Primary CD56 þ nasal-type T/natural killer-cell subcutaneouspanniculitic lymphoma: presentation as haemophagocyticsyndrome

K-A.JANG, J-H.CHOI, K-J.SUNG, K-C.MOON, J-K.KOH, Y-M.KWON* AND H-S.CHI†Departments of Dermatology, *Pathology and †Clinical Pathology, Asan Medical Center, College of Medicine, University of Ulsan,388-1, Poongnap-dong, Songpa-gu, Seoul, 138-736, Korea

Accepted for publication 20 May 1999

Summary Natural killer (NK) cells are large granular lymphocytes that mediate cytotoxic reactions which arenot restricted by the major histocompatibility complex. In recent years it has become apparent that aminor proportion of malignant lymphomas expresses an NK-cell phenotype defined by its reactivitywith the CD56 antibody. Primary purely cutaneous CD56 þ lymphomas have rarely been reported.They share a generally aggressive course and are highly associated with Epstein–Barr virus. Wedescribe a patient with a primary cutaneous nasal-type T/NK-cell lymphoma that presented as ahaemophagocytic syndrome and showed an aggressive clinical course.

Key words: Haemophagocytic syndrome, Primary cutaneous nasal-type T/NK-cell lymphoma

Natural killer (NK) cells have their T-cell antigen recep-tor (TCR) in germ-line configuration and commonlyexpress CD16, CD56 and CD57.1 The surface moleculeCD56 marks a category of malignant lymphoma ofputative NK-cell origin. T cells share immune effectorcell functions and can acquire NK markers upon activa-tion, and then are referred to as NK-like T cells.2 NKcells develop in the marrow from a bipotential progeni-tor capable of differentiation into T and NK cells.3

Because of a common ontogeny with T cells, NK cellsalso express some T-cell markers including CD2 andCD7, but not CD5.3 The TCR gene is not rearranged andsurface CD3 is not expressed.4 NK-cell lymphomas showa predilection for the nasal cavity and upper aerodiges-tive tract. Tumours with similar histological and immu-nophenotypic appearances occur in non-nasal sites andare referred to as nasal-type NK lymphoma. NK-celllymphomas commonly show the histopathological find-ings of necrosis and angiocentric growth, and havestrong associations with Epstein–Barr virus (EBV) andhaemophagocytic syndrome. They are rare in Westerncountries, but relatively common in Asian countries.5

Primary purely cutaneous CD56 þ lymphomas haverarely been reported.1,6–9 We describe a Koreanwoman with a primary CD56 þ nasal-type

T/NK-cell subcutaneous panniculitic lymphoma thatshowed an aggressive clinical course.

Case report

A 25-year-old woman presented with multiple painfulsubcutaneous nodules on the left cheek (Fig. 1) andboth forearms and lower legs of 3 months duration. Shehad suffered from fever, arthralgia of multiple joints andfatigue for 2 months. Laboratory examination revealedmicrocytic and hypochromic anaemia (haemoglobin8·5 g/dL) and elevated liver function tests (aspartateaminotransferase 449 U/L, alanine aminotransferase546 U/L). Results of other laboratory tests werenormal or negative, including cultures from blood,urine and sputum, and viral markers for hepatitis.Computed tomography scans of chest, abdomen andpelvis showed hepatomegaly but were negative fortumour or lymphadenopathy. A skin biopsy specimentaken from a nodule on the left forearm showed lobularpanniculitis (Fig. 2) with an infiltrate composed of smallto medium size pleomorphic cells. These had granularcytoplasm and immunocytochemistry demonstratedthem to be CD3 –, CD4 –, CD8 –, CD20 –, CD56 þ

(Dako, Kyoto, Japan, Fig. 3A), TIA-1 þ (Becton Dick-inson, Mountain View, CA, U.S.A., GMP-17) (Fig. 3B)and negative TCR using the polymerase chain reaction.

British Journal of Dermatology 1999; 141: 706–709.

706 q 1999 British Association of Dermatologists

Correspondence: Dr K-A.Jang. E-mail: derm@www.amc.seoul.kr

Numerous cells with lymphophagocytosis anderythrophagocytosis were noted (Fig. 2). Phagocyticmacrophages (so-called bean-bag cells) were foundmainly in the subcutis mimicking cytophagic histiocyticpanniculitis. The nuclei of these macrophages werenormal, but some phagocytosed cells were pleomorphic.The phagocytosed cells were usually CD56 þ. In situhybridization for EBV demonstrated a positive result forthe infiltrated lymphoid cells (Fig. 3C). Bone marrowexamination showed features of refractory anaemiawith several haemophagocytic histiocytes which werenot atypical. Aspiration biopsy from the liver revealedhaemophagocytic macrophages, which were CD68 þ;the phagocytosed cells were CD3 þ but CD56 –. Despitetreatment with chemotherapy composed of cytoxan(750 mg/m2 per day), prednisolone (100 mg per day)and cyclosporin (50 mg per day), the cutaneous lesionsas well as her general condition deteriorated. Severalpurplish patches developed in the upper and lowerextremities and a biopsy from the patch on the rightshin showed similar findings to the previous one with

more cells and fibrosis. She died 1 month after thediagnosis of primary nasal-type T/NK-cell lymphoma.

Discussion

In our patient, the specimens from the skin showedlobular panniculitis-mimicking lymphoma with numer-ous cells demonstrating haemophagocytosis. Biopsyspecimens from bone marrow and liver revealed severalhaemophagocytic histiocytes without atypical cells. Thediagnosis of a primary CD56 þ nasal-type T/NK-cellsubcutaneous panniculitic lymphoma was established.Since Gonzalez et al.10 described subcutaneous panni-culitis-like T-cell lymphoma (SPTCL) as an uncommonform of cutaneous lymphoma localized within the sub-cutaneous tissue mimicking lobular panniculitis, a fewcases of SPTCL have been reported. However, almost allcases of SPTCL to date have been of probable T-celllineage, especially cytotoxic CD8 þ, large granular cell

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Figure 1. An ill-defined subcutaneous nodule on the left cheek. Figure 2. Diffuse cellular infiltrate in the subcutaneous area (originalmagnification × 40). Inset shows numerous cells with lymphophago-cytosis and pleomorphic small to medium sized lymphoid cells (origi-nal magnification × 400).

origin.11,12 Previously, only one case of CD56 þ nasal-type T/NK-cell subcutaneous panniculitic lymphomawith haemophagocytic syndrome has been reported.13

CD56 þ lymphomas are uncommon and have dis-tinctive clinicopathological features. The frequentinvolvement of extranodal sites (such as the skin,central nervous system, skeletal muscle, and respiratory

and gastrointestinal tracts), aggressive clinical courseand high association with EBV have been described.6

Primary purely cutaneous CD56 þ lymphomas haverarely been reported,1,6–9,14 especially with haemopha-gocytic syndrome, although nasal T/NK-cell lympho-mas with haemophagocytic syndrome have beendescribed.1 Haemophagocytic syndrome is a prolifera-tive disorder of activated monocyte-macrophages and ischaracterized by fever, hepatosplenomegaly and pan-cytopenia.15 As macrophages can be activated throughcytokines, the haemophagocytosis might have beentriggered by factors released from the abnormal NK-cell clone. Kobayashi et al.15 examined the tumour cellfraction and the origin of cytokines and suggested thatinterferon-g released from abnormal NK cells activatesmacrophages to phagocytose cells. EBV is also respon-sible for the haemophagocytic syndrome. EBV maytherefore play an aetiological part in the tumorigenesisof this lymphoma.16 There is a report that EBV mightactivate secretion of varied cytokines such as tumournecrosis factor-a and -b from atypical lymphoid cells tolead to tissue necrosis, angiodestruction and haemo-phagocytic syndrome,17 and EBV was strongly corre-lated with CD56 positivity in the previous reports.12

Although haemophagocytosis might be seen in manyother malignancies, particularly T-cell lymphoma, aswell as in reactive conditions,18 NK-cell lymphoma hasto be considered as an important differential diagnosis.NK-cell lymphoma/leukaemia has an extremely poorprognosis with a median survival of less than a year.19

Our patient showed a fulminant course despite treat-ment with extensive chemotherapy. The aggressiveclinical course may be related to the expression of themultidrug resistance gene-coded P-glycoprotein.20 Theaddition of P-glycoprotein inhibitors or drugs not invol-ving the P-glycoprotein pathway may improve thetreatment outcome,20 or new modalities of treatment,including the use of high-dose chemotherapy and stemcell rescue, may be needed.19

In conclusion, we describe a patient with a primaryEBV-induced CD56 þ nasal-type T/NK-cell subcuta-neous panniculitic lymphoma presenting as a haemo-phagocytic syndrome. Our patient showed an aggressiveclinical course. We suggest that CD56 should beincluded in the routine panel for immunophenotypicanalysis.

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Figure 3. Infiltrated cells are CD56 þ (A), TIA-1 (GMP-17) þ (B). Insitu hybridization for Epstein–Barr virus demonstrated a positive resultfor the infiltrated lymphoid cells (C).

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