ORIGINAL ARTICLE: CLINICAL

Cyclosporin in subcutaneous panniculitis-like T-cell lymphoma

PONLAPAT ROJNUCKARIN1, THANYAPHONG NA NAKORN1,

THAMATHORN ASSANASEN2, PONGSAK WANNAKRAIROT2, &

TANIN INTRAGUMTORNCHAI1

1Department of Medicine, and 2Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

(Received 21 September 2006; revised 19 October 2006; accepted 21 October 2006)

AbstractSubcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of hematologic malignancy characterized by lesionsin subcutaneous fat associated with systemic symptoms. The standard treatment of the disease, currently, is not established,but CHOP or CHOP-like regimens are usually given. We report, herein, 4 cases of SPTCL diagnosed by histopathology andimmunohistochemistry who were refractory to CHOP and/or ESHAP and/or fludarabine-based regimen, but showed rapidimprovement within weeks after oral cyclosporin 4 mg/kg/day. Three sustained complete remission for the durations of8 – 9 months off-treatments. T-cell receptor gene rearrangement revealed polyclonality in 3 cases and monoclonality in1 case. Our data suggest the benefit of incorporating cyclosporin into the treatment regimen for SPTCL.

Keywords: T-cell lymphoma, panniculitis, cyclosporin

Introduction

Subcutaneous panniculitis-like T-cell lymphoma

(SPTCL) usually presents with multiple erythematous

subcutaneous nodules typically starting from extre-

mities to the trunks and constitutional symptoms.

It is sometimes associated with fulminant hemo-

phagocytic syndrome characterized by hepatospleno-

megaly, pancytopenia, and disseminated intravascular

coagulation [1,2,3]. The distinctive histopathological

features of SPTCL are infiltrating cells with variable

sizes, in contrast to solely mature cells in benign

lobular panniculitis. The diagnosis of malignancy was

based on the cellular atypia, necrosis, and mitosis.

Immonohistochemistry shows that the atypical

cells are T lymphocytes. Molecular studies revealed

monoclonal T-cell receptor gene rearrangement in

85% of reported SPTCL [4]. Nevertheless, gene

rearrangement was not performed in most cases in

the literature.

The natural history of SPTCL is highly variable

ranging from a chronic relapsing to a rapidly fatal

course [3]. The presence of hemophagocytic

syndrome [4], low white blood cell count or elevated

lactate dehydrogenase (LDH) [5] is associated with

shorter survival. Recent studies suggest two distinct

subtypes of SPTCL classified by the cellular origins

[6,7]. The a/b T cells constituting approximately

70% of cases confer longer survival [8], while the gdphenotype is commonly associated with hemopha-

gocytosis with ensuing unfavorable course.

A wide variety of treatment modalities for SPTCL

has been reported, ranging from corticosteroids,

immunosuppressive agents, radiotherapy, and com-

bination chemotherapy [4,5]. The anthracycline-

based regimen was commonly given, producing

long-term remission in a subset of patients [4]. In

addition, stem cell transplantation in patients with

aggressive form of disease has been found to improve

survival [5]. We report herein four cases of SPTCL

diagnosed by histopathology and immunohistochem-

istry. All showed only partial and transient responses

to combination chemotherapy and/or high-dose

steroid, but displayed a marked complete remission

after a course of cyclosporin with or without sub-

sequent chemotherapy.

Correspondence: Tanin Intragumtornchai, MD, Department of Medicine, Faculty of Medicine, Chulalongkorn Hospital, Rama IV Road, Bangkok 10330,

Thailand. Tel: þ66-2256-4564. Fax: þ66-2253-9466. E-mail: Tanin.I@Chula.ac.th

Leukemia & Lymphoma, March 2007; 48(3): 560 – 563

ISSN 1042-8194 print/ISSN 1029-2403 online � 2007 Informa UK Ltd.

DOI: 10.1080/10428190601078456

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Results

The summary of cases is shown in Table I. All

four presented with multiple subcutaneous nodules

on extremities and trunks and systemic symptoms.

One case (JM) was previously diagnosed as benign

lobular pannicultitis on skin biopsy. She was treated

with prednisolone and, later, added azathioprine and,

finally, cyclophosphamide for two and a half years.

The symptoms were improved but promptly recurred

on tapering of steroid. The nodules, subseq-

uently, became ulcerated. Re-biopsy showed subcu-

taneous panniculitis-like T-cell lymphoma (SPTCL,

Figure 1A). Similarly, another case (JS) was treated

with prednisolone 20 mg/day for 1 month with some

improvement. However, the lesions relapsed after

decreasing the steroid dose. The review of the histo-

pathological section suggested SPTCL (Figure 1B).

The other two patients (SJ and AT) presented with

subcutaneous nodules and fever for 2 – 3 months

before the diagnostic skin biopsy.

Initial laboratory values were shown in Table I.

Two had leukopenia and three had anemia. All

displayed liver function abnormalities and elevated

LDH. Physical examination, chest X ray, CT scan of

abdomen, and bone marrow studies, including

immunohistochemistry for lymphoma, revealed no

other site involvement except for the subcutaneous

tissue. Histopathology revealed medium-to-large

lymphoid cells infiltrating subcutaneous tissue

around adipocytes with cellular atypia and mitosis

(Figure 1). Immunostaining results showed positive

for CD3 and TIA-1, suggesting the cytotoxic T-cell

phenotype, while negative for CD20. T-cell receptor

g gene rearrangement was, retrospectively, per-

formed on the diagnostic paraffin sections in these

four cases. Three (SJ, JM and JS) showed polyclonal

results, while the other (AT) had detectable mono-

clonality. Unfortunately, the antibody to differentiate

between a/b and gd T cells is unavailable in our

country.

All patients were treated with CHOP regimen,

resulting in transient disappearance of the nodules

and fever (Table II). However, symptoms recurred

approximately 2 weeks after each course. ESHAP

(Etoposide, methylprednisolone, Ara-C, and cis-

platinum) was then administered in two cases and

fludarabine and cyclophosphamide (FC) in one case.

Merely temporary responses, again, occurred. Oral

cyclosporin (4 mg/kg/day) was then given, and a

marked convalescence of both lesions and systemic

symptoms in 2 weeks was noticed.

In the first case (SJ), prednisolone 30 mg/day was

also given. Prednisolone dose was reduced to 10 mg/

day in 3 weeks without recurring lesions. However,

she developed biopsy-proven aspergillus sinusitis

4 months later. Despite amphotericin treatment,

the fungus invaded central nervous system. She

expired with no active panniculitic lesion. The

second case (JM) was treated with cyclosporin

200 mg/day with subsequent tapering doses for

1 year. She refused any further chemotherapy. Oral

Table I. Clinical features of 4 cases.

SJ JM JS AT

Age (year) 52 23 28 15

Sex Female Female Male Female

Presentation Fever & nodules

3 months

Fever & nodules, steroid,

azathioprine,

cyclophosphamide for

two and a half years,

not CR, re-biopsy: NHL

Fever & nodules 3 months,

9 kg weight loss, steroid

1 month, improved but

promptly recurred

Fever & nodules

2 months

Hb (g/dl) 7.7 8.9 13.0 8.4

WBC (109/l) 1.77 5.35 6.93 2.77

ANC (109/l) 1.30 4.17 4.91 2.29

Platelet (109/l) 129 465 345 330

SGOT (0 – 38 u/l) 254 113 53 67

SGPT (0 – 38 u/l) 740 52 42 54

AP (39 – 117 u/l) 99 67 118 105

LDH (u/l) (230 – 460) 615 1292 1179 1883

Histologic findings Large lymphoid cells,

hyperchromatism,

rimming,

karyorrhexis,

hemophagocytosis

Medium-to-large lymphoid

cells with irregular nuclei,

hyperchromatism, mitosis,

rimming, karyorrhexis

Large, pleomorphic cells,

hyperchromatic nuclei,

atypical mitosis,

karyorrhexis, rimming,

hemophagocytosis

Abnormal

lymphoid cells,

hyperchromatism

abnormal mitosis,

hemophagocytosis

T-cell receptor gene

rearrangement

Polyclonal Polyclonal Polyclonal Monoclonal

Cyclosporin in T-cell lymphoma 561

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cyclosporin was prescribed for the third (JS) and

fourth (AT) cases for 6 and 12 weeks, respectively

and followed by standard CHOP. These three

patients were still in complete remission during the

follow-up period of 8, 9, and 9 months after

discontinuation of all treatments, respectively.

Discussion

Anthracycline-based combination chemotherapy

(CHOP or CHOP-like) is usually used for SPTCL

patients with unsatisfactory complete remission rate

[4,5]. All of our cases failed to achieve adequate

responses with CHOP and ESHAP or fludarabine-

based regimens. However, they all showed rapid

improvement after cyclosporin treatment despite

the differences in presenting clinical courses

(Table II).

In a review of literature [9], cyclosporin appeared

to be the treatment of choice for benign lobular

panniculitis with no mortality in six cases compared

with 70% mortality in 27 cases receiving other

treatments. However, there was no randomized

controlled trial due to the rarity of the disease.

Subsequent articles also demonstrated successful

outcomes using either cyclosporin combined with

CHOP or oral cyclosporin alone [10,11]. In one

study [11], serum levels of interferon g and soluble

interleukin-2 receptor were tremendously elevated

during the active disease and normalized after

cyclosporin, suggesting that cytokine modulation

may be the mechanism of action of this drug.

Regarding patients with malignant SPTCL, two

reports found its efficacy in 2 pediatric and 1 adult

cases, resulting in long-term remission [12,13].

Combination chemotherapy was subsequently given

in the former, but not in the latter report [12]. All of

our cases received combination chemotherapy be-

fore cyclosporin and two of three long-term respon-

ders received it afterwards. The significance of

Table II. Responses to treatments.

SJ JM JS AT

Initial treatments CP63

CHOP64

FC61

CHOP64

ESHAP64

CHOP61 CHOP61

ESHAP61

Cyclosporin 200 mg/day

Tailing to 25 mg/day

in 4 months

200 mg/day

Tailing off

in 1 year

200 mg/day

for 6 weeks

followed by

CHOP66

150 mg/day

for 3 months

followed by

CHOP64

Outcome

(Follow-up duration

off-therapy)

Death due to

severe infection

without NHL

CR (8 months) CR (9 months) CR (9 months)

CP, Cyclophosphamide/prednisolone; CHOP, Cyclophosphamide/doxorubicin/vincristine/prednisolone; FC, Fludarabine/cyclophospha-

mide; ESHAP, Etoposide/steroid high dose/Ara-C/Cis-platinum; CR, Complete remission.

Figure 1. Histopathology of 2 cases (JM, panel A; SJ, panel B) with polyclonal T-cell receptor gene rearrangement at 206 magnification

showed large atypical cell infiltration around adipocytes. These cells were positive for CD3.

562 P. Rojnuckarin et al.

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chemotherapy remains to be determined. Further-

more, another report found the efficacy of cyclo-

sporin combined with oral prednisolone and

cyclophosphamide in a patient with angioimmuno-

blastic T-cell lymphoma [14]. This disease is also

characterized by cytokine upregulation.

In three cyclosporin-responsive cases in literature,

the T-cell receptor gene rearrangement was found

to be negative, inconclusive, and not performed in

each case [12,13]. In this study, we reported one

patient (AT) with molecularly confirmed SPTCL

who sustained long-term remission after cyclosporin

and chemotherapy, although she was formerly

refractory to the chemotherapy alone. Because of

the similar clinical presentations, histopathology,

immunohistochemistry and responses to treatments

of polyclonal and monoclonal forms of the disease,

the clinical significance of the clonality remains

unclear. Further studies correlating monoclonality

and the natural history in a larger patient popula-

tion are required. We propose that the mechanism

of action of cyclosporin in SPTCL is also down-

regulation of cytokines, similar to benign lobular

panniculitis.

In summary, we found that patients with full-blown

SPTCL responded well to cyclosporin-containing

regimens, suggesting that T-cell derived cytokines is

essential in pathogenesis. Further studies are required

to confirm our results. In addition, the role of

clonality determination deserves further studies.

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