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DOI: 10.1111/j.1468-3083.2011.04150.x

ORIGINAL ARTICLE

Erythroderma as a paraneoplastic cutaneous disorder in


systemic anaplastic large cell lymphoma
T. Hanafusa, K. Igawa,,* S. Takagawa, H. Yahara, J. Harada, M. Tani, Y. Sawada, I. Katayama

Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, Japan, Department of Dermatology, Tokyo
Metropolitan Bokutoh Hospital, Tokyo, Japan, and Department of Dermatology, Kameda Medical Center, Kamogava, Japan
*Correspondence: K. Igawa. E-mail: igawa@derma.med.osaka-u.ac.jp

Abstract
Background Paraneoplastic cutaneous disorders (PCDs) or dermadromes are skin conditions that have an
association with internal malignancies but are not themselves malignant. We report the first two cases of systemic
anaplastic large cell lymphoma (s-ALCL) accompanied by erythroderma and multiple leg ulcers as PCDs.
Case 1. A 52-year-old Japanese man presented with disseminated itchy papular erythemas which he had over his
entire body for the preceding 5 years that later exacerbated to erythroderma. Multiple punched-out ulcers also
developed on his lower legs. Superficial lymph nodes (LNs) were swollen, and a left axillary LN biopsy demonstrated
dense CD30+ atypical large cell (ALC) infiltration. By contrast, lymphocytes infiltrating into the erythroderma and leg
ulcers were CD30), and T-cell receptor b (TCRb) chain gene rearrangement was negative in skin biopsy specimens.
Thus, he was diagnosed with s-ALCL. Not only his s-ALCL but also his erythroderma and leg ulcers responded well
to chemotherapy.
Case 2. A 71-year-old Japanese woman presented with erythroderma that persisted for approximately 20 years
after mastectomy. At her initial hospital visit, she was diagnosed with s-ALCL by biopsy of swollen left inguinal LNs.
Similar to Case 1, CD30+ ALCs were negative in skin samples with normal TCRb chain gene rearrangement. As the
erythrodermic skin lesion responded well to chemotherapy for s-ALCL, it was considered a PCD.
Conclusion s-ALCL development may be predicted by the precedence and concurrence of intractable
paraneoplastic erythrodermic and ulcerative skin lesions, as reported in our two cases.
Received: 17 February 2011; Accepted: 31 May 2011

Conflicts of interest
None declared.

Funding sources
None.

Introduction
Paraneoplastic cutaneous disorders (PCDs) or dermadromes are
skin conditions that have an association with internal malignancies
but are not themselves malignant.1 Several cases of dermatomyositis, bullous dermatosis, erythroderma, prurigo, lichen planus and
porokeratosis are considered PCDs.25 The most important point
is that no malignant cells infiltrate into the skin lesions of PCDs.
Herein, we report two cases of systemic anaplastic large cell
lymphoma (s-ALCL) accompanied by erythrodermic and ulcerative skin lesions with negative CD30+ atypical cell infiltration.
Interestingly, these skin lesions preceded s-ALCL and showed
resistance to conventional therapy. However, the skin lesions dramatically improved after treating the internal malignancy s-ALCL.
Taking these clinical courses into consideration, we assumed that

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the skin lesions were non-specific but PCDs were closely related to
s-ALCL.
In May 2007, a 52-year-old Japanese man was referred to our
outpatient clinic for 5-year persistent, disseminated, itchy, papular
erythemas that covered his entire body. Topical steroids and oral
immunosuppressants, including steroids, cyclosporine and methotrexate, were ineffective for his skin lesions. Moreover, multiple
punched-out ulcers developed on his lower legs, and he was
admitted to our hospital in June 2007. On admission, physical
examination revealed a high body temperature of greater than
38C and multiple coalescing, scaly, papular erythemas on his
trunk and extremities (Fig. 1a). Deep, painful, thumb-sized,
punched-out ulcers around his foot joints and dorsal feet were also
noted (Fig. 1b).

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Hanafusa et al.

(a)

(b)

(c)

(d)

Figure 1 Clinical appearance of Case 1. (a) On admission, multiple, itchy, papular erythemas were scattered and fused over the
entire body, except for the face, which developed into erythroderma. (b) Painful, multiple, thumb-sized, punched-out, deep ulcers
with thick necrotic tissue were seen bilaterally on the dorsal feet. (c) After resolution of the dermatological disorders, the erythroderma changed pigmentation with rapid resolution of itching and (d) ulcer debridement promoted good granulation of tissues.

Laboratory findings were as follows: white blood cell count:


4.5 103 lL [(normal range: 3.39.4 103 lL); metamyelocytes:
1.0% (0.0%); band neutrophils: 1.0% (0.02.0%); segmented
neutrophils: 77.0% (40.073.0%); lymphocytes (Ly): 16.0%
(18.052.0%); monocytes (Mo): 4.0% (2.210.0%); and eosinophils (Eo): 1.0% (0.07.0%)]; haemoglobin: 13.3 g dL (13.8
17.0 g dL); platelet count: 2.8 105 lL (1.33.2 lL); C-reactive
protein: 15.2 mg L (0.00.2 mg L); total protein: 6.5 g dL (6.4
8.1 g dL); albumin: 3.4 g dL (3.64.7 g dL); BUN: 20 mg dL
(722 mg dL); creatinine: 0.6 mg dL (0.50.9 mg dL); aspartate
aminotransferase (AST): 14 U L (40 U L); alanine aminotransferase (ALT): 22 U L (40 U L); cGTP: 35 U L (851 U L);
alkaline phosphatase (ALP): 291 U L (134359 U L); lactate
dehydrogenase (LDH): 229 U L (103229 U L); antinuclear antibody (ANA): <20 (40); classical antineutrophil cytoplasmic
antibody (c-ANCA): <3.1 EU (10 EU); perinuclear-ANCA
(p-ANCA): < 3.1 EU (20 EU); IgG: 1008 mg dL (8701700
mg dL); IgE: 1439 U mL (173 U mL); human T-lymphotropic
virus type I (HTLV-1): negative; and soluble interleukin-2 receptor
(sIL-2R): 2016 U mL (150505 U mL). Histological examination
of biopsied specimens taken from his erythrodermic skin lesion
revealed chronic skin inflammation with no evidence of malignancy. No evidence of malignancy or specific dermatological disorders, such as vasculitis, tumour cell emboli, or compression of
blood vessels by infiltrating cells, were found in the biopsied specimens from the lesional skin around his leg ulcer. Non-specific
inflammatory cells (neutrophils were dominant) infiltrated into
the dermis. Therefore, we speculated that the patients ulcerative
skin lesions might be due to the development of pyoderma gangrenosum (PG) or a PG-like reaction in his lower leg. At this time,
unexpectedly, oral prednisolone (40 mg day for 2 weeks) did not
improve the leg ulcers or erythroderma. Superficial lymph node
swelling was detected by careful physical examination and imaging
analysis, including enhanced computed tomography and gallium
scintigrapy. Therefore, a left axillary lymph node biopsy was
performed. Histologically, extensive infiltration of CD30 + atypical
large lymphocytes was observed in the lymph nodes (Fig. 2a and

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(a)

(b)

Figure 2 Left axial lymph node biopsy revealed an increased


number of CD30 + atypical large lymphocytes, leading to a final
diagnosis of ALCL. Immunohistochemical staining analysis
revealed that these lymphocytes were positive for CD30, CD3
and CD4, and negative for CD8, CD20, CD79a, CD5, CD10,
CD15 and EMA. (a) Haematoxylin and eosin staining (original
magnification: 100). (b) Immunohistochemical staining for CD30
(original magnification: 100).

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Systemic ALCL with paraneoplastic erythroderma

2b). T-cell receptor b (TCRb) chain gene rearrangement was positive in these lymph node specimens. Retrospectively, we analysed
previous skin biopsy specimens taken from erythrodermic and
ulcerative lesions and found no infiltration of CD30+ atypical large
cells or other atypical lymphocytes. TCRb chain gene rearrangement was also negative in both skin specimens. Thus, he was
diagnosed with s-ALCL and received combination CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy. As not only the patients s-ALCL but also his
erythroderma and leg ulcers responded well to chemotherapy with
no recurrence to date, his erythroderma and leg ulcers were considered non-specific PCDs closely related to s-ALCL (Fig. 1c and 1d).
In March 2006, a 71-year-old Japanese woman visited us
because of persistent erythroderma for the preceding 20 years. Her
erythroderma was resistant to conventional therapies, including
topical and oral steroids, topical and oral immunosuppressants,
and phototherapy. Histological examination of biopsy specimens
taken from her erythrodermic skin lesion revealed chronic skin
inflammation with no evidence of malignancy. Physical examination revealed tender, painful lymph node swelling in her inguinal
lesion, and a lymph node biopsy was performed. Extensive infiltration of CD30+ atypical large cells into the lymph node was
observed, and she was diagnosed with s-ALCL. Retrospectively, no
CD30+ atypical large cells infiltrated and TCRb gene rearrangement was negative in the biopsied specimens from her skin lesion.
Although the THP-COP (tetrahydropyranyl-adriamycin, cyclophosphamide, vincristine and prednisolone) regimen was effective,
she discontinued THP-COP because of the adverse effects of
severe bone marrow suppression and high-grade body temperature of unknown origin. Instead, a 40-Gy dose of irradiation successfully decreased the swollen lymph node size. Within 1 month,
however, systemic lymph node swelling became worse, sIL-2R
values increased (2073 U mL), and the erythroderma was exacerbated. In September 2006, she was again admitted to our hospital.
As shown in Fig. 3a, multiple, scaly, erythematous plaques with
(a)

severe induration were disseminated over her entire body. Laboratory findings were as follows: white blood cell count, 4.0 103 lL
[neutrophils: 70.9% (40.073.0%); Ly: 12.3%; Mo: 2.0%; and Eo:
13.5%]; haemoglobin: 10.9 g dL; platelet count: 38.6 104 lL;
C-reactive protein: 10.0 mg L; LDH: 260 U L; and sIL-2R:
2073 U mL. Histologically, similar to the previous examination,
no CD30 + atypical large cells were found in the biopsied specimens from her abdominal erythema. Inflammatory cells, including
lymphocytes and eosinophils, infiltrated into the dermis, mainly in
the perivascular region. TCRb gene rearrangement was also negative. Clinically, low-dose etoposide (50 mg daily for 21 days, every
4 weeks) successfully improved her systemic lymph node swelling
and erythroderma. Finally, with additional oral etretinate
(30 mg day), her erythroderma was completely resolved with no
recurrence to date (Fig. 3b).

Discussion
Erythroderma as a PCD has been linked to malignancies such as
mycosis fungoides or its leukaemic variant, Sezary syndrome.
Additional reported cases exist that describe erythroderma associated with cancers of the liver, lung, colon, stomach, pancreas, thyroid, prostate and cervix.1 Papuloerythroderma of Ofuji has also
been associated with lymphoma or other internal malignancies.6,7
The precise mechanisms underlying these PCDs remain unclear
but are thought to be toxic or allergic reactions caused by
unknown factors derived from malignant tumours.2
Helen Ollendorff Curth proposed rigid criteria for the diagnosis
of PCDs 8 and a less rigid definition of PCDs in common use is as
follows1: malignancy and cutaneous disorders may occur concurrently and follow a parallel course. Strictly speaking, our two cases
did not fulfil the proposed criteria. We speculated that some
abnormal immune status leading to refractory erythrodermic skin
conditions might develop prior to s-ALCL initiation, although we
could not determine the exact timing of the initiation of the
s-ALCL.
(b)

Figure 3 Clinical appearance of Case 2.


(a) On admission, multiple, scaly, differentsized, erythematous plaques with
indurations and severe itching were noted
over the entire body. The plaques later
fused together, developing into
erythroderma. (b) Chemotherapy with lowdose etoposide and additional etretinate
rapidly improved the erythroderma.

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Hanafusa et al.

In our two cases, the clinical courses were unusual: the erythrodermas were resistant to conventional therapy and easily flared
up over several years, although they showed usual eczematous
manifestations. In fact, the conditions of the two patients gradually
developed with on-and-off episodes. However, the treatment of
s-ALCL combined with conventional therapy for erythroderma
rapidly improved these intractable erythrodermas with no recurrence to date. Retrospectively, no CD30 atypical large cells but
normal-appearing lymphocytes and neutrophils infiltrated into the
erythrodermic and ulcerative skin lesions, respectively. Taking
these clinical courses into consideration, we consider these
erythrodermic skin lesions PCDs closely related to s-ALCL.
The ulcerative skin lesions, such as those seen in Case 1, have
not been reported as PCDs to our knowledge. Clinical appearance
of the punched-out ulcerative skin lesions with the histological
findings of neutrophil-dominant infiltration into the dermis led us
to diagnose the lesions as PG-like reactions. Treatment of the
malignancy dramatically improved the leg ulcers, whereas, at first,
they were resistant to prednisolone administration. Therefore, we
also speculate that neutrophils, non-specifically activated by
the existence of an internal malignancy, might induce PG-like
reactions; we consider these ulcerative skin lesions as PCDs.
In case 2, etretinate, along with low-dose etoposide, might have
indirectly improved the erythrodermic skin lesions by reducing
the malignancy because etretinate, a retinoid, physiologically
regulates a large number of essential biologic processes, including
differentiation, proliferation and apoptosis.9
In conclusion, the development of internal malignancy may be
predicted by the precedence and concurrence of dermatological
disorders that are resistant to conventional therapies, as reported

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in our two cases. In the future, we must clarify the mechanisms


underlying such PCDs.

References
1 Rook A, Burns T. Rooks Textbook of Dermatology, 8th edn. Wiley-Blackwell,
Chichester, West Sussex, UK; Hoboken, NJ, 2010.
2 Motoori M, Tsujinaka T, Kobayashi K, Fujitani K, Kikkawa N. Synchronous rectal and esophageal cancer associated with prurigo chronica
multiformis: report of a case. Surg Today 2001; 31: 10871090.
3 Umekoji A, Tsuruta D, Inoue T, Nishimori T, Ishii M. Bullous pemphigoid as a dermadrome associated with spindle cell carcinoma of the
gallbladder. J Dermatol 2010; 37: 251254.
4 [No authors listed] Lichen planus and liver diseases: a multicentre casecontrol study. Gruppo Italiano Studi Epidemiologici in Dermatologia
(GISED). BMJ 1990; 300: 227230.
5 Kono T, Kobayashi H, Ishii M, Nishiguchi S, Taniguchi S. Synchronous
development of disseminated superficial porokeratosis and hepatitis C
virus-related hepatocellular carcinoma. J Am Acad Dermatol 2000; 43:
966968.
6 Ofuji S, Furukawa F, Miyachi Y, Ohno S. Papuloerythroderma. Dermatologica 1984; 169: 125130.
7 Nomura T, Kodama K, Moriuchi R et al. Papuloerythroderma of
Ofuji associated with early gastric cancer. Int J Dermatol 2008; 47:
590591.
8 Chung VQ, Moschella SL, Zembowicz A, Liu V. Clinical and pathologic
findings of paraneoplastic dermatoses. J Am Acad Dermatol 2006; 54:
745762.
9 Zhang C, Duvic M. Treatment of cutaneous T-cell lymphoma with
retinoids. Dermatol Ther 2006; 19: 264271.

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Journal of the European Academy of Dermatology and Venereology 2011 European Academy of Dermatology and Venereology