||64 y/o male with B cell non-Hodgkin’s lymphoma and
64 y/o male
Intermittently for 2 years.
Oral mucosa, eyes.
The patient is a 64-year-old Caucasian male with a history
of low-grade B cell non-Hodgkin's lymphoma (NHL) status post
treatment with a 9 month course of fludarabine with resolution
of his lymphadenopathy. He was subsequently followed by surveillance
CT scans which showed gradual enlargement of his nodal adenopathy.
A few years later, the patient bit the inside of his mouth
and noticed that he developed blisters at the site. He was
prescribed a course of oral antibiotics by his primary care
physician with no improvement. He was then referred to an
ENT physician who performed a biopsy. He was given a two week
taper of prednisone starting at 60mg, but his oral lesions
continued to worsen and he also developed swollen eyes with
drainage. He presented to the emergency room when his mouth
“had closed shut” due to blistering and crusting.
There is dark hemorrhagic crusting of lips and mucosal surface
with inability of the patient to open his mouth. Erythema
and angulated erosions plague the posterior pharynx. There
is peri-orbital erythema and edema with painful conjunctival
WBC 6.48 H/H 14.5/4.8 Platelets 152
Na 139 K 3.9 Cl 104 HCO3 27 BUN 17 Cr 1.0 Glu 100 Ca 9.5
ALT 22 AST 49 AlkP 60 T Bili 0.8
A sample from the buccal mucosa reveals irregular epidermal
hyperplasia, dyskeratosis, and blister formation. There is a
dense lichenoid infiltrate comprised primarily of lymphocytes
as well as a deep mixed inflammatory infiltrate. DIF was negative
though the biopsy was secured after the patient had initiated
therapy and his B cell count was nearly zero.
The patient was admitted from the emergency room and treated
with methylprednisolone and Rituximab and his oral lesions improved
markedly. Shortly after discharge, he was started on CVP-R (Cytoxan,
Vincristine, Prednisone and Rituximab) to aggressively treat
his NHL. Following his first course of CVP-R, he was also started
on mycophenolate mofetil and his prednisone was gradually tapered
down to 10mg PO daily with control of his oral lesions.
After seven courses of CVP-R, he declined further treatment
due to fear of recurrent bouts of neutropenia. He has since
been treated with Rituximab for maintenance therapy. Since stopping
CVP-R, his oral lesions have worsened and he has developed “grittiness”
in his eyes. He responds to increases in prednisone but his
lesions recur once his steroids are tapered. He is also on dexamethasone
washes and tacrolimus 0.1% topically BID, although these are
only for symptomatic control at sites of recurrent ulceration.
Although he has never developed shortness of breath, dyspnea
on exertion, paroxysmal nocturnal dyspnea, or platypnea, the
disease became rapidly progressive and blistering attacks prevented
the patient from being able to eat. He became depressed due
to an inability to sleep through the night and massive lower
extremity edema (as a complication of high dose oral prednisone
pulses), which have severely impacted his ambulation.
After several discussions, daclizumab was offered as therapy,
but due to a theoretical reactivation of his lymphoma, the patient
declined. Rather, alemtuzumab was used three times weekly for
a twelve week course. Intravenous immunoglobulin was also infused
monthly. After three infusions with alemtuzumab, the patient
has been in near complete remission. He is able to enjoy foods,
has no dysphagia or hoarseness and we have been able to rapidly
wean off his prednisone dosing back to 20 mg per day.
If this regimen fails, a trial of photopheresis, and possibly
plasmapheresis may be future considerations.
Paraneoplastic pemphigus (PNP) is most commonly associated
with non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Castleman's
disease, thymomas, spindle cell neoplasms and Waldenstrom's
These patients present with mucosal lesions that appear lichenoid
or Stevens-Johnson-like with crusting of the lips. Recalcitrant
stomatitis, consisting of erosions and ulcerations is often
the most persisting feature of PNP. Involvement of other mucocutaneous
surfaces, including the eyes, can occur in the form of pseudomembranous
conjunctivitis, which may progress to scarring and obliteration
of the conjunctival fornices. Furthermore, cutaneous lesions
are polymorphic and can resemble pemphigus vulgaris, bullous
pemphigoid, EM, and lichenoid eruptions. Upper GI, respiratory,
and genital mucosal lesions also occur, as well as involvement
of the kidneys, muscle and heart.
Indeed, because of the multiorgan involvement and variable
cutaneous manifestations that can occur, it has also been proposed
that the term PNP only describes the classic epithelial manifestations
of this syndrome, and that a more appropriate name for this
constellation of findings is paraneoplastic autoimmune multiorgan
Classic histological findings in PNP/PAMS include epidermal
acantholysis, suprabasal cleft formation, dyskeratotic keratinocytes
and vacuolar change of the basalar epidermis.
Autoantibodies can be directed against desmogleins 1 and 3,
the major plaque protein of BP Ag1 (230 KD), and all the plakin
family members. DIF shows IgG and C3 deposition in the intercellular
spaces of the epithelium or at the basement membrane zone. However,
antigens other than the ones listed above have also been identified,
and recently several seemingly “IF negative” cases
of PNP/PAMS, such as our patient, have been reported.
Furthermore, in addition to the humoral response, the pathophysiology
of PNP/PAMS also incorporates a cellular autoimmunity response,
mediated by CD8+ cytotoxic T lymphocytes, CD56+ natural killer
cells, and CD68+ monocytes and macrophages. There is also an
association of PNP/PAMS with HLA-DRB1*03.
PNP/PAMS is traditionally difficult to treat. Prednisone +/-
additional immunosuppressive agents, including immunoablative
cyclophosphamide without stem cell rescue, cyclosporin A, plasmapheresis,
immunoapheresis and rituximab are often recommended.
Newer therapies include daclizumab and alemtuzumab, though
most reports detail progress when these advanced therapeutics
are used to treat concurrent, active lymphoma. Prognosis depends
on the nature of the underlying malignancy, and the development
of severe respiratory compromise. Identifying patients with
respiratory complaints early is paramount, as development of
bronchiolitis obliterans-like symptomatology is usually difficult
to treat and is an ominous sign. Delay in diagnosis is often
the case because these respiratory complaints are out of proportion
with clear radiographic studies. Chest roenterograms and computed
tomography studies are often negative. On pulmonary function
testing however, marked obstructive patterns with limitation
in diffusion capacity are diagnostic
Unfortunately, because the inciting malignancy and the paraneoplastic
syndrome need not evolve in the same direction, patients with
PNP/PAMS may often progress to recalcitrant mucosal disease
or pulmonary disease even in cases when the malignancy has been
treated and is in remission.
The above case was presented at a meeting of the New England
Dermatological Society at Harvard Medical School on February 9,
||Anhalt GJ, Kim S, Stanley JR, et al. (1990). Paraneoplastic
pemphigus. An autoimmune mucocutaneous disease associated with
neoplasia. N Engl J Med. 323:1729-35.
Cummins DJ, Mimouni, D, Tzu, J., et al. (2007). Lichenoid paraneoplastic
pemphigus in the absence of detectable antibodies. J Am Acad
Kaplan I, Hodak E, Ackerman L, et al. (2004). Neoplasms associated
with paraneoplastic pemphigus: a review of literature with emphasis
on non-haematologic malignancy and oral manifestations. Oral
Martel P, Loiseau P, Joly P, et al. (2003). Paraneoplastic
pemphigus is associated with the DRB1*03 allele. 1: J Autoimmun.
Nousari HC, Deterding R, Wojtczack H, et al. (1999). The mechanism
of respiratory failure in paraneoplastic pemphigus. N Engl J
Nguyen, VT, Ndoye, A, Bassler, KD, et al. (2001). Classification,
clinical manifestations, and immunopathological mechanisms of
the epithelial variant of paraneoplastic autoimmune multiorgan
syndrome: a reappraisal of paraneoplastic pemphigus. Arch Dermatol.137(2):193-206.
Wade MS, and Black MM (2005). Paraneoplastic pemphigus: a brief
update. Australas J Dermatol. 46(1):1-8.
||Paraneoplastic pemphigus, paraneoplastic autoimmune multiorgan
syndrome, non- Hodgkin's lymphoma
|Comments from Faculty and Members
David Elpern M.D., Dermatologist, Williamstown, MA,
USA on May 25, 2008
This is a superb presentation. Dr. Ibrahimi and his colleagues
are to be congratulated. I found a very useful review of this
syndrome from the Department of Dermatology, Mayo Clinic, USA
Billet SE, Grando SA, Pittelkow MR. Paraneoplastic autoimmune
multiorgan syndrome: review of the literature and support for
a cytotoxic role in pathogenesis. Autoimmunity. 2006 Nov;39(7):617-30.
Paraneoplastic autoimmune multiorgan syndrome (PAMS), first
described as paraneoplastic pemphigus in 1990, is an autoimmune
blistering disease associated with neoplasia. Patients with
this rare disorder have severe blistering and painful erosions
of the oral cavity and various other cutaneous findings ranging
from classic pemphigus vulgaris-like erosions to targetoid lesions
resembling erythema multiforme and papular to more confluent
lichenoid eruptions. This syndrome involves multiple organ systems,
and its high rate of mortality often stems from constrictive
bronchiolitis obliterans. The histologic findings are as diverse
as the clinical presentation, often making diagnosis difficult
initially. Immunodermatologic and serologic laboratory findings
typically establish the diagnosis. These results can be confirmed
with immunoprecipitation profiling of specific molecular weight
protein markers. The proposed pathogenesis of PAMS continues
to evolve, and recent reports implicate the involvement of cell-mediated,
cytotoxic immunity, in addition to humoral autoantibodies. This
review characterizes and summarizes the clinical, pathologic,
and immunohistologic features of PAMS and outlines the possible
role of cytotoxic T lymphocytes in the pathogenesis of this
Henry Foong FRCP, Dermatologist, Ipoh, Malaysia
on May 25, 2008
This is an excellent and a very instructive case. The clinical
images and the histology are of superb quality.
It is interesting to note that "IF negative” cases
of PNP/PAMS have been reported and does not exclude the diagnosis
of PAMS. Especially so if the patient has initiated therapy
with rituximab and if the B cell count is very low. We must
be aware of this disease and the difficulty in relying on IF
studies to make a diagnosis.
Ref: Daniel D. "Delayed detection of autoantibodies
in paraneoplastic pemphigus" J Am Acad Dermatol 2007;57:1094-1095
Shahbaz Janjua MD, Dermatologist, Ayza Skin & Research
Center, Lalamusa, Pakistan on May 30, 2008
It's a wonderful case presentation. I learnt a lot about PAMS
from this case. Thank you and congratulations. Would you suggest
to consult a pulmonologist to evauate the respiratory invovement
in such cases?
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