Dr,F iraji
Clinical History
 52 year old white female presented for removal of multiple
mucosal and cutaneous lesions. Over the course of her
lifetime, the patient has had more than 30 surgical
procedures to address her mucocutaneous as well as
internal lesions. These procedures included removal of a
large benign ovarian tumor at the age of 16, meningioma
resection at the age of 37, removal of gastric and colonic
polyps, history of goiter and most recently diagnosis of
breast cancer for which patient has undergone left
mastectomy and right lympectomy. Patient’s father and
grandfather both have been diagnosed with the same
genetic condition as our patient but have had less
prominent manifestations of the syndrome.
Physical Exam
 Physical exam of the patient was significant for diffuse
flesh colored mucocutaneous papules along with
prominent cobblestoning of the oral mucosa (Figures 14). Pathology showed a verrucous lesion consisting of
lobular proliferation of bland cells with peripheral nuclear
palisading. Lobules were surrounded by a prominent
basement membrane. All histological findings were
consistent with a trichilemomma (Figures 5-7).
 Patient’s medical and family histories, cutaneous
manifestations along with pathology were diagnostic
of Cowden syndrome
Discussion
 Clinical findings of Cowden or multiple hamartoma
syndrome were first described by Costello in 1940 in a
female patient who died from breast cancer at an early
age.1 In 1963, a term Cowden syndrome was coined by
Rachel Cowden, with family history of the disorder,
presented with multiple cutaneous and mucosal
lesions, fibrocystic disease of the breast and thyroid
abnormalities.
Discussion
 The gene responsible for the multiple hamartoma syndrome was
mapped to chromosome 10 and then identified as PTEN. PTEN
which stands for phosphatase and tensin homolog deleted on
chromosome 10, is a tumor suppressor gene which encodes a
phosphatase that normally dephosphorylates serine and
threonine residues thus opposing the activity of downstream
AKT serine/threonine kinase. When functioning normally,
PTEN regulates cell cycle, cell migration, angiogenesis and
apoptosis through various interconnecting pathways. Mutations
in PTEN have been found in a number of malignancies most of
which are common to Cowden syndrome including breast
carcinoma, meningioma, endometrial carcinoma, ovarian
tumors, renal cell carcinoma and melanoma.
Discussion
 The most prominent and common features of the Cowden syndrome are the
mucocutaneous hamartomas (most often trichilemmomas) that present as
facial papules and lead to cobblestone appearance of the mucosa in as many as
80% of the patients. Acral, including palmoplantar keratoses, hemangiomas,
lipomas, neuromas and xanthomas are other cutaneous lesions that can be
seen in patients with this multiple hamartoma syndrome.
 As the history of our patient demonstrates, all patients with Cowden syndrome
must be regularly screened for breast, thyroid and endometrial carcinomas that
are part of the International Cowden Consortium Diagnostic –Major
Criteria. Other malignancies associated with Cowden Syndrome but with less
frequency include SCCs, BCCs, Merkel cell carcinomas, melanomas,
lymphomas, hepatocellular and renal cell carcinomas.
 Differential diagnosis of Cowden syndrome should always include a family of
Hamartomatous Tumor Syndromes (PHTS) that also have been found to have
PTEN gene abnormalities with variable frequencies. In this category is
Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba Syndrome, Proteus
Syndrome and VATER syndrome
Clinical History
 A 38 year-old white male presented with a 25-year
history of multiple “warts” over his distal upper and
lower extremities, inculding the dorsal hands and
feet. He stated that the lesions are asymptomatic and
he often “pulls them off”. Some moisturizers he had
tried in the past help to soften the lesions, although
nothing completely resolved them. He had no
significant past medical history or chronic medical
diseases. On further history, he stated that his father
has similar lesions with a similar course.
Physical Exam
 Physical exam revealed hundreds to thousands of 1-
3mm gray-white verrucous papules with a “stuck-on”
appearance over the patient’s hands, feet, and distal
upper and lower extremities. (Fig. 1 and 2) His head,
neck, trunk, and groin were within normal limits.
 Histopathology:
 Biopsy revealed a verrucous lesion on low power with
hyperkeratosis, acanthosis, and papillomatosis in a
“church-spire” configuration. (Fig. 3 and 4)
Discussion
 Acrokeratosis verruciformis (AV) is a rare autosomal
dominant genodermatosis first described by Gustav
Hopf in 1931. It is characterized by multiple fleshcolored to gray hyperkeratotic papules over the distal
upper and lower extremities. Lesions may also be
reddish-brown or pigmented and present over the
knees and elbows. They usually appear in childhood,
but may be present at birth or not appear until
adulthood. AV has been associated with degeneration
to squamous cell carcinoma, but it is unclear whether
sun exposure played a role in these cases (i.e., the
lesions were incidental in the affected area).
Discussion
 There are also associations of AV with
epidermodysplasia verruciformis and basal cell nevus
syndrome, but these are controversial. Histologically,
the lesions are characterized by hyperkeratosis,
acanthosis, and papillomatosis with a “church-spire”
configuration, essentially undistinguishable from a
stucco keratosis. Recently it has been shown that
some patients with AV have a mutation in ATP2A2,
allelic to Darier’s Disease. A genetic analysis of
Chinese patients with AV showed no mutations in
ATP2A2, however, which demonstrates genetic
heterogeneity in this disorder.
Discussion
 Treatments include: 1) destructive methods, such as
keratolytics, cryotherapy, and laser ablation; and 2)
medical treatments, such as topical and oral
retinoids. There is a report of clearing with oral
acitretin, but the benefits of life-long therapy must be
weighed against the risks of the medication. The
lesions will return after therapy is discontinued.
Clinical History
 42 year old Caucasian male with past medical history
significant for insulin dependent diabetes mellitus was
referred from an outside dermatologist for “tough
skin” on the posterior neck and upper back, which had
been present for ten years. Due to this “tightness,” his
skin did not form folds with movement of the neck,
back, and shoulders. He reported no associated
symptoms other than stiffness. Specifically, he had no
respiratory or cardiac complaints. He had been
previously biopsied by an outside dermatologist,
yielding nonspecific findings, and a deeper biopsy was
recommended.
Physical Exam:
 The patient was well developed, well nourished, and in
no apparent distress. The skin of the posterior neck
and upper back was firm, indurated, and mildly
erythematous (Figure 1). He had no other cutaneous
findings.
Laboratory investigations:

CBC, LFT, BUN, and serum creatinine were normal.
ANA was 18. HbA1c was 6.9. Serum protein
electrophoresis was normal.
 Histology:
We performed a deep wedge biopsy of the posterior
neck. Histology revealed an unaffected epidermis with
a dramatic increase in dermal thickness. There was
dermal fibrosis and edematous spaces between
collagen bundles , corresponding to hyaluronic acid
(mucin) deposition (Figures 5-6).
Scleredema adultorum of Buschke
 Scleredema is a skin disease characterized by firm,
nonpitting edema of the skin of the neck/face, back,
shoulders, arms, and less commonly, the distal
extremities. The skin texture is firm and wood-like,
and fails to form skin folds with movement of the
affected body parts. Except in diabetes-associated
cases, there is no clear-cut demarcation from
surrounding skin.
Scleredema adultorum of Buschke
 Scleredema is seen in three settings: post-infectious
(classic type of scleredema described by Buschke in
1902), diabetes-associated (which was the case with
our patient), and with paraproteinemia (usually IgG
kappa). In the diabetes-associated form, males tend to
outnumber females 10:1. The diabetes is usually late
onset, insulin dependent, and poorly controlled, with
associated neuropathy, retinopathy, atherosclerosis,
and obesity. The lesions develop insidiously, persist for
a long duration, and are generally refractory to
therapy. Unfortunately, tighter diabetic control does
not influence disease course.
Scleredema adultorum of Buschke
 In contrast, the post-infectious type, which is seen more
commonly in women, begins abruptly and spontaneously
resolves within two years in most cases. Although
Streptococcus is most commonly associated, other
infectious etiologies have been described (influenza,
measles, mumps). Scarlet fever, tonsillitis, pharyngitis,
otitis, furunculosis, erysipelas, and impetigo have been
described. Finally, it is important to recognize the
association between scleredema and monoclonal
gammopathies. In all patients presenting with the skin
findings of scleredema, evidence for paraproteinemia
should be sought.
Scleredema adultorum of Buschke

Given these clinical associations, patients presenting
with skin findings of scleredema should undergo a
workup including fasting blood sugar, hemoglobin
A1c, serum protein electrophoresis,
immunoelectrophoresis, antistreptolysin O (ASO)
titer, bacterial culture, and erythrocyte sedimentation
rate.
Scleredema adultorum of Buschke

Scleredema can affect other organ systems, including the heart and upper
aerodigestive tract. Tongue involvement can result in complaints of dysphagia
or difficulty opening the mouth. Facial skin changes can impart a mask-like
facies. Cardiac arrthymias and pleural, pericardial, or peritoneal effusions are
recognized complications. Eye involvement (exopthalmos, opthalmoplegia,
chemosis, eyelid induration) has also been reported.
Aside from diagnosing and treating any underlying disease process,
some treatment options include electron beam therapy, bath or cream PUVA,
UVA-1, high dose penicillin, cyclosporine, methotrexate, and extracorporeal
photophoresis. Given the risks of these treatments and the possibility for
spontaneous resolution, conservative management is also appropriate in some
cases. Physiotherapy also plays a role in management of scleredema.
In conclusion, scleredema is yet another example of a dermatologic
manifestation of internal disease. Often, skin findings are the first
manifestation of systemic disease. As dermatologists, we must therefore learn
to recognize such associations and order appropriate screening tests for our
patients.
Clinical History
 A 65 y/o white woman with past medical history of acute myelogenous
leukemia status post allogeneic, unrelated peripheral blood stem cell
transplant in 2007. She had been in clinical remission since the transplant with
immunosuppressive therapy including cyclosporin (100mg PO QAM and
125mg PO QPM), mycophenolate mofetil 250mg PO daily, and hydrocortisone
5mg PO every other day. Prophylactic therapy for infectious disease included
acyclovir 400mg PO BID, fluconazole 200mg PO BID, and monthly
pentamidine.
 At the time of evaluation in the clinic, she had reported a 2-week history of
violaceous papules on both knees that were neither painful nor pruritic. She
also denied fevers, chills, night sweats, joint pain or restriction of mobility.
While she denied any specific trauma to her legs, she noted having fell on a
granite tile floor on her home porch. At the time of the fall, she did not recall
any bleeding or laceration, only a scrapes on both knees after she crawled a
short distance before standing up. She had treated this â rash with over-thecounter hydrocortisone however there was no improvement. The Hillman
Cancer Center Hematology/Oncology Service referred her to UPMC
Dermatology Shadyside clinic for further workup of this cutaneous eruption.
Physical Exam
 Examination of the knees revealed several firm
violaceous papules scattered on the anterior aspect of
the knees, bilaterally.
 Histopathology
 Punch biopsy was performed on the left knee revealing
non-caseating granulomas with presence of foreign
body giant cells in the superficial and deep dermis.
Birefringent foreign material was observed on
polarized light microscopy in several of these
granulomas. Gram and Gomori methenamine silver
stain were negative.
Foreign body granuloma vs
sarcoidal granuloma
 The chief histologic feature of granulomatous
dermatitis is distinct collections of histocytes and
giant cells. These granulomas can be subdivided into
several categories based upon histologic features and
etiology. Some distinguishing features include
presence of necrosis, necrobiosis, foeign bodies,
microorganisms, and suppuration. Sarcoidal
granulomas feature â naked granulomas, having
histiocytes and giant cells with a relative lack of
surrounding inflammatory lymphocytes.
Foreign body granuloma vs
sarcoidal granuloma
 Tuberculoid granulomas often feature an area of central
necrosis as well as a more robust peripheral inflammatory
infiltrate of lymphocytes and plasma cells.
Necrobiotic/palisaded granulomas have a more diffuse
inflammatory infiltrate with characteristic apoptotic or
non-necrotic central areas of degeneration. Suppurative
granulomas feature neutophilic infiltrate and are most
often associated with infectious agents including fungi,
atypical mycobacteria, and various bacterial
microorganisms. Finally, foreign body granulomas feature
characteristic giant cells with identification of either
endogenous or exogenous foreign material.
Foreign body granuloma vs
sarcoidal granuloma
 Of interest in this case report is the development of a foreign body
granulomatous reaction in the context of a history of acute
myelogenous leukemia. With a history of trauma to affected skin
area and histolopathologic picture of foreign body granuloma with
polarizable foreign bodies, the eruption could certainly represent a
reaction to traumatically embedded silica fragments. Granulomatous
dermatitis has been associated with malignancy including sarcoidal
granulomas as well as palisaded neutrophilic granulomatous
dermatitis. Specifically, sarcoidal granulomas have been associated
with several cases of acute myeloid and myeloblastic leukemia, acase of
hairy cell leukemia, lymphomas, lung cancer, and pancreatic cancer.
Most of these cases either featured the development of malignancy
after or concurrent with the diagnosis of sarcoidosis. In the present
case, there was no prior history or radiologic evidence of sarcoidosis
prior to the diagnosis of leukemia after review of prior radiologic
imaging and the patient history.
Foreign body granuloma vs
sarcoidal granuloma
 Given the patient immunosuppressive therapy, further
tissue from the affected skin of the knees as well as
bone marrow was obtained by Hematology/Oncology
and Infectious Disease to culture for microorganisms
including atypical mycobacteria. These culture were all
negative for microorganisms. Empiric therapy with
clarithromycin 500mg PO BID and doxycycline 100mg
PO BID was initiated by Infectious Disease. All lesions
resolved after 2 months of antibiotic therapy without
recurrence. She was continued on this regimen for the
duration of 1 year.
Clinical History
 A 32 year old Caucasian man, veteran, in previous good
health was evaluated in the clinic for a multiple year history
of painful blisters after minimal trauma, progressively
worsening. The condition was not present during his
childhood. The patient denied any constitutional
symptoms, no dysphagia, odynophagia, and no visual
abnormalities. He had no family history of blistering
disorders.
 Physical examination
 Few tense fluid and blood-filled bullae were noted over his
extremities (Figure 1). Areas of prior bullae healed with
resultant overlying scarring with milia formation (Figures 2
and 3).
Laboratory/Radiographic data
 During the course of his workup a pan-CT scan was
within normal limits.
 Histopathology
 Sub-epidermal split with few scattered lymphocytes
and subtle pigment incontinence (Figures 4, 5, and 6).
Direct immunofluorescence on salt-split skin revealed
linear IgG (Figure 7) and C3 (Figure 8) on the dermal
side of the split.
Epidermolysis bullosa acquisita
 Epidermolysis bullosa acquisita (EBA) is a rare
acquired immunobullous disorder in which the target
antigen is collagen VII. Age of onset tends to be in
adulthood, though some cases have been described to
arise in children. Its clinical spectrum is still being
defined. Though it is not hereditary, it shares clinical
exam findings to recessive dystrophic epidermolysis
bullosa with non-inflammatory (at least classically)
mechanobullous skin fragility which leads to
sometimes hemorrhagic tense bullae.
Epidermolysis bullosa acquisita
 The natural course of the disease leads to scar
formation with milia. Lesions can appear at any
mucocutaneous surface but regions of repetitive
trauma are most susceptible, such as extensor surfaces.
Some clinical features, especially early in the course or
in less severe disease, will have overlap with other
immunobullous dermatoses, making diagnosis
challenging. It can clinically mimic bullous
pemphigoid (BP), bullous systemic lupus
erythematosus, mucous membrane pemphigoid, or
linear IgA bullous dermatosis.
Epidermolysis bullosa acquisita
 If suspicion for EBA exists, then a biopsy for direct
immunofluorescence is warranted with, if possible,
serology used for indirect immunofluorescence on
salt-split skin (SSS). The use of SSS helps to delineate
between BP and EBA. BP targets (BPAG180 and
BPAG230) are above the lamina lucida, whereas
collagen VII is located below the lamina lucida. Hence,
immunofluorescence on SSS will reveal a linear
staining pattern of IgG at the epidermal side for BP.
On the other hand, the staining is at the dermal side
for EBA.
Epidermolysis bullosa acquisita
 Due to its rarity, treatment choices have not been well studied.
However, responses have been attained and described through
the use of immunosuppressive therapy commonly used in
dermatology, including corticosteroids, mycophenolate mofetil,
cyclosporine, azathioprine, dapsone, cyclophosphamide, and
rituximab. In a recent review, Ishii et al. advocates the use of oral
steroids (0.5-1.0 mg/kg/day) with or without adjuvant use of
colchicine (50-100 mg daily) and/or dapsone (100-300 mg daily)
in patients with mild disease. For more moderate disease, one
can continue the above with a higher dose of colchicine at 100200 mg daily. For intractable disease, the authors advocate the
use of the higher oral steroid dose with colchicine with another
immunosuppressive agent, namely cyclosporine (3-60
mg/kg/day), plasmapheresis, IVIG, or rituximab.
 1-dermatophytosis
 2 terry nail
 3yellow nail
 15 blue pig due to minocycline
 17 beus line
 19 pachynichia congenita
 20 periangual epidermal cyst