Unusual case of metachronous EBV‐associated B‐cell and NK/T‐cell lymphoma mimicking polymyositis‐diagnostic challenges and pitfalls
Authors: Esther H.L. Chan, Suat‐Jin Lu, Fredrik Petersson, Kong‐Bing Tan, Wee‐Joo Chng, Siok‐Bian Ng
Journal: American Journal of Hematology (2013)

A 68-year-old previously healthy Chinese lady first presented in June 2010 with a rapidly enlarging left neck swelling. Laboratory tests for retroviral and hepatitis infections were negative. A biopsy of the mass showed soft tissue infiltration by an aggressive B-cell lymphoma with features consistent with Burkitt lymphoma (BL). The tumor cells were of medium size, appeared monotonous (Fig. 1A), and stained positively for CD20 (Fig. 1B), CD79a, CD10 (Fig. 1C), and Epstein-Barr Virus-encoded RNA (EBER) in situ hybridization (EBER, Fig. 1D). Bcl2 was negative (Bcl2, Fig. 1E) and Ki-67 proliferation index was almost 100% (Ki-67, Fig. 1F). Fluorescent in situ hybridization for c-MYC rearrangement failed due to technical reason. The patient was started on the rituximab-etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisolone (R-EPOCH) regimen for Stage 1 disease with good response. She remained well and in remission for more than 2 years post-treatment. Although the presence of MYC rearrangement could not be demonstrated in this patient, the morphology and phenotype (CD10-positive, bcl2-negative, Ki67 proliferation of almost 100%, and EBER-positivity) is characteristic of BL. In the absence of immune deficiency, this represents a case of sporadic BL. EBV may be detected in approximately 30% of sporadic BL cases; however, a low socio-economic status and early EBV infection are associated with a higher prevalence of EBV-positive sporadic BL 1. In endemic and sporadic BL, the tumor is highly aggressive but potentially curable. Intensive combination chemotherapy regimens (R-EPOCH, R-HyperCVAD, CODOX-M/IVAC, GMALL) result in cure rates of up to 90% in patients with low stage disease and 60–80% in patients with advanced stage disease 2. In February 2013, she complained of right forearm swelling of about 2 weeks duration. This was followed by bilateral facial swelling 1 week later. She was otherwise feeling well with no systemic symptoms. Laboratory investigations at this point revealed a bicytopenia (Total white cell count 1.87 × 109/L (ANC 0.42), Platelet 99 × 109/L, abnormal liver function tests (AST 90 U/L [10–50], ALT 71 U/L [10–71], a raised lactate dehydrogenase (LDH) 1,377 U/L [250–580], and raised muscle enzymes (creatinine kinase 1,008 U/L [20–200] and aldolase (22.6 U/L [0–7.6]). C-reactive protein was not raised and blood culture performed showed no bacterial growth. Patient was treated empirically with intravenous augmentin. A computed tomography (CT) scan of the neck, chest, abdomen, and pelvis performed did not reveal any significant lymphadenopathy or organomegaly. However, CT scan of the face showed asymmetrical enlargement and heterogeneous attenuation of the temporalis, masseter, and medial pterygoid muscles bilaterally as well as enhancing soft tissues over the right maxilla and right platysma. A magnetic resonance imaging of the right forearm showed edema of the subcutaneous tissues, mainly affecting the superficial subcutaneous fat, and deep fascial planes with minimal edema of the muscles. The differential diagnoses considered at this point included recurrence of BL, in view of the raised LDH and new onset bicytopenia, and paraneoplastic polymyositis given the presence of muscle swelling and elevated muscle enzymes (creatinine kinase and aldolase). Polymyositis is associated with hematological malignancies and the majority is aggressive B-cell non-Hodgkin lymphomas 3. The MRI findings of subcutaneous edema affecting the superficial subcutaneous fat and deep fascial planes could represent an inflammatory process 4. The absence of muscle enlargement and mass lesion suggested that lymphomatous involvement is less likely. Although subcutaneous tissue and fascia can be abnormal in muscle lymphoma, these are usually accompanied by muscle enlargement and abnormal muscle signal on MRI 5, 6. A muscle biopsy of the right forearm was subsequently performed and revealed a multifocal, chronic inflammatory infiltrate of small lymphocytes with scattered muscle fiber necrosis, consistent with a diagnosis of polymyositis. Immunohistochemistry (IHC) was not performed. Bone marrow (BM) examination done at this point did not reveal any morphologic evidence of lymphoma. In view of the history of BL, a muscle biopsy was performed to distinguish between polymyositis and recurrence of BL. The presence of patchy infiltrate of small lymphocytes without significant atypia coupled with foci of muscle fiber necrosis appears consistent with a diagnosis of polymyositis. IHC was not performed since there was no obvious lymphoid cell atypia or suspicion of BL based on the H&E section. Retrospectively, performing a routine limited panel of immunohistochemical stains, such as CD3, CD20, and CD79A, can exclude BL recurrence but would not be helpful to distinguish between reactive from neoplastic T or NK-cell infiltrate. She was started on prednisolone for treatment of the polymyositis. However, her symptoms rapidly progressed with worsening of facial swelling and new onset of thigh swelling. A [18F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan performed to investigate the possibility of tumor as an etiology for the polymyositis showed multiple intensely FDG-avid muscle lesions scattered throughout the body (Fig. 2A), including muscles of mastication (Fig. 2B, arrows) as well as muscles in the neck, chest, abdomen, upper and lower limbs, and gluteal (Fig. 2C, arrows) regions. Indeterminate FDG-avid nodules scattered in both lungs (Fig. 2D, arrows, SUVmax of 6.4, size 1.2 cm) and an indeterminate FDG-avid lesion in the oropharynx (Fig. 2E, arrows, SUVmax of 9.7) were also detected. The most prominent FDG-avid lesion was in the right buttock (Fig. 2C, arrows, SUVmax of 26.5). A biopsy of the most FDG-avid right buttock muscle lesion revealed a diffuse lymphomatous infiltrate composed of medium to large cells (Fig. 3A) which stained positive for CD3 (CD3, Fig. 3B), CD2, CD8, granzyme B, TCR-beta, and EBER (EBER, Fig. 3C), consistent with a diagnosis of nasal-type extranodal NK/T-cell lymphoma (NKTCL). CD56, CD4, and all B-cell markers, including CD20, CD79A, and PAX5, were negative. EBV DNA level from the peripheral blood was significantly increased at 1.4 E+04 copies viral DNA/mL plasma. A review of the forearm muscle biopsy, with added IHC, showed that the lymphoid infiltrate consisted mainly of small lymphocytes with minimal atypia (Fig. 3D, inset shows high magnification of small infiltrating lymphocytes) and few scattered large lymphoid cells. The majority of the lymphocytes are CD3+ T-cells (CD3, Fig. 3E) which co-expressed EBER (EBER, Fig. 3F). Taken together, findings are consistent with involvement by NKTCL. Scattered EBER+ cells were also identified upon review of the BM biopsy. At this point, the patient's clinical condition deteriorated with worsening cytopenias, liver function tests, and coagulation profile. A repeat BM examination showed significant hemophagocytic activity. She developed fulminant hemophagocytic syndrome, rapidly deteriorated and passed away due to multiorgan failure about 6 weeks after the initial complaint of right arm swelling. The most common hematological malignancies associated with polymyositis are B-cell lymphomas 3. In this case, however, despite a clinical picture of polymyositis, the cause of the muscle involvement was due to infiltration by NK/T-cell lymphoma cells. Extranodal NK/T-cell lymphomas (NKTCL) characteristically involve the nasal and upper aerodigestive tract. However, cases involving extranasal locations, such as the skin, gastrointestinal tract, and testis, have also been reported 7, 8. Muscle involvement is rare and a review of the literature of T- and NK-cell lymphomas involving muscle revealed only six other cases of NKTCL with initial presentation of muscle swelling or weakness mimicking myositis (Table 1) 9-14. Two of the cases were originally reported as EBV-associated peripheral T-cell lymphomas because the tumor cells were of T-cell lineage 11, 14. However, the WHO recognizes that a subset of NKTCL are derived from cytotoxic T-cells 7 and in view of the extranodal presentation and association with EBV, these two cases should be reclassified as NKTCL. All six cases reported had involvement of nasal and/or other extranodal sites, either at presentation or with disease evolution, and five out of six cases involved mainly muscles of the extremities. All six cases reported died of disease with survival ranging from 8 months to 6 years from initial presentation. What is striking in this case is that our patient had extensive and generalized muscle involvement, although small amount of tumor in the lung and oropharynx cannot be excluded. Our patient also had an extremely fulminant clinical course and she died just 6 weeks after initial presentation of the forearm swelling. EBV-associated lymphoproliferative disorders (LPD) are known to occur in immunocompromised patients, such as post-transplant LPD and diffuse large B cell lymphoma of the elderly, the latter is believed to be attributed to age-related senescence of the immune system 15. Metachronous EBV-associated B- and T/NK-cell LPD are uncommon and only a few cases have been reported in transplant patients 16. Our patient first presented with sporadic BL and subsequently developed a second EBV-related T/NK lymphoma more than 2 years after completion of therapy, during which time she remained well with no immunosuppressive medications. To our knowledge, this is the first case of metachronous EBV-associated BL and NKTCL occurring in a patient without known immune deficiency. The unusual clinical course of this patient presenting with multi-neoplastic disease offers different, although to a great extent speculative, explanations regarding the pathogenesis. While the occurrence of metachronous tumors may be purely coincidental, the interplay between EBV, age-related immune senescence, and prior immunosuppression contributing to clonal evolution should also not be underestimated in the development of multi-lineage lymphoid neoplasms. This case also highlights several clinicopathologic diagnostic challenges. Clinically, this unusual case of NKTCL mimicked polymyositis and is the first that presented with such extensive and generalized muscle involvement. Early diagnosis is important as NKTCL with predominant subcutaneous and muscle involvement is associated with a fulminant clinical course. Histologically, the diagnosis of NKTCL on the forearm biopsy was challenging for several reasons. Firstly, the lymphoid infiltrate comprised mainly small lymphocytes without significant atypia. Secondly, this patient had a prior history of an aggressive B-cell lymphoma that characteristically consists of sheets of monotonous, malignant B-cells. The occurrence of a predominant small T-lymphocytic infiltrate without significant atypia would favor an inflammatory condition and argue against tumor recurrence. Thirdly, as NK cells express CD3ε that reacts with polyclonal anti-CD3 antibodies, it is easy to misdiagnose the tumor cells as reactive T-cells. Hence, performing a limited panel of T- and B-cell IHC, without EBER, will not be helpful to diagnose NKTCL involving muscle. This case also underscores the importance of ancillary testing to confirm tumor recurrence and exclude metachronous lymphoid malignancies, albeit uncommon. It is also important to emphasize that “non-specific” extranodal T-cell infiltrate occurring in unusual locations in older patients should be viewed with caution due to the possibility of metachronous and synchronous tumors. As in all other reports of NKTCL involving muscle, a definite diagnosis with limited IHC may not always be possible. In case of doubt, close follow-up and rebiopsy or review of previous biopsy with EBER testing and broad panel of IHC markers should be performed when confronted with a presumed inflammatory lesion in (1) an unusual location, (2) in the elderly and/or immunocompromized, and (3) in patients with a previous history of a hematolymphoid malignancy.