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Cutaneous Intravascular Natural Killer–Cell Lymphoma

A Case Report and Review of the Literature

Yanli Liu, MD, Wen Zhang, MD, Jie An, MD, Hui Li, MD, and Shuang Liu, MD, PhD

From the Department of Pathology, Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China.

Key Words: Intravascular lymphoma; Natural killer (NK)–cell lymphoma; Subcutaneous lesions; Poor prognosis

Am J Clin Pathol August 2014;142:243-247

DOI: 10.1309/AJCP1JLYXLGDNOCH

ABSTRACT

Objectives: To our knowledge, since 2003, there have been 11 reported cases of intravascular natural killer (NK)–cell lymphoma (IVNKL). Herein we describe the 12th case.

Methods: H&E and Envision immunohistochemical stains as well as in situ hybridization were used to study this disease in combination with review of the literature.

Results: Half of the cases reported to date are from China and Taipei. The clinical manifestation of IVNKL is erythema in the limbs and trunk, although patients’ conditions have varied notably from each other. One-year survival rate is about 40%.

Conclusions: IVNKL should be distinguished from extranodal NK/T-cell lymphoma (nasal type) and aggressive NK-cell leukemia. These three diseases have a similar phenotype and are all related to Epstein-Barr virus infection. However, the pathogenesis of similarities and differences needs further study. In particular, IVNKL is quite unusual. The treatment of IVNKL is difficult, and the prognosis is poor. Currently, IVNKL is not included in the World Health Organization classification subtypes and has been classified into NK/T-cell lymphoma (nasal type). However, in view of the unique characteristics of this disease, we propose that the diagnosis be independent, since this will facilitate further study of this disease.

Intravascular lymphoma is a rare and aggressive variant of extranodal non-Hodgkin lymphoma, characterized by the proliferation of neoplastic lymphocytes within blood vessels. About 90% of reported cases of intravascular lymphoma are large B-cell lymphomas, and only 10% to 15% of intravas-cular lymphomas are of T-cell lineage.1 To date, 11 cases of intravascular natural killer (NK)–cell lymphoma (IVNKL) have been reported. The first case was reported by Santucci et al2 in 2003. The next seven cases were reported in the English literature.3-9 Another three cases were reported from China in 2011 and 2012.10,11 Our case is the 12th worldwide. We have reviewed the 12 cases, and the clinical characteristics and prognosis have been analyzed ❚Table 1❚.2-7,9-11

Case History

A 38-year-old woman sought care because of a 9-month history of increasing numbers of erythematous, plaque-like, firm, subcutaneous lesions involving the skin of the chest and back ❚Image 1❚ and an intermittent fever (temperature up to 39.5°C). The lesions were not painful or pruritic, skin temperature was slightly increased, and the skin felt hard but without edema. There was no peripheral adenopathy and no mass in her nose. All laboratory studies were normal. WBCs were 4.09 × 109/L. Bone marrow biopsy specimens and aspi-rate revealed no evidence of tumor. The liver and spleen were of normal size, and no abnormalities were observed in any other systems by computed tomography scan.

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Materials and Methods

A biopsy of the chest skin was performed. The tissue was fixed in 4% formalin and paraffin embedded, and 3- to 4-µm-thick sections were cut. These were stained with H&E as well as Envision (Fuzhou, China) immunohistochemical stains.

The following antibodies were purchased from Maixin Biotechnology Development Company (Fuzhou, China): CD20, Pax-5, CD3, CD56, Granzyme B (GrB), CD2, CD5, CD7, CD4, CD8, Ki-67, and CD34. In situ hybridization studies were performed on paraffin-embedded sections using a probe synthesized in the pathology department at Aarhus University (Aarhus, Denmark), which allows for the testing of two kinds of Epstein-Barr virus (EBV)–encoded messen-ger RNAs (EBERl and EBER2). In situ hybridization was performed according to a published method.12 The lymph node from the infectious mononucleosis case was used as a positive control.

❚Table 1❚Review of 12 IVNKL Cases

Patient No. Age, y Sex Clinical Features Source CD Phenotype (Positive) EBV MI Treatment Follow-up Reference

1 54 M Torso, thighs scattered erythema

Italy NA CD3, CD56, GrB, TIA-1, CD30, Ki-67+100%

+ ND CHOP CNS involvement; died 17 months later

2

2 41 M Lower extremity erythema United States

Several months

CD3, CD56, TIA-1, Ki-67+100%, perforin CD2, CD7, CD43

+ – CHOP, SCT 1 year; complete remission

3

3 47 F Fever, myalgia, arthralgia, reduced whole blood, confusion

United States

Half-month CD3, CD56, GrB, TIA-1, CD7, CD2

– + No treatment Died after 1 month; multiple organ involvement

3

4 71 F Erythema, nodules Taiwan 36 mo CD3, CD56, TIA-1, Ki-67+99%

+ – No treatment 4 months; alive

4

5 4 F Systemic erythema, dysphagia, right-side weakness

Korea 10 mo CD3, GrB, CD56, TIA-1, CD45, Ki-67+100%

+ – CODOX-M/VAC7 7 months; alive

5

6 63 M Trunk, limb erythema, joint pain, weight loss, fever, mania

Austria 2 mo CD3, CD56, TIA-1, CD45RO, CD2

+ – NA Died 6 months later

6

7 23 F Abdomen erythema, leg edema, ileal ulcer, splenomegaly, fever

Japan NA CD3, CD56, TIA-1 + – CHOP, ProMACE/CytaBOM, L-ASP/CY, hyperCVAD/TX-AraC, SCT

Died 9 months later of acute graft-vs-host disease

7

8 68 F Trunk, limb erythema, fever China 6 mo CD3, CD5, GrB, Ki-67+100%

+ ND LAsP/BAM/VDs/MP

Died after 2 months

9

9 22 M Torso and lower limb erythema, fever, splenomegaly

China 2 mo CD3, GrB, CD56, CD2, CD7, Ki-67+90%

+ – CHOP-L Died after 2 months

10

10 42 F Erythema of lower limbs Taiwan NA CD3e, CD56, GrB, Ki-67+99%

+ – CHOP, immunotherapy

14 months; alive

10

11 18 F Double leg erythema, nodules

China 2 y CD3, GrB, CD56, CD2, CD30, Ki-67+100%

+ – Radiation 1 month; alive 11

12 37 F Chest and back erythema, fever

China 15 mo CD3, GrB, CD56+, Ki-67+90%

+ – CHOP Died of CNS involvement after 13 months

This article

CD, course of disease; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CNS, central nervous system; EBV, Epstein-Barr virus; GrB, Granzyme B; IVNKL, intravascular natural killer–cell lymphoma; MI, marrow involvement; NA, not available; ND, not done; SCT, stem cell transplantation; +, positive; –, negative.

❚Image 1❚ Cutaneous erythema in the skin of the back and chest.

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Results

The histologic study revealed many distended vessels filled with atypical large lymphoid cells in the dermis and sub-cutaneous tissue ❚Image 2❚. The tumor cells were all confined to the vessels and had large, irregular hyperchromatic nuclei with an ample eosinophilic cytoplasm. Many mitotic figures and necrosis were observed. Immunohistochemical studies showed that tumor cells were CD3+, CD56+, GrB+, CD4–, CD5–, CD8–, CD20–, CD30–, Pax-5–, and TdT–. More than 90% of the tumor cells were Ki-67+. In situ hybridiza-tion for EBER was positive. The immunohistochemical tests and EBER in situ hybridization suggested IVNKL (Image 2) ❚Image 3❚, ❚Image 4❚, ❚Image 5❚, ❚Image 6❚, ❚Image 7❚, ❚Image 8❚, and ❚Image 9❚. Following five courses of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and pred-nisone (CHOP), the erythema was reduced and the patient became afebrile. Seven months after initial diagnosis, reex-amination of the patient revealed clinical findings worrisome for central nervous system involvement. The patient refused intrathecal chemotherapy, and 13 months after initial diagno-sis, the patient succumbed to disease.

Discussion

Since 2003, 11 cases of IVNKL have been reported worldwide. The current case is the 12th. The clinical char-acteristics and follow-up of each case are shown in Table 1. Among the 12 cases, four (33.3%) were reported in China, two (16.7%) in Taiwan, two (16.0%) in the United States, one (8.0%) in Austria, one (8.0%) in Japan, one (8.0%) in Korea, and one (8.0%) in Italy. China and Taiwan accounted for six (50%) of 12 of the reported cases, which was consistent with the distribution characteristics of extranodal NK/T-cell lym-phoma, nasal type (ENKTCL), which has a high incidence in China. Of the 12 patients, eight were female and four were male. The maximum age was 71 years, and the minimum age was 4 years. The clinical course lasted from 2 months to 3 years, and more than half of the patients had fever. The clini-cal manifestation was erythema in the limbs and trunks. The patients’ conditions varied notably from each other. Multisys-tem involvement (brain, bone marrow, spleen, and kidney) occurred in most patients (eight of 12). The other four patients developed only a rash. Four of 12 patients showed nervous system involvement.

In the 12 published cases in which the morphology of IVNKL was described, the venules, capillaries, and arterioles at the dermal and subcutaneous levels were involved. Tumor cells were all confined within the vessels. Fibrin thrombi mixed with atypical lymphoid cells were occasionally found in some cases. The size of the tumor cell was medium to large

and was similar in morphology to lymphoblastoid cells. The cytoplasm was pale or eosinophilic. Nuclei were round, ovoid, or irregular. The chromatin was coarse and the nucleolus was visible in some cases. Scattered mitotic figures and necrosis usually were found. In all 12 cases, IVNKL, CD3, CD56, and Ki-67 were always positive; CD3ε, GrB, EBER, TIA-1, CD2, CD7, CD30, CD43, CD45, and CD45RO were positive in partial cases. CD20, CD4, CD8, CD5, CD57, CD79a, Pax-5, and TdT were consistently negative in all the cases reported. The immunophenotype of our case was identical to that of ENKTCL—that is, CD3, CD56, perforin, GrB, and EBER were positive, while CD5, CD4, and CD8 were negative. After a follow-up of 2 to 17 months, seven of 12 patients had died, with a 1-year survival rate of less than 40%.

❚Image 2❚ Necrosis was observed (H&E; ×200).

❚Image 3❚ Tumor cells showed cytoplasmic CD3 positivity (immunoperoxidase hematoxylin counterstain; ×200).

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We believe that IVNKL should be distinguished from the ENKTCL. Patients with IVNKL had no nasal symptoms, and no nasal abnormalities were found. ENKTCL can also occur in the skin but presents with multiple nodules with ulceration. In ENKTCL, tumor cells were distributed in tissues and showed vascular invasion. IVNKL tumor cells were confined to the endovascular system, a feature that is different from ENKTCL. IVNKL should also be distinguished from aggressive NK-cell leukemia. A rash is typically prominent in IVNKL without obvious abnormalities in the peripheral blood, although bone marrow abnormalities might be present in some patients. In aggressive NK-cell leukemia, tumor cells are diffusely

scattered in the extravascular tissue rather than deposited in blood vessels. The features of IVNKL and aggressive NK-cell leukemia may overlap during the course of disease, which may represent different disease states. Because of the similar pheno-type of ENKTCL, IVNKL, and aggressive NK-cell leukemia, as well as the common association with EBV infection, their pathogenic similarities and differences need further study.

For example, why are all tumor cells distributed intravas-cularly in IVNKL? The lack of adhesion molecule (CD29 and CD57) expression8 by tumor cells in intravascular large B-cell lymphoma is thought to explain why these tumor cells do not infiltrate extravascular sites. Whether similar mechanisms exist

❚Image 4❚ Tumor cells showed Granzyme B punctate perinuclear staining (immunoperoxidase hematoxylin counterstain; ×200).

❚Image 6❚ Ki-67 was expressed in more than 90% of tumor cells (immunoperoxidase hematoxylin counterstain; ×400).

❚Image 5❚ Tumor cells showed cytoplasmic and membranous CD56 expression (immunoperoxidase hematoxylin counterstain; ×200).

❚Image 7❚ CD20 had negative expression in the tumor cell (immunoperoxidase hematoxylin counterstain; ×200).

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in IVNKL is not yet known. The high prevalence of EBER positivity in IVNKL suggests that EBV infection is somehow involved in the pathogenesis of this rare lymphoma. Because these are rare cases, the origin of intravascular NK-cell lym-phoma has not been studied in depth. Only two of the 12 cases had T-cell receptor gene rearrangement analysis performed, which confirmed NK-cell origin.

IVNKL treatment is ineffective, and the disease has a poor prognosis. The CHOP regimen, combined with other chemo-therapy drugs and radiation therapy or stem cell transplanta-tion therapy, may be efficacious for a limited time in some patients. Most deaths occurred within a few months (seven of 12 [58.3%]), and only five (41.7%) of 12 had even temporary remission. The poor prognosis may be due to multiorgan, mul-tisystem involvement. Currently, IVNKL is not classified in the World Health Organization classification subtypes and is linked with ENKTCL. However, in view of the unique characteristics of this disease, we propose that the diagnosis should be inde-pendent, which will help further study of this disease.

Address reprint requests to Dr S. Liu: Dept of Pathology, Bethune International Peace Hospital, No 398 Zhongshan West Rd, Shijiazhuang, Hebei Province, China; liu_shuang@hotmail.com. Acknowledgments: The EBER test was performed by Xiaoge Zhou, MD, PhD, Department of Pathology, Beijing Friendship Hospital, Beijing, China. This article was revised by Handin, MD, Department of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

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❚Image 8❚ The endothelial lining cells of vessels containing tumor cells were reactive for the vascular endothelial cell marker CD34 (immunoperoxidase hematoxylin counterstain; ×200).

❚Image 9❚ Epstein-Barr virus–encoded messenger RNA positive expression in the tumor cell nuclei. In situ hybridization (hematoxylin counterstain; ×100).