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Case Report
Graft-Versus-Host-Like Disease
- A Case of Thymoma-Related Erythroderma
Yu-Ta Yen Ji-Chen Ho Cheng-Yu Wang
Graft-versus-host disease (GVHD) is a T-cell-mediated reaction that most commonly develops after transplantation of hematopoietic stem cells. In rare conditions, GVHD-like symptoms
are observed in patients with thymoma. We present the case of a 58-year-old man with thymoma
noted 6 years earlier who initially presented with myasthenia gravis and subsequently developed GVHD-like disease with symptoms of generalized itching, scaly erythroderma, and liver
dysfunction. The histopathological features of a skin biopsy were consistent with those noted in
the case of GVHD. We assume that the altered thymic microenvironment in thymoma patients
causes immune dysregulation, leading to GVHD-like disease. (Dermatol Sinica 27: 241-247,
2009)
Key words: Thymoma, Erythroderma, Myasthenia gravis, Graft-versus-host disease, GVHD
INTRODUCTION
Graft-versus-host disease (GVHD) occurs most commonly after immunocompetent
hematopoietic stem cells are transplanted
into an immunocompromised recipient. It
also occurs through maternal-fetal transfer
of lymphocytes; blood transfusion; and solid
organ transplantation-particularly transplantation of a liver containing numerous immunocompetent lymphocytes. In most cases,
GVHD first affects the skin, but hepatic and
gastrointestinal manifestations aid in establishing the diagnosis. However, symptoms/
signs resembling those of GVHD may develop in some cases despite the lack of a history
of transplantation or transfusion.
The thymus plays an important role in
immune maturation. In thymoma patients, the
altered microenvironment of the thymus may
induce immune dysregulation and autoreactivity. Several autoimmune disorders, including myasthenia gravis, pure red-cell aplasia,
and acquired hypogammaglobulinemia are
reported to be associated with thymoma.
We report the case of a patient who
had thymoma accompanied with myasthenia
gravis for 6 years, but no history of blood
transfusion or transplantation. The patient
developed generalized erythroderma, liver
dysfunction, and histopathological features
of GVHD.
From the Department of Dermatology, Chang Gung Memorial Hospital - Kaohsiung Medical Center, and Chang Gung University
College of Medicine
Corresponding author: Cheng-Yu Wang, Department of Dermatology, Chang Gung Memorial
Hospital-Kaohsiung Medical Center, Ta-Pei Road 123, Niao-Sung Hsiang, 83301 Kaohsiung,
Taiwan
TEL: 886-7-7317123 ext. 2299 FAX: 886-7-7337612 E-mail: [email protected]
Funding source: none
Conflict of interest: none declared
241
Received: December 29, 2008
Revised: March 05, 2009
Accepted: March 12, 2009
Graft-Versus-Host-Like Disease
A
B
C
F
D
E
Fig. 1
A 58 year-old male patient presented with generalized erythroderma.
(A) Face showing papulosquamous lesions over eyelids and erosions over lips, but the scalp and mucosa were not involved.
(B, C) Confluent erythematous scaly papulosquamous eruptions with pain and an itching sensation involving most of his
trunk.
(D, E) Severe scaly erythroderma involving lower limbs.
(F) Closer view of left upper arm showing scaly papulosquamous eruptions.
CASE REPORT
A 58-year-old man visited our dermatology outpatient department, presenting with
generalized erythroderma with scales and
an itching sensation involving 90% of his
body surface. Six years earlier, he had been
diagnosed with thymoma accompanied with
myasthenia gravis and had refused surgical
intervention. The patient was lost to followup. Subsequently, he was prescribed prednisolone and pyridostigmine by another medical professional and had been receiving this
treatment until he gradually began to develop
generalized erythroderma 6 months ago.
The patient had no history of atopy or treatment with any other drug. Skin examination
Dermatol Sinica, Dec 2009
revealed a confluent erythematous and scaly
papulosquamous eruption with pain and an
itching sensation involving 90% of the body
surface. The scalp and mucosa were not involved, but papulosquamous lesions over the
eyelids and erosions over the lips were noted
(Fig. 1). Skin biopsy was performed and the
specimen was examined considering psoriasis, drug eruption, and mycosis fungoides.
Pathological analysis of a section
revealed parakeratosis; mild acanthosis;
dyskeratosis of the epidermis; vacuolar
degeneration and cleft formation at the dermoepidermal junction; perivascular lymphocytic infiltration into the superficial dermis;
and periadnexal infiltration of lymphocytes,
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A
B
C
D
Fig. 2
Histopathology of a skin biopsy from left upper arm was consistent with GVHD.
(A, B) Low-power magnification showing hyperkeratosis, parakeratosis in the stratum corneum; acanthosis with dyskeratotic
cells in the epidermis; vacuolar degeneration and cleft formation at the dermoepidermal junction; solar elastosis and perivasular as well as periadnexal inflammatory infiltrate in superficial dermis. (H&E, original magnification x40, x100)
(C) Prominent periadnexal infiltration of lymphocytes, histiocytes, and plasma cells. (H&E, original magnification x400)
(D) High-power magnification showing parakeratosis, apoptotic keratinocytes in the epidermis, subepidermal cleft formation,
and melanin incontinence at papillary dermis. (H&E, original magnification x400)
histiocytes, and plasma cells. All these findings were consistent with those in the case
of GVHD (Fig. 2). The patient was admitted
for an additional systemic survey. Computed
tomography (CT) of the chest and abdomen
revealed a 4.75 cm lobular mass in the right
anterior mediastinal region (Fig. 3), where a
1 cm nodule was noted 6 years earlier.
A laboratory examination revealed the
following values: white blood cell count,
10.6 x 10 3 cells/mm 3 (normal range, 3.910.6 x103 cells/mm3); hemoglobin, 16.4 g/dL
(normal range, 13.5-17.5 g/dL); hematocrit,
48.3% (normal range, 41-53%); platelet
count, 333 x 103 cells/mm3 (normal range,
150-400 x 10 3 cells/mm 3); eosinophil, 3%
(normal range, 0-5%); IgE, 826 IU/ml (normal < 100 U/L); aspartate aminotransferase,
159 U/L (normal range, 0-37 U/L); alanine
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aminotransferase, 310 U/L (normal, 0-40
U/L); alkaline phosphate, 96 U/L (normal
range, 28-94 U/L ); albumin, 3.4 gm/dL
(normal, 3.0-5.0gm/dL); acetylcholine receptor antibody, 67.1 nmol/mL (normal, <0.2);
C-reactive protein, 9.59 mg/L (normal, <5
mg/L); and erythrocyte sedimentation rate, 7
mm/h (normal, 0-20 mm/h).
On admission, the patient was administered prednisolone (up to 30 mg/d),
pyridostigmine (60 mg t.i.d.), and topical
applications containing keratolytic agents
and corticosteroids. Although the scaly eruption showed an improvement, erythroderma
persisted. Computed tomography revealed
that the thymoma was large, and surgery was
scheduled. Unfortunately, the thoracic surgeon postponed the surgery because of the
patient’s skin conditions, and the patient was
Dermatol Sinica, Dec 2009
Graft-Versus-Host-Like Disease
A
B
Fig. 3
Images of computed tomography on chest showed an enlarged thymoma.
(A) Coronal view showing a lobular contour mass over right anterior mediastinum.
(B) Horizontal view showing the tumor measured 47.49 mm in the long axis, consistent with an enlarged thymoma.
discharged. Two weeks later, the patient had
an emergency condition of bleeding in the
upper gastrointestinal region, and he expired
despite intensive rescue procedures.
DISCUSSION
GVHD is a T-cell-mediated reaction
that most commonly develops after transplantation of hematopoetic stem cells. Acute
cutaneous GVHD develops in 20% to 80%
of patients who undergo allogeneic bone
marrow transplantation. In most cases, the
skin is the first organ targeted, with faint erythematous macules developing initially. The
macules then become confluent over a larger
surface, and the condition may progress to
erythroderma or bulla formation in the advanced stages. Involvement of the liver and
the gastrointestinal system is also commonly
noted. The presence of diarrhea and the detection of elevated bilirubin levels may serve
as the diagnostic criteria; however, the possibility of GVHD should be considered even
in the absence of such signs/symptoms.1
Previous reports have described thymoma-associated conditions with symptoms/
signs identical to GVHD, where the patients
had no history of either transfusion or transplantation. Various terms such as graft-verDermatol Sinica, Dec 2009
sus-host-like disease complicating thymoma,
thymoma-associated multiorgan autoimmunity, GVHD-like syndrome in malignant
thymoma, and thymoma-associated graftversus-host-like reaction, have been coined
for such conditions.2-5
The thymus is a primary lymphoid
organ whose function is to “educate” thymocytes.6 In the course of migration from the
bone marrow to the thymus, hematopoietic
progenitor cells proliferate to generate a large
population of immature thymocytes. In the
thymic cortex, each of these cells develops
distinct T-cell receptors through gene rearrangement. Thymocytes that can bind strongly to cell-surface molecules such as major
histocompatibility complex/human leukocyte
antigen (MHC/HLA), undergo positive selection, while the other cells that can only bind
weakly to these receptors undergo apoptosis. The selected thymocytes then enter the
thymic medulla where cells that exhibit an
affinity for self-antigens undergo negative
selection. This process for the development
of central tolerance mainly depends on the
autoimmune regulator gene (AIRE). It has
been reported that 3 patients with thymoma
presented with GVHD-like disease associated with the absence of AIRE expression.3
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Thymoma is a rare type of neoplasm
that arises from the epithelial cells of the
thymus. Approximately 40% of all thymoma
patients develop a parathymic syndrome; of
such syndromes, myasthenia gravis is the
most common, followed by pure red-cell
aplasia and acquired hypogammaglobulinemia. 7 A few cases of thymoma-associated
skin eruption have been reported; the underlying conditions in these cases included pemphigus vulgaris, paraneoplastic pemphigus,
dermatomyositis, and subcorneal pustular
dermatosis. Wadhera et al. reviewed 7 cases
of thymoma-associated GVHD-like disease2
and found that all the patients had diarrhea as
a clinical symptom; however, this symptom
was absent in the present case. Moreover, all
the patients in the study by Wadhera et al.2
underwent surgical resection of the thymoma; however, surgery was not performed in
the present case because of hesitation on the
part of both, the patient and the surgeon.
On the basis of the clinical features
and histopathological findings of the present
case, we considered several disease entities for differential diagnosis. Psoriasis was
histopathologically ruled out owing to the
absence of Munro and Kogoj microabscess,
regular epidermal acanthosis, and dilated
and tortuous capillaries in the papillary dermis. Further, we did not observe epidermotropism, large convoluted lymphocytes, or
fibrotic expansion of the papillary dermis;
therefore, cutaneous T-cell lymphoma was
ruled out. In addition, epidermal spongiosis
was absent, dyskeratotic keratinocytes were
observed, and the patient showed a poor
clinical response to prednisolone treatment;
on these grounds, eczematous dermatitis was
also ruled out as a differential diagnosis. The
findings of hyperkeratosis and parakeratosis
in the stratum corneum, acanthosis with dyskeratotic keratinocytes in the epidermis, vacuolar degeneration and cleft formation at the
dermoepidermal junction, and solar elastosis
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as well as perivasular and periadnexal mononuclear infiltrates in the superficial dermis
were consistent with GVHD; but, they could
also have been attributed to drug eruption or
paraneoplastic pemphigus. However, drug
eruption was ruled out because the patient
did not have a history of treatment with drugs
except prednisolone and pyridostigmine,
which he had continually been receiving for
6 years for myasthenia gravis. Paraneoplastic
pemphigus has been reported in association
with Hodgkin’s lymphoma, thymoma, chronic lymphocytic leukemia, and Castleman’s
disease. In all these cases, this condition is
associated with painful oral ulcers and generalized, polymorphous eruption of blisters
and lichenoid papules. Although we did not
perform immunohistochemistry for diagnosis, we considered a diagnosis of paraneoplastic pemphigus to be less likely because
the patient did not have painful oral ulcers
or blisters. Transfusion and transplantationassociated GVHD may also be considered
in the differential diagnosis of conditions
with GVHD-like symptoms; however, since
the patient had no history of transfusion and
transplantation, this diagnosis was also ruled
out. Although the elevated IgE levels of our
patient were indicative of atopic dermatitis,
this possibility was also ruled out owing to
the absence of a previous atopic history and
the discordance between the patient’s pathological features and those of atopic dermatitis. As in the case of our patient, elevated IgE
levels have been previously noted in patients
with acute GVHD after bone marrow trans8-9
plantation had been reported; this finding
may further indicate a diagnosis of GVHDlike disease. Computed tomography revealed
that the thymoma had enlarged from 1 cm
(6 years earlier) to 4.75 cm at the time of the
present study; hence, thymoma associated
with GVHD-like disease was considered the
appropriate diagnosis. We assume that the
aberrant thymic microenvironment in the
Dermatol Sinica, Dec 2009
Graft-Versus-Host-Like Disease
case of thymoma patients may induce immune dysregulation and autoimmunity leading to GVHD-like disease.
In summary, we report a case of thymoma, wherein the patient presented with
erythroderma. Examination of a biopsy specimen revealed interface dermatitis, which is
consistent with GVHD. Thus, when a patient
clinically presents with erythroderma, myasthenia gravis, liver function impairment,
and any other symptoms/signs, thymomaassociated GVHD-like disease should be
included in the differential diagnosis, even if
the patient does not have a history of transplantation or transfusion.
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2. Wadhera A, Maverakis E, Mitsiades N, et al.:
Thymoma-associated multiorgan autoimmunity:
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Offerhaus GJ, Schipper ME, Lazenby AJ, et
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Holder J, North J, Bourke J, et al.: Thymomaassociated cutaneous graft-versus-host-like reaction. Clin Exp Dermatol 22: 287-290, 1997.
Wang MH, Wong JM , Wang CY: Graft-versusHost disease-like syndrome in malignant thymoma. Scand J Gastroenterol 35: 667-670, 2000.
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Rosenow EC, Hurley BT: Disorders of the thymus. A review. Arch Intern Med 144: 763-770,
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Saarinen U, Strandjord S, Warkentin P, et al.:
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移植物抗宿主病樣疾病
-胸腺瘤關連紅皮症的病例報告
顏育達
何宜承
高雄長庚紀念醫院皮膚科
王振宇
長庚大學醫學院
移植物抗宿主病為T細胞所引起之反應，最常發生於造血幹細胞移植後。在少數情形下，胸
腺瘤的病人被觀察到有類似移植物抗宿主病反應。我們描述一位58歲男性病人，在六年前被發現
胸腺瘤合併重症肌無力，在未接受器官移植或輸血情形下，後來發展成移植物抗宿主病樣疾病，
形成全身性癢而有鱗屑之紅皮症，併有肝功能異常。皮膚切片符合移植物抗宿主病之病理表現。
我們認為胸腺瘤微環境的改變造成免疫異常，進而造成移植物抗宿主病樣疾病。（中華皮誌：27:
241-247, 2009）
247
Dermatol Sinica, Dec 2009