein-Barr
virus infections. Curr Infect Dis Rep. 2009;11:449-456.
270
22. Portnoy J, Ahronheim GA, Ghibu F, et al. Recovery of Epstein-Barr
virus from genital ulcers. N EngI JMed. 1984;311:966-968.
23. Trcko K, Belic M, Miljković J. Ulcus vulvae acutum. Acta
Dermatovenerol Alp Panonica Adriat. 2007;16:174-176.
24. Huppert JS. Lipschutz ulcers: Evaluation and management of acute
genital ulcers in women. Dermatol Ther. 2010;23:533-540.
25. Brinca A, Canelas MM, Carvalho MJ, et al. Lipschűtz ulcer (ulcus
vulvae actum): A rare cause of genital lesion. An Bras Dermatol.
2012;87:622-624.
26. Alpsoy E, Zouboulis CC, Ehrlich GE. Mucocutaneous lesions of
Behcet's disease. Yonsei Med J. 2007;48:573-585.
27. Altenburg A, Mahr A, Maldini C, et al. Epidemiology and clinical
aspects of Adamantiades-Behçet disease in Gemany. Current data.
Ophthalmologe. 2012;109:531-541.
28. Zouboulis CC. Epidemiology of Adamantiades-Behçet's disease.
Ann Med Interne (Paris). 1999;150:488-498.
29. Zouboulis CC, Kötter I, Djawari D, et al. Epidemiological features of
Adamantiades-Behçet's disease in Germany and in Europe. Yonsei
Med J. 1997;38:411-422.
30. Yamamoto S, Toyokawa H, Matsubara J, Yanai H, Nakae K. A
nationwide survey of Behcet's disease in Japan. Epidemiological
survey. Jpn J Ophthalmol. 1974;18:282-290.
31. Melikoglu M, Kural-Seyahi E, Tascilar K, et al. The unique features of
vasculitis in Behçet's syndrome. Clin Rev Allerg Immunol. 2008;35:
40-46.
32. Müftüoğlu AU, Yazici H, Yurdakul S, et al. Behçet's disease: Lack of
correlation of clinical manifestations with HLA antigens. Tissue
Antigens. 1981;17:226-230.
33. Baricordi OR, Sensi A, Pivetti-Pezzi P, et al. Behçet's disease
associated with HLA-B51 and DRw52 antigens in Italians.
Hum Immunol. 1986;17:297-301.
34. Zouboulis CC. Adamatiades-Behcet's disease. Med Microbiol
Immunol. 2003;192:149.
35. Shaker O, Ay El-Deen MA, El Haddidi H, et al. The role of heat shock
protein 60, vascular endothelial growth factor and antiphospholipid
antibodies in Behçet disease. Br J Dermatol. 2007;156:32-37.
36. Katsantonis J, Adler Y, Orfanos CE, et al. Adamantiades-Behçet's
disease: Serum IL-8 is a more reliable marker for disease activity than
C-reactive protein and erythrocyte sedimentation rate. Dermatology.
2000;201:37-39.
37. Yanagihori H, Oyama N, Nakamura K, et al. Role of IL-12B promoter
polymorphism in Adamantiades-Behçet's disease susceptibility: An
involvement of Th1 immunoreactivity against Streptococcus sangui-
nis antigen. J Invest Dermatol. 2006;126:1534-1544.
38. Zouboulis CC. Adamatiades-Behcet disease. In: Wolff K, Goldsmith
LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, eds. Fitzpatrick's
Dermatology in Genereal Medicine. 7th ed. New York: McGraw Hill;
2008. p. 1620-1626.
39. Ghate JV, Jorizzo JL. Behcet's disease and complex apthosis. J Am
Acad Dermatol. 1999;40:1-18.
40. Schreiner DT, Jorizzo JL. Behcet's disease and complex apthosis.
Dermatol Clin. 1987;5:769-778.
41. Alpsoy E, Durusoy C, Yilmaz E, et al. Interferon alpha-2a in the
treatment of Behcet's disease: A randomized, placebo controlled and
double blind study. Arch Dermatol. 2002;138:467-471.
42. Chajek T, Fainaru M. Behcet's disease: Report of 41 cases and review
of literature. Medicine (Baltimore). 1975;54:179-196.
43. Arbesfeld SJ, Kurban AK. Behcet's disease. New perspectives on an
enigmatic syndrome. J Am Acad Dermatol. 1988;19:767-779.
44. Golan G, Beeri R, Mevorach D. Henoch-Schoenlein purpura-like
disease representing a flare of Behcet's disease. Br J Rheumatol.
1994;33:1198-1199.
45. Zouboulis CC. Genitoanal lesions in Adamantiades-Behçet's disease.
J Eur Acad Dermatol Venereol. 1997;9:S106-S107.
46. Mat MC, Goksugur N, Engin B, et al. The frequency of scarring after
genital ulcers in Behçet's syndrome: A prospective study. Int J
Dermatol. 2006;45:554-556.
V.N. Sehgal et al.
47. Anonymous. Criteria for diagnosis of Behçet's disease. International
Study Group for Behçet's disease. Lancet. 1990;335:1078-1080.
48. Madke B, Doshi B, Pande S, et al. Phenomena in dermatology. Indian
J Dermatol Venereol Leprol. 2011;77:264-275.
49. Tuzun Y, Yazici H, Pazarli H, et al. The usefulness of the non specific
skin hyperreactivity (the pathergy test) in Behcet's disease in Turkey.
Acta Derm Venereol. 1979;59:77-79.
50. Friedman-Birnbaum R, Bergman R, Aizen E. Sensitivity and
specificity of pathergy test results in Israeli patients with Behcet's.
Cutis. 1990;45:261-264.
51. Davies PG, Fordham JN, Kirwan JR, et al. The pathergy test and
Behcet's syndrome in Britain. Ann Rheum Dis. 1984;43:70-73.
52. Lee ES, Bang D, Lee S. Dermatologic manifestation of Behçet's
disease. Yonsei Med J. 1997;38:380-389.
53. McCarty MA, Garton RA, Jorizzo JL. Complex aphthosis and
Behçet's disease. Dermatol Clin. 2003;21:41-48.
54. Altenburg A, Papoutsis N, Orawa H, Martus P, et al. Epidemiology
and clinical manifestations of Adamantiades-Behçet disease in
Germany—Current pathogenetic concepts and therapeutic possibili-
ties. Dtsch Dermatol Ges. 2006;4:49-64.
55. Alpsoy E, Er H, Durusoy C, et al. The use of sucralfate suspension in
the treatment of oral and genital ulceration of Behçet disease: A
randomized, placebo-controlled, double-blind study. Arch Dermatol.
1999;135:529-532.
56. Davatchi F, Sadeghi Abdollahi B, Tehrani Banihashemi A, et al.
Colchicine versus placebo in Behçet's disease: Randomized, double-
blind, controlled crossover trial. Mod Rheumatol. 2009;19:542-549.
57. Sharquie KE, Najim RA, Abu-Raghif AR. Dapsone in Behçet's
disease: A double-blind, placebo-controlled, cross-over study.
J Dermatol. 2002;29:267-279.
58. Zouboulis CC, Orfanos CE. Treatment of Adamantiades-Behçet
disease with systemic interferon alfa. Arch Dermatol. 1998;134:
1010-1016.
59. Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine
in Behçet's syndrome. N Engl J Med. 1990;322:281-285.
60. Jorizzo JL, White WL, Wise CM, et al. Low-dose weekly
methotrexate for unusual neutrophilic vascular reactions: Cutaneous
polyarteritis nodosa and Behçet's disease. J Am Acad Dermatol.
1991;24:973-978.
61. Arida A, Fragiadaki K, Giavri E, et al. Anti-TNF agents for Behçet's
disease: Analysis of published data on 369 patients. Semin Arthritis
Rheum. 2011;41:61-70.
62. Jorizzo JL, Taylor RS, Schmalstieg FC, et al. Complex aphthosis: A
forme fruste of Behçet's syndrome? J Am Acad Dermatol. 1985;13:
80-84.
63. Challacombe SJ, Barkham P, Lehner T. Haematologic features and
differentiation of recurrent oral ulceration. Br J Oral Surg. 1977;15:
37-48.
64. Challacombe SJ, Scully C, Kerval B, et al. Serum ferritin in recurrent
oral ulceration. J Oral Pathol. 1983;12:290-299.
65. Field EA, Brookes V, Tyldesley WR. Recurrent aphthous ulceration in
children: A review. Int J Paediatr Dent. 1992;2:1.
66. Nolan A, McIntosh WB, Allam BF, et al. Recurrent aphthous
ulceration: Vitamin B1, B2, and B6 status and response to replacement
therapy. J Oral Pathol Med. 1991;20:389-391.
67. Palopoli J, Waxman J. Recurrent aphthous stomatitis and vitamin B12
deficiency. South Med J. 1990;83:475-477.
68. Porter SR, Kingsmill V, Scully C. Audit of diagnosis and in-
vestigations in patients with recurrent aphthous stomatitis. Oral Surg
Oral Med Oral Pathol. 1993;76:449-452.
69. Porter SR, Scully C, Flint S. Hematologic status in recurrent aphthous
stomatitis compared with other oral disease. Oral Surg Oral Med Oral
Pathol. 1988;66:41-44.
70. Scully C, Macfayden EE, Campbell A. Oral manifestations in cyclic
neutropenia. Br J Oral Surg. 1982;20:96-101.
71. Wray D, Ferguson MM, Hutcheon AW, et al. Nutritional deficiencies
in recurrent aphthae. J Oral Pathol. 1978;7:418-423.
Nonspecific genital ulcers
72. Lange RD, Jones JB. Cyclic neutropenia. Review of clinical
manifestations and management. Am J Pediatr Haematol Oncol.
1981;3:363-367.
73. Thomas HC, Ferguson A, McLennon JG, et al. Food antibodies in oral
disease: A study of serum anti-bodies to food proteins in aphthous
ulceration and other oral disease. J Clin Pathol. 1973;26:371-374.
74. Wray D. Gluten-sensitive recurrent aphthous stomatitis. Dig Dis Sci.
1981;26:737-740.
75. Hay KD, Reade PC. The use of an elimination diet in the treatment of
recurrent aphthous ulceration of the oral cavity. Oral Surg Oral Med
Oral Pathol. 1984;57:504-507.
76. Wright A, Ryan FP, Willingham SE, et al. Food allergy or intolerance
in severe recurrent aphthous ulceration of the mouth. Br Med J (Clin
Res Ed). 1986;292:1237-1238.
77. O'Farrelly C, O'Mahony C, Graeme-Cook F, et al. Gliadin antibodies
identify gluten-sensitive oral ulceration in the absence of villousa-
trophy. J Oral Pathol Med. 1991;20:476-478.
78. Nolan A, Lamey PJ, Milligan KA, et al. Recurrent aphthous ulceration
and food sensitivity. J Oral Pathol Med. 1991;20:473-475.
79. Healy CM, Thornhill MH. An association between recurrent
orogenital ulceration and non-steroidal anti-inflammatory drugs.
J Oral Pathol Med. 1995;24:46-48.
80. Andrews VH, Hall HR. The effects of relaxation/imagery training on
recurrent aphthous stomatitis: A preliminary study. Psychosom Med.
1990;52:526-535.
81. Mizoguchi M, Matsuki K, Mochizuki M, et al. Human leukocyte
antigen in Sweet's syndrome and its relationship to Behçet's disease.
Arch Dermatol. 1988;124:1069-1073.
82. Ficarra G. Oral lesions of iatrogenic and undefined etiology and
neurologic disorders associated with HIV infection. Oral Surg Oral
Med Oral Pathol. 1992;73:201-211.
83. MacPhail LA, Greenspan D, Greenspan JS. Recurrent aphthous ulcers
in association with HIV infection. Diagnosis and treatment. Oral Surg
Oral Med Oral Pathol. 1992;73:283-288.
84. Reyes-Teran G, Ramirez-Amador V, de la Rosa E, et al. Major
recurrent oral ulcers in AIDS: report of three cases. J Oral Pathol Med.
1992;21:409-411.
85. Chang HK, Kim JU, Cheon KS, et al. HLA-B51 and its allelic types in
association with Behçet's disease and recurrent aphthous stomatitis in
Korea. Clin Exp Rheumatol. 2001;19:S31-S35.
86. Verpilleuxa MP, Bastuji-Garinb S, Revu J. Comparative analysis of
severe aphthosis and Behçet's disease: 104 Cases. Dermatology.
1999;198:247-251.
87. Bang D, Hur W, Lee ES, et al. Prognosis and clinical relevance of
recurrent oral ulceration in Behçet's disease. J Dermatol. 1995;22:
926-929.
88. Burgdorf W. Cutaneous manifestations of Crohn's disease. J Am Acad
Dermatol. 1981;5:689-695.
89. Schrodt BJ, Callen JP. Metastatic Crohn's disease presenting as
chronic perivulvar and perirectal ulcerations in an adolescent patient.
Pediatrics. 1999;103:500-502.
90. Danese S, Semeraro S, Papa A, et al. Extraintestinal manifestations
in inflammatory bowel disease. World J Gastroenterol. 2005;11:
7227-7236.
91. Loftus Jr EV, Schoenfeld P, Sandborn WJ. The epidemiology and
natural history of Crohn's disease in population-based patient cohorts
from North America: A systematic review. Aliment Pharmacol Ther.
2002;16:51-60.
92. Sangwan YP, Schoetz Jr DJ, Murray JJ, et al. Perianal Crohn's
disease. Results of local surgical treatment. Dis Colon Rectum. 1996;
39:529-535.
93. Lockhart-Mummery HE. Symposium. Crohn's disease: Anal lesions.
Dis Colon Rectum. 1975;18:200-202.
94. Fielding JF. Perianal lesions in Crohn's disease. J R Coll Surg Edinb.
1972;17:32-37.
95. McClane SJ, Rombeau JL. Anorectal Crohn's disease. Surg Clin
North Am. 2001;81:169-183.
271
96. Palamaras I, El-Jabbour J, Pietropaolo N, et al. Metastatic Crohn's
disease: A review. J Eur Acad Dermatol Venereol. 2008;22:1033-1043.
97. Emanuel PO, Phelps RG. Metastatic Crohn's disease: A histopatho-
logic study of 12 cases. J Cutan Pathol. 2008;35:457-461.
98. Shum DT, Guenther L. Metastatic Crohn's disease. Case report and
review of the literature. Arch Dermatol. 1990;126:645-648.
99. Singh B, McC Mortensen NJ, Jewell DP, et al. Perianal Crohn's
disease. Br J Surg. 2004;91:801-814.
100. Lebwohl M, Fleischmajer R, Janowitz H, et al. Metastatic Crohn's
disease. J Am Acad Dermatol. 1984;10:33-38.
101. Panackel C, John J, Krishnadas D, et al. Metastatic Crohn's disease of
external genitalia. Indian J Dermatol. 2008;53:146-148.
102. Hackzell-Bradley M, Hedblad MA, Stephansson EA. Metastatic
Crohn's disease. Report of 3 cases with special reference to
histopathologic findings. Arch Dermatol. 1996;132:928-932.
103. Crowson AN, Nuovo GJ, Mihm Jr MC, et al. Cutaneous manifesta-
tions of Crohn's disease, its spectrum, and its pathogenesis:
Intracellular consensus bacterial 16S rRNA is associated with the
gastrointestinal but not the cutaneous manifestations of Crohn's
disease. Hum Pathol. 2003;34:1185-1192.
104. Perret CM, Bahmer FA. Extensive necrobiosis in metastatic Crohn's
disease. Dermatologica. 1987;175:208-212.
105. Anonymous. Case records of the Massachusetts General Hospital.
Case 21–2000. A 13-year-old boy with genital edema and abdominal
pain. N Engl J Med. 2000;343:127-133.
106. Ninan T, Aggett PJ, Smith F, et al. Atypical genital involvement in a
child with Crohn's disease. J Pediatr Gastroenterol Nutr. 1992;15:
330-333.
107. Slaney G, Muller S, Clay J, et al. Crohn's disease involving the penis.
Gut. 1986;27:329-333.
108. Kafity AA, Pellegrini AE, Fromkes JJ. Metastatic Crohn's disease. A
rare cutaneous manifestation. J Clin Gastroenterol. 1993;17:300-303.
109. Ploysangam T, Heubi JE, Eisen D, et al. Cutaneous Crohn's disease in
children. J Am Acad Dermatol. 1997;36:697-704.
110. Chiba M, Iizuka M, Horie Y, et al. Metastatic Crohn's disease
involving the penis. J Gastroenterol. 1997;32:817-821.
111. McCallum DI, Gray WM. Metastatic Crohn's disease. Br J Dermatol.
1976;95:551-554.
112. Bardazzi F, Guidetti MS, Passarini B, et al. Cyclosporin A in
metastatic Crohn's disease. Acta Derm Venereol. 1995;75:324-325.
113. Bloget F, Bisiau S, Delaporte E, et al. Metastatic. Crohn's disease of
the penis. Ann Pathol. 1996;16:296-298.
114. Guest GD, Fink RL. Metastatic Crohn's disease: Case report of an
unusual variant and review of the literature. Dis Colon Rectum.
2000;43:1764-1766.
115. Lavery HA, Pinkerton JH, Sloan J. Crohn's disease of the vulva—two
further cases. Br J Dermatol. 1985;113:359-363.
116. Gelbmann CM, Rogler G, Gross V, et al. Prior bowel resections,
perianal disease, and a high initial Crohn's disease activity index are
associated with corticosteroid resistance in active Crohn's disease.
Am J Gastroenterol. 2002;97:1438-1445.
117. Casson DH, Eltumi M, Tomlin S, et al. Topical tacrolimus may be
effective in the treatment of oral and perineal Crohn's disease. Gut.
2000;47:436-440.
118. Hodgson T, Hegarty A, Porter S. Topical tacrolimus and Crohn
disease. J Pediatr Gastroenterol Nutr. 2001;33:633.
119. Ierardi E, Principi M, Francavilla R, et al. Oral tacrolimus long-term
therapy in patients with Crohn's disease and steroid resistance.
Aliment Pharmacol Ther. 2001;15:371-377.
120. Rispo A, Scarpa R, Di Girolamo E, et al. Infliximab in the treatment of
extra-intestinal manifestations of Crohn's disease. Scand J Rheumatol.
2005;34:387-391.
121. Kaufman I, Caspi D, Yeshurun D, et al. The effect of infliximab on
extraintestinal manifestations of Crohn's disease. Rheumatol Int.
2005;25:406-410.
122. Mahadevan U, Sandborn WJ. Infliximab for the treatment of orofacial
Crohn's disease. Inflamm Bowel Dis. 2001;7:38-42.
272
123. Konrad A, Seibold F. Response of cutaneous Crohn's disease to
infliximab and methotrexate. Dig Liver Dis. 2003;35:351-356.
124. Escher JC, Stoof TJ, van Deventer SJ, van Furth AM. Successful
treatment of metastatic Crohn disease with infliximab. J Pediatr
Gastroenterol Nutr. 2002;34:420-423.
125. Miller AM, Elliott PR, Fink R, et al. Rapid response of severe
refractory metastatic Crohn's disease to infliximab. J Gastroenterol
Hepatol. 2001;16:940-942.
126. Van Dullemen HM, de Jong E, Slors F, Tytgat GN, van Deventer SJ.
Treatment of therapy-resistant perineal metastatic Crohn's disease after
proctectomy using anti-tumor necrosis factor chimeric monoclonal
antibody, cA2: Report of two cases. Dis Colon Rectum. 1998;41:98-102.
127. Mountain JC. Cutaneous ulceration in Crohn's disease. Gut. 1970;11:
18-26.
128. Peltz S, Vestey JP, Ferguson A, et al. Disseminated metastatic
cutaneous Crohn's disease. Clin Exp Dermatol. 1993;18:55-59.
129. Cockburn AG, Krolikowski J, Balogh K, et al. Crohn disease of penile
and scrotal skin. Urology. 1980;15:596-598.
130. Ruocco E, Sangiuliano S, Gravina AG, et al. Pyoderma gangrenosum: An
updated review. J Eur Acad Dermatol Venereol. 2009;23:1008-1017.
131. Su WP, Davis MD, Weenig RH, et al. Pyoderma gangrenosum:
Clinicopathologic correlation and proposed diagnostic criteria. Int J
Dermatol. 2004;43:790-800.
132. Renn CN, Helmer A, Megahed M. Pyogenic arthritis, pyoderma
gangrenosum and acne syndrome (PAPA syndrome). Hautarzt.
2007;58:383-384.
133. Bolognia JL, Jorizzo JL, Rapini RP, eds. Pyoderma gangrenosum.
Dermatology, 1. London: Mosby; 2003. p. 415-418.
134. Larsen CG, Thyssen JP. Pustular penile pyoderma gangrenosum
successfully treated with topical tacrolimus ointment. Acta Derm
Venereol. 2012;92:104-105.
135. Georgala S, Georgala C, Nicolaidou E. Pyoderma gangrenosum of
the penis: A potentially dramatic skin disease. Urology. 2008;72:
1185e9-1185e10.
136. Stingl G, Hintner H, Wolff K. Pyoderma gangraenosum. Hautarzt.
1981;32:165-172.
137. Perry HO, Brunsting LA. Pyoderma gangrenosum: A clinical study of
nineteen cases. Arch Dermatol. 1957;75:380-386.
138. English JS, Fenton DA, Barth J, et al. Pyoderma gangrenosum and
leucocytoclastic vasculitis in association with rheumatoid arthritis—a
report of two cases. Clin Exp Dermatol. 1984;9:270-276.
139. Wong E, Graves MW. Pyoderma gangrenosum and leucocytoclastic
vasculitis. Clin Exp Dermatol. 1985;10:68-72.
140. Powell FC, Hackatt BC. Pyoderma Gangrenosum. In: Wolff K,
Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, eds.
Fitzpatrick's Dermatology in Genereal Medicine. 7th ed. New York:
McGraw Hill; 2008. p. 296-301.
141. Kontochristopoulos GJ, Stavropoulos PG, Gregoriou S, et al.
Treatment of pyoderma gangrenosum with low-dose colchicine.
Dermatology. 2004;209:233-236.
142. Griffiths CE. IVIG for PG. J Dermatol Treat. 2001 Mar;12(1):1.
143. Mimouni D, Anhalt GJ, Kouba DJ, et al. Infliximab for peristomal
pyoderma gangrenosum. Br J Dermatol. 2003;148:813-816.
144. Romero-Gomez M, Sanchez-Munoz D. Infliximab induces remission
of pyoderma gangrenosum. Eur J Gastroenterol Hepatol. 2002;
14:907.
145. Regueiro M, Valentine J, Plevy S, et al. Infliximab for treatment of
pyoderma gangrenosum associated with inflammatory bowel disease.
Am J Gastroenterol. 2003;98:1821-1826.
146. Brooklyn TN, Dunnill MG, Shetty A, et al. Infliximab for the
treatment of pyoderma gangrenosum: A randomised, double blind,
placebo controlled trial. Gut. 2006;55:505-509.
147. Foss CE, Clark AR, Inabinet R, et al. An open-label pilot study of
alefacept for the treatment of pyoderma gangrenosum. J Eur Acad
Dermatol Venereol. 2008;22:943-949.
148. Edwards FC, Truelove SC. The course and prognosis of ulcerative
colitis, part Ill, complications. Gut. 1964;5:1-15.
V.N. Sehgal et al.
149. Russell B. Phagedenic and gangrenous ulceration of the skin complicating
ulcerative colitis. (Phagedena Geometricum). Br J Dermatol. 1950;62:
114-124.
150. Johnson ML, Wilson HTH. Skin lesions in ulcerative colitis. Gut.
1969;10:255-263.
151. Thornton JR, Teague RH, Lon-Beer TS, et al. Pyoderma gangrenosum
and ulcerative colitis. Gut. 1980;21:247-248.
152. Bunker CB, Neill SM. The genital, perianal and umbilical regions.
In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook's
Textbook of Dermatology. 8th ed. UK: Blackwell Publishing Ltd;
2010. p. 71.1-71.102.
153. Sehgal VN, Srivastava G. Fixed drug eruption (FDE):
Changing scenario of incriminating drugs. Int J Dermatol. 2006;
45(8):897-908.
154. Meneux E, Wolkenstein P, Haddad B, et al. Vulvovaginal involve-
ment in toxic epidermal necrolysis: A retrospective study of 40 cases.
Obstet Gynecol. 1998;91:283-287.
155. Correia O, Delgado L, Polónia J. Genital fixed drug eruption: Cross-
reactivity between doxycycline and minocycline. Clin Exp Dermatol.
1999;24:137.
156. Sehgal VN, Srivastava G. Toxic epidermal necrolysis (TEN) Lyell's
syndrome. J Dermatolog Treat. 2005;16:278-286.
157. Drummond C, Fischer G. Vulval fixed drug eruption due to
paracetamol. Australas J Dermatol. 2009;50:118-120.
158. Gaffoor PM, George WM. Fixed drug eruptions occuring on the male
genitals. Cutis. 1990;45:242-244.
159. Gruber F, Stasic A, Lenkovic M, et al. Postcoital fixed drug eruption in
a man sensitive to trimethoprim-sulphamethoxazole. Clin Exp
Dermatol. 1997;22:144-145.
160. Zawar V, Kirloskar M, Chuh A. Fixed drug eruption—a sexually
inducible reaction? Int J STD AIDS. 2004;15:560-563.
161. Fischer G. Vulval fixed drug eruption. A report of 13 cases. J Reprod
Med. 2007;52:81-86.
162. Malik M, Ahmed AR. Involvement of the female genital tract in
pemphigus vulgaris. Obstet Gynecol. 2005;106:1005-1012.
163. Torgerson RR, Edwards L. Diseases and disorders of the female
genitalia. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller
AS, Leffell DJ, eds. Fitzpatrick's Dermatology in Genereal Medicine.
7th ed. New York: McGraw Hill; 2008. p. 675-687.
164. Dereure O, Stoebner P, Barnéon G, et al. Surgical treatment of
pemphigus vulgaris localized to the genital mucosa. Acta Derm
Venereol. 1998;78:75-76.
165. Bunker CB. Diseases and disorders of the male genitalia. In: Wolff K,
Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, eds.
Fitzpatrick's Dermatology in Genereal Medicine. 7th ed. New York:
McGraw Hill; 2008. p. 654-675.
166. Guenther LC, Shum D. Localized childhood vulvar pemphigoid. J Am
Acad Dermatol. 1990;22:762-764.
167. Rupprecht M, Stäbler A, Hornstein OP. Genital mucous membrane
manifestation of localized bullous pemphigoid. Hautarzt. 1991;42:
183-185.
168. Kortekangas-Savolainen O, Kiilholma P. Treatment of vulvovaginal
erosive and stenosing lichen planus by surgical dilatation and
methotrexate. Acta Obstet Gynecol Scand. 2007;86:339-343.
169. Diestelmeier MR, Hayne ST. Erosive lichen planus involving the
glans penis alone. Int J Dermatol. 1984;23:288-289.
170. Alinovi A, Barella PA, Benoldi D. Erosive lichen planus involving the
glans penis alone. Int J Dermatol. 1983;22:37-38.
171. Verma P, Pandhi D. Lichen planus of the external urinary meatus
masquerading sexually transmitted disease. Int J STD & AIDS.
2012;23:73-74.
172. Worheide J, Bonsmann G, Kolde G, et al. Squamous epithelial
carcinoma at the site of lichen ruber hypertrophicus of the glans penis.
Hautarzt. 1991;42:112-115.
173. Bain L, Geronemus R. The association of lichen planus of the penis
with squamous cell carcinoma in situ and with verrucous squamous
carcinoma. J Dermatol Surg Oncol. 1989;15:413-417.
Nonspecific genital ulcers
174. Leal-Khouri S, Hruza GJ. Squamous cell carcinoma developing within
lichen planus of the penis: Treatment with Mohs micrographic
surgery. J Dermatol Surg Oncol. 1994;20:272-276.
175. Helgesen AL, Gjersvik P, Jebsen P, et al. Vaginal involvement in
genital erosive lichen planus. Acta Obstet Gynecol Scand. 2010;89:
966-970.
176. Cooper SM, Wojnarowska F. Influence of treatment of erosive
lichen planus of the vulva and its prognosis. Arch Dermatol. 2006;
142:289-294.
177. Kirtschig G, Wakelin SH, Wojnarowska F. Mucosal vulval lichen
planus: Outcome, clinical and laboratory features. J Eur Acad
Dermatol Venereol. 2005;19:301-307.
178. Goldstein AT, Metz A. Vulvar lichen planus. Clin Obstet Gynecol.
2005;48:818-823.
179. Usatine RP, Tinitigan M. Diagnosis and treatment of lichen planus.
Am Fam Physician. 2011;84:53-60.
180. Schmitt EC, Pigatto PD, Boneschi V, et al. Erosive lichen planus of the
glans penis. Treatment with cyclosporin A. Hautarzt. 1993;44:43-45.
181. McPherson T, Cooper S. Vulval lichen sclerosus and lichen planus.
Dermatol Ther. 2010;23:523-532.
182. Bousema MT, Romppanen U, Geiger JM, et al. Acitretin in the
treatment of severe lichen sclerosus et atrophicans of the vulva: A
double-blind, placebo-controlled study. J Am Acad Dermatol.
1994;30:225-231.
183. Kreuter A, Tigges C, Gaifullina R, et al. Pulsed high-dose
corticosteroids combined with low-dose methotrexate treatment in
patients with refractory generalized extragenital lichen sclerosus.
Arch Dermatol. 2009;145:1303-1308.
184. Vano-Galvan S, Fernandez-Guarino M, Beà-Ardebol S, et al.
Successful treatment of erosive vulvar lichen sclerosus with
methylaminolaevulinic acid and laser-mediated photodynamic thera-
py. J Eur Acad Dermatol Venereol. 2009;23:71-72.
185. Verma GK, Sharma NL, Shanker V, et al. Amoebiasis cutis: Clinical
suspicion is the key to early diagnosis. Australas J Dermatol. 2010;51:
52-55.
186. Bumb RA, Mehta RD. Amoebiasis cutis in HIV positive patient.
Indian J Dermatol Venereol Leprol. 2006;72:224-226.
187. Prashad S, Grover PS, Sharma A, et al. Primary cutaneous amoebiasis:
A case report with review of the literature. Int J Dermatol. 2002;41:
676-680.
188. Valverde J, Arrese JE, Piérard GE. Granulomatous cutaneous
centrofacial and meningocerebral amebiasis. Am J Clin Dermatol.
2006;7:267-269.
189. Kenner BM, Rosen T. Cutaneous amebiasis in a child and review of
the literature. Pediatr Dermatol. 2006;23:231-234.
190. Al-Daraji WI, Husain EA, Robson A. Primary cutaneous amebiasis
with a fatal outcome. Am J Dermatopathol. 2008;30:398-400.
191. Magaña M, Magaña ML, Alcántara A, et al. Histopathology of
cutaneous amebiasis. Am J Dermatopathol. 2004;26:280-284.
192. Ramdial PK, Calonje E, Singh B, et al. Amebiasis cutis revisited.
J Cutan Pathol. 2007;34:620-628.
193. Richens J. Genital manifestations of tropical diseases. Sex Transm
Infect. 2004;80:12-17.
194. Citronberg RJ, Semel JD. Severe vaginal infection with Entamoeba
histolytica in a woman who recently returned from Mexico: Case
report and review. Clin Infect Dis. 1995;20:700-702.
195. Mylius RE, Ten Seldam RE. Venereal infection by Entamoeba
histolytica in a New Guinea couple. Trop Geogr Med. 1962;14:20-26.
196. Cabello I, Caraballo A, Millan Y. Leishmaniasis in the genital area.
Rev Inst Med Trop Sao Paolo. 2002;44:105-107.
197. Castro-Coto A, Hidalgo-Hidalgo H, Solano-Aguilar E, et al. Leish-
maniasis en organos genitales. Med Cutan Ibero Lat Am. 1987;15:
145-150.
198. Blickstein I, Dgani R, Lifschitz-Mercer B. Cutaneous leishmaniasis of
the vulva. Int J Gunaecol Obstet. 1993;42:46-47.
199. Sehgal VN, Wagh SA. Cutaneous tuberculosis. Current concepts. Int J
Dermatol. 1990;29:237-249.
273
200. Chen YJ, Shieh PP, Shen JL. Orificial tuberculosis and Kaposi's
sarcoma in an HIV-negative individual. Clin Exp Dermatol. 2000;25:
393-397.
201. Mathew S. Anal tuberculosis: report of a case and review of literature.
Int J Surg. 2008;6:e36-e39.
202. Akgun E, Tekin F, Ersin S, et al. Isolated perianal tuberculosis. Neth J
Med. 2005;63:115-117.
203. Ezzedine K, Belin E, Pistone T, et al. Orificial tuberculosis in
an immunocompetent careworker. Acta Derm Venereol. 2010;90:
552-553.
204. Sehgal VN. Cutaneous tuberculosis. Dermatol Clin. 1994;12:
645-653.
205. Sah SP, AshokRaj G, Joshi A. Primary tuberculosis of the glans penis.
Australas J Dermatol. 1999;40:106-107.
206. Wong S, Rizvi H, Cerio R, et al. An unusual case of vulval
papulonecrotic tuberculid. Clin Exp Dermatol. 2011;36:277-280.
207. Israelewicz S, Dharan M, Rosenman D, et al. Papulonecrotic tuberculid
of the glans penis. J Am Acad Dermatol. 1985;12:1104-1106.
208. Ramdial PK, Mosam A, Mallett R, et al. Papulonecrotic tuberculid in a
2-year-old girl: With emphasis on extent of disease and presence of
leucocytoclastic vasculitis. Pediatr Dermatol. 1998;15:450-455.
209. Barbagallo J, Tager P, Ingleton R, et al. Cutaneous tuberculosis:
Diagnosis and treatment. Am J Clin Dermatol. 2002;3:319-328.
210. Pandhi D, Reddy BS. Childhood herpes zoster complicated by
neurogenic bladder dysfunction. Pediatr Dermatol. 2004;21:279-280.
211. Spray A, Glaser DA. Herpes zoster of the penis: An unusual location
for a common eruption. J Am Acad Dermatol. 2002;47:S177-S179.
212. Krol AL. Perianal streptococcal dermatitis. Pediatr Dermatol. 1990;7:
97-100.
213. Sica A, Dekou A, Kaba L, et al. Genital site of Buruli ulcer (BU):
Clinical and therapeutic aspects. Prog Urol. 2005;15:736-738.
214. Piot P, Duncan M, van Dyck E, et al. Ulcerative balanoposthitis
associated with non-syphilitic spirochaetal infection. Genitourin Med.
1986;62:44-46.
215. Engelkens HJ, Judanarso J, van der Sluis JJ, et al. Disseminated early
yaws: Report of a child with a remarkable genital lesion mimicking
venereal syphilis. Pediatr Dermatol. 1990;7:60-62.
216. Akkilic M, Weger W, Kranke B, et al. Bullous necrotic lesion of the
penis. J Eur Acad Dermatol Venereol. 2006;20:1024-1025.
217. Cunningham DL, Persky L. Penile ecthyma gangrenosum. Compli-
cation of drug addiction. Urology. 1989;34:109-110.
218. Smith GL, Bunker CB, Dineen MD. Fournier's gangrene. Br J Urol.
1998;81:347-355.
219. Jayalakshmi P, Goh KL, Soo-Hoo TS, et al. Disseminated histoplas-
mosis presenting as penile ulcer. Aust N Z J Med. 1990;20:175-176.
220. Preminger B, Gerard PS, Lutwick L, et al. Histoplasmosis of the penis.
J Urol. 1993;149:848-850.
221. Severo LC, Kauer CL, Oliveira F, et al. Paracoccidioidomycosis of the
male genital tract: Report of eleven cases cases and a review of
Brazilian literature. Rev Inst Med Trop Sao Paulo. 2000;42:37-40.
222. Cohen-Ludmann C, Kerob D, Feuilhade M, et al. Zygomycosis of the
penis due to Rhizopus oryzae successfully treated with surgical
debridement and a combination of high dose liposomal and topical
amphotericin B. Arch Dermatol. 2006;142:1657-1658.
223. Sehgal VN, Shyam Prasad AL. Chancroid or chancroidal ulcers.
Dermatologica. 1985;170:136-141.
224. Huben RP, Sufrin G. Benign and malignant lesions of the penis. In:
Gillenwater JY, Grayhack JT, Howards SS, eds. Adult and Pediatric
Urology. 2nd ed. St Louis, MO: Mosby; 1991. p. 1643.
225. Micali G, Nasca MR, Innocenzi D, et al. Invasive penile carcinoma: A
review. Dermatol Surg. 2004;30:311-320.
226. Garcia-Cruz A, Feal Cortizas C, Posada Garcia C, et al. Genital ulcer
in a patient with chronic lymphocytic leukaemia. Clin Exp Dermatol.
2011;36:107-109.
227. Antoniou C, Stefanaki C, Ioannidou D, et al. Recurrent penile ulcer as
a manifestation of chronic lymphocytic leukaemia. Int J Std AIDS.
2008;19:795-796.
274
228. Steinbach F, Essbach U, Florschütz A, et al. Ulcerative balanoposthitis
as the initial manifestation of acute promyelocyticleukemia. J Urol.
1998;160:1430-1431.
229. Tazi I, Rachid M, Quessar A, et al. Scrotal ulceration following all-
trans retinoic Acid therapy for acute promyelocytic leukemia. Indian J
Dermatol. 2011;56:561-563.
230. Lee HY, Ang AL, Lim LC, Thirumoorthy T, Pang SM. All-trans
retinoic acid-induced scrotal ulcer in a patient with acute pro
myelocytic leukaemia. Clin Exp Dermatol. 2010 Jan;35(1):91-92.
231. Canavan TP, Cohen D. Vulvar cancer. Am Fam Physician. 2002;66:
1269-1274.
232. Hacker NF. Vulvar cancer. In: Berek JS, Hacker NF, eds. Practical
Gynecologic Oncology. 3rd ed. Philadelphia: Williams & Wilkins;
2000. p. 553-596.
233. Pisani C, Poggiali S, De Padova L, et al. Basal cell carcinoma of the
vulva. J Eur Acad Dermatol Venereol. 2006;20:446-448.
234. Piura B, Rabinovich A, Dgani R. Malignant melanoma of the vulva:
Report of six cases and review of the literature. Eur J Gynaecol Oncol.
1999;20:182-186.
235. Zoon JJ. Chronic benign circumscript plasmocytic balanoposthitis.
Dermatologica. 1952;105:1-7.
236. Garnier G. Vulvite erythemateuse circonscrite benigne a type
erythroplasique. Bull Soc Fr Dermatol Syphilol. 1954;61:102-104.
237. Marconi B, Campanati A, Simonetti O, et al. Zoon's balanitis
treated with imiquimod 5% cream. Eur J Dermatol. 2010;20:
134-135.
238. Sehgal VN, Rege VL, Malik G. Chronic plasma cell balanitis of Zoon.
Report of two cases. Br J Vener Dis. 1973;49:86-88.
239. Woodruff JD, Sussman J, Shakfeh S. Vulvitis circumscripta
plasmacellularis: A report of four cases. J Reprod Med. 1989;34:
369-372.
V.N. Sehgal et al.
240. Retamar RA, Kien MC, Chouela EN. Zoon's balanitis: Presentation of
15 patients, five treated with a carbon dioxide laser. Int J Dermatol.
2003;42:305-307. Bardazzi F, Antonucci A, Savoia F, Balestri R. Two
cases of Zoon's balanitis treated with pimecrolimus 1% cream. Int J
Dermatol. 2008;47:198-201.
241. Lacarrubba F, Nasca MR, Micali G. Advances in the use of topical
imiquimod to treat dermatologic disorders. Ther Clin Risk Manag.
2008;4:87-97.
242. Verma P, Pandhi D, Yadav P. Dermatitis artefacta manifesting as
genital scars: A result of an unusual behaviour pattern. Int J Std &
AIDS. 2012;23:527-528.
243. Kempson RL, Sherman AI. Sclerosing lipogranuloma of the vulva.
Am J Obstet Gynecol. 1968;101:854-856.
244. Al-Mutairi N, Sharma AK, Zaki A, et al. Penile self-injections: An
unusual act. Int J Dermatol. 2004;43:680-682.
245. Wollina U. Genital ulcers in a psoriasis patient using topical
tazarotene. Br J Dermatol. 1998;138:713-714.
246. Puri N. A study on the use of imiquimod for the treatment of genital
molluscum contagiosum and genital warts in female patients. Indian J
Sex Transm Dis. 2009;30:84-88.
247. Borgstrom E. Penile ulcer as complication in self-induced papaverine
erections. Urology. 1988;32:416-417.
248. Evans LM, Grossman ME. Foscarnet-induced penile ulcer. J Am Acad
Dermatol. 1992;27:124-126.
249. Gross AS, Dretler RH. Foscarnet-induced penile ulcer in an uncircum-
cised patient with AIDS. Clin Infect Dis. 1993;17:1076-1077.
250. Toquero L, Briggs CD, Bassuini MM, et al. Anal ulceration associated
with nicorandil: Case series and review of the literature. Colorectal
Dis. 2006;8:717-720.
251. Birnie A, Dearing S, Littlewood S, Carlin E. Nicorandil-induced
ulceration of the penis. Clin Exp Dermatol. 2008;33:215-216.