ARTICLE
Auteur(s) :, Kristin Technau1, Andreas
Renkl1, Johannes Norgauer2, Mirjana
Ziemer2,*
1Department of Dermatology, University of Freiburg
i.Br., Germany
2Department of Dermatology and Allergology,
Friedrich-Schiller-University, Erfurter Strasse 35, 07743 Jena,
GermanyFax: (+49) 3641937364.
accepté le 5 Juin 2004
Glucagonoma syndrome is a rare disease that is usually associated
with an underlying pancreatic islet cell carcinoma. The cutaneous
lesions are called necrolytic migratory erythema (NME) because of
their similarities to both toxic epidermal necrolysis and annular
erythema and they manifest with recurrent extending annular or
circinate erythemas and superficial epidermal necrosis [1, 2].
Although the pathogenesis of this disorder is still poorly
understood, the cutaneous manifestation seems to be a consequence
of deficiency of amino acids secondary to diversion of them to
synthesis of glucagon [3]. Beside glucagonoma syndrome and
circumstances with increased serum glucagon as in liver diseases
[4], NME was described in association with a jejunal and rectal
adenocarcinoma [5, 6], neuroendocrine insulin-producing tumor [7]
and villous atrophy of the small intestine [2].
Case report
We report the case of an 85-year-old male with a 2-year history of
recurrent cutaneous lesions presenting as generalized circinate
erythematous plaques with superficial epidermal necrosis without
involvement of the face. Most affected areas were the trunk and
lateral sides of the extremities (figures 1 and 2) but also both
palmar surfaces. Additionally, flaccid bullae and crusted erosions
were observed. Skin biopsies previously obtained had been
interpreted as fixed bullous drug eruption. However, changes in the
medication prescribed (bisoprolol, ramipril) had no effect. The
patient’s case history was remarkable for thrombocytopenia due to a
myelodysplastic syndrome (MDS). Other blood parameters, serum
glucose levels and hemoglobin A1c values were normal. No symptoms
such as weight loss or gastrointestinal problems were observed in
the last 12 months. A newly performed skin biopsy showed typical
histological changes for NME with distinct pallor and focal to
confluent necrosis of the upper epidermis ( (figure 3) ). In addition,
a superficial perivascular inflammatory infiltrate of mononuclear
cells was seen.
Computerized tomographic and
99TCm-octreotide scannings of the thorax and
abdomen did not show any signs of malignancies. Tumor markers such
as carcino embryonic antigen, cancer antigen 19-9,
alpha-fetoprotein as well as serum-glucagon were normal. Bone
marrow aspirate indicated a MDS due to abundant megacaryocytes with
some dysmorphic forms, hypocellularity with a left shift
myelopoesis and slightly reduced erythropoesis.
With regard to the MDS but also the extensive cutaneous
manifestation we treated the patient symptomatically with
cyclosporine A 300 mg per day (3.5 mg/kg) intravenously in
combination with topical steroids (clobetasol, desoxymetasone)
twice a day. Within 2 weeks of treatment the patient showed a fast
reduction of all cutaneous manifestations. In regard to the MDS we
observed a normalization of the thrombocytopenia.
Discussion
NME is a cutaneous eruption that is typically associated with
glucagonomas of the pancreas. The glucagonoma syndrome typically
consists of NME, diabetes or glucose intolerance, hyperglucagonemia
and decreased plasma amino acids [8]. In a typical case the
clinical features include diabetic status, anemia, glossitis,
stomatitis, diarrhea, steatorrhea and weight loss [8]. Speculation
exists that the syndrome relates to an excess of glucagon or
insufficient amounts of zinc, amino acids or essential fatty acids
[2, 9]. There have been several reports of NME without accompanying
pancreatic tumor [4, 7]. In most of these cases NME has been
associated with chronic liver disease, pancreatitis, and
malabsorption, situations potentially leading primarily or
secondary to decreased levels of plasma amino acids. Most patients
with NME have the skin disease for at least one year before the
correct diagnosis is made. The cutaneous manifestation is usually a
late finding. The disease commonly manifests on the skin as a
figurate, annular or circinar erythema, and as a consequence of
superficial epidermal necrosis with vesicles or bulla formation,
subsequently with erosions, crusting and scaling. The trunk, lower
extremities, inguinal area, perioral skin and sites of minor trauma
are the preferred locations [8, 10]. The most distinctive
histopathologic pattern of NME is the presence of pale and
sometimes vacuolated keratinocytes of the upper epidermis. Necrotic
keratinocytes are common, leading to confluent superficial
epidermal necrosis. The presence of a distinct pallor of the upper
epidermis with superficial necrosis in the specimen from our
patient was the histologic clue to the diagnosis of NME. Diagnostic
tests have not revealed an increased glucagon level. In the case
presented here, it was supposed that the cutaneous eruption had
been caused by the MDS. The treatment of MDS remains still
unsatisfactory. It is possible that immunosuppressive therapy might
be effective for a certain subset of patients with MDS. Several
reports have demonstrated a high incidence of hematological
responses in MDS after treatment with immunosuppressive agents,
such as cyclosporine A [11, 12]. In our patient the treatment with
cyclosporine A resulted in complete healing of the skin lesions as
well as in normalization of thrombocytopenia.
Our case could be further indicative of the fact that NME can
occur without glucagonoma. Beside adenocarcinoma, rectum carcinoma
and neuroendocrine insulin-producing tumor the here described case
suggests that MDS might be able to cause this skin disorder.
References
1 Binnick AN, Spencer SK, Dennison Jr. WL,
et al. Glucagonoma syndrome. Report of two cases and
literature review. Arch Dermatol 1977; 113: 749-54.
2 Thorisdottir K, Camisa C, Tomecki KJ,
et al. Necrolytic migratory erythema: a report of three cases.
J Am Acad Dermatol 1994; 30: 324-9.
3 Van der Loos TL, Lambrecht ER, Lambers JC.
Successful treatment of glucagonoma-related necrolytic migratory
erythema with dacarbazine. J Am Acad Dermatol 1987; 16: 468-72.
4 El Darouty M. Abu el Ela M. Necrolytic migratory erythema
without glucagonoma in patients with liver disease. J Am Acad
Dermatol 1996; 34: 1092-3.
5 Walker NP. Atypical necrolytic migratory erythema in
association with a jejunal adenocarcinoma. J R Soc Med 1982; 75:
134-5.
6 Konstantinow A, Balda BR, Starz H. Erythema
necrolyticum migrans after rectal adenocarcinoma. Hautarzt 1998;
49: 591-5.
7 Wilkinson SM, Cartwright PH, Allen C,
et al. Necrolytic migratory erythema: association with
neuroendocrine tumour with predominant insulin secretion. Br J
Dermatol 1990; 123: 801-5.
8 Schwartz RA. Glucagonoma and pseudoglucagonoma syndromes.
Int J Dermatol 1997; 36: 81-9.
9 Goodenberger DM, Lawley TJ, Strober W,
et al. Necrolytic migratory erythema without glucagonoma. Arch
Dermatol 1979; 115: 1429-32.
10 Wilkinson DS. Necrolytic migratory erythema with
carcinoma of the pancreas. Trans St Johns Hosp Dermatol Soc 1973;
59: 244-50.
11 Guan M. Application of cyclosporine a in myelodysplastic
syndrome. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2003; 11: 678-80.
12 Jonasova A, Neuwirtova R, Cermak J,
et al. Cyclosporin A therapy in hypoplastic MDS patients and
certain refractory anaemias without hypoplastic bone marrow. Br J
Haematol 1998; 100: 304-9.
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