Primary chest wall Burkitt lymphoma in a case of HIV infection with immune reconstitution

Abstract

Burkitt lymphoma (BL) develops at an increased frequency in patients with HIV irrespective of the CD4 count. Lymph nodes and gastrointestinal tract are common sites of involvement by BL; however, primary chest wall BL is rare. A 52-year-old man on highly active antiretroviral therapy (HAART) for HIV with a CD4 count of 0.204 x 10⁹ cells/L presented with a 3-month history of enlarging chest wall mass. PET-CT scan imaging showed a bulky mass involving the musculoskeletal planes of left chest wall with the involvement of underlying pleura. Biopsy with immunohistochemistry confirmed BL. Patient received EPOCH-R (infusional etoposide, vincristine, and doxorubicin with prednisone, cyclophosphamide and rituximab) regime for six cycles along with HAART, attained complete remission (CR) and remains free of BL at 5 years. BL should be considered in the differential diagnosis of soft tissue masses in HIV-infected patients irrespective of their CD4 count.

Background

The risk of developing non-Hodgkin’s lymphoma (NHL) is increased in HIV patients by 60–200 folds.¹ Burkitt lymphoma (BL) constitutes up to 25% of HIV-associated lymphomas.² With the advent of HAART, the incidence of HIV-associated diffuse large B-cell lymphoma (DLBCL) has markedly decreased; however, the incidence of HIV-associated BL remains unchanged as it develops regardless of the CD4 count.³ It is well known that HIV-associated lymphomas are more commonly present with extranodal involvement than the same lymphomas in patients who are HIV negative. More than 90% of sporadic as well as HIV-associated BL present with symptoms related to the sites of extranodal involvement, with symptoms related to gastrointestinal tract or bone marrow involvement being the most common. BL in the chest wall is exceedingly rare.³ We report an unusual case of HIV-associated chest wall BL that presented with a rapidly enlarging chest wall mass.

Case presentation

A 52-year-old-man presented with 3 months history of progressive swelling over the posterior aspect of left chest wall and increasing pain in the left lower chest. There was no history of fever, weight loss and night sweats. The patient was incidentally diagnosed with HIV 5 years ago on annual health screening and was receiving HAART (zidovudine +lamivudine+nevirapine) in view of low CD4 count (0.210 x 10⁹ cells/L) since then. Following HAART, his CD4 count varied between 0.2 x 10⁹ to 0.4 x 10⁹ cells/L and he never developed any opportunistic infections. At presentation, he had a 16×15 cm soft tissue mass involving the posterior left chest wall extending from the spine of scapula superiorly to 5 cm below the lower border of scapula inferiorly. The mass extended from the left posterior axillary line up to the lateral border of vertebral column medially (figure 1). The mass was non-tender with irregular contours, firm to hard in consistency and tethered to overlying skin. A solitary left axillary lymph node of 4×2 cm was present but there was no hepatosplenomegaly. The patient had ECOG-Performance Status of 2 at presentation.

Figure 1.

Large mass involving the posterior (A) and lateral (B) left sided chest wall.

Investigations

Complete blood count (CBC) showed macrocytic anaemia (Hb 104 g/L, MCV 122fL) with normal leucocyte and platelet counts and no circulating atypical cells. The serum lactate dehydrogenase (LDH) was elevated at 1469 IU/L (control <260 IU/L) while renal, liver function tests and uric acid levels were within normal limits. CD4 count during this admission was 0.204 x 10⁹ cells/L and HIV RNA levels were undetectable. Eighteen fluorodeoxy glucose (18FDG) whole body PET-CT showed a conglomerate 16×9×19.7 cm soft tissue mass involving the left subscapularis, latissimus dorsi, posterior head of left deltoid, serratus anterior, supraspinatus and infraspinatus muscles with extension into the intercostal space of the third to sixth ribs on the left side posteriorly near the costovertebral junction. The lesion also involved the underlying parietal pleura with loss of fat planes and infiltration of the underlying ribs (figure 2). There was a discrete 4.4×3.4 cm left axillary lymph node and subcentimetric FDG-avid peripancreatic lymph nodes. Histological examination of a biopsy specimen from the chest wall mass revealed extensive necrosis and infiltration by small round atypical lymphoid cells with starry sky appearance. On immunohistochemistry (IHC), the lymphoid cells showed diffuse membranous positivity for CD20, CD79a with focal c-myc positivity, negativity for CD3, CD30 and had a Ki-67 index of nearly 100%. Bone marrow aspiration, biopsy and cerebrospinal fluid examination did not show infiltration by lymphoma (figure 3A–H). The patient was diagnosed as a case of primary chest wall BL Ann Arbor stage IV-E-X, BL-IPI 2/4 (high risk).

Figure 2.

PET–CT cross-sectional (A) and coronal image (B) showing fluorodeoxy glucose-avid chest wall mass with involvement of underlying pleura and erosion of sixth rib.

Figure 3.

(A) Extensive areas of necrosis seen in biopsy from the swelling in the back. (40× H&E) (B) Preserved segments show infiltration by medium to large size atypical lymphoid cells having irregular nuclear contour, coarse chromatin, inconspicuous nucleoli and scant cytoplasm. (40× H&E) (C) Immunostains show the lymphoid cells to be CD20 positive (diffuse membranous). (D) CD79a positive cells. (E) Background show infiltration by CD3 positive mature lymphoid cells. (F) CD30 is negative. (G) Focal C-myc positive. (H) 100% Ki67 proliferation index.

Treatment

He was started on prephase chemotherapy with cyclophosphamide and then received six cycles of EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) hemotherapy regimen. For Central Nervous System (CNS) prophylaxis, he received intrathecal methotrexate with every cycle. Considering the zidovudine-related macrocytic anaemia and increased frequency of drug interactions of zidovudine as well as nevirapine with chemotherapy, his HAART regimen was changed to tenofovir, lamuvidine and efavirenz (TLE).

Outcome

The patient attained complete remission (CR) after six cycles EPOCH-R regime with clinical and radiological resolution of chest wall mass and continues to be in remission after 18 months of therapy (figure 4).

Figure 4.

Follow-up image at 5 years showing persistent clinical remission of the chest wall mass.

Discussion

Patients with HIV share the highest burden of virus-associated cancer.⁴ DLBCL, BL, Hodgkin lymphoma (HL), primary effusion lymphoma and plasmablastic lymphoma are the most common HIV-associated lymphomas.⁴ The relationship of CD4 count with the development of HIV-associated lymphoma is complex. BL and HL are typically seen with CD4 counts > 0.2 x 10⁹ cells/L and are rare at CD4 counts <³0.05x 10⁹ cells/L.³ While most patients of NHL present with lymph nodal disease, extranodal presentations are relatively more common in HIV patients.⁵ Up to 3% of HIV-associated NHL present with primary extranodal involvement.⁶ Gastrointestinal tract, liver and bone marrow are the common sites of extranodal involvement while soft tissue involvement is seen only in 0.1% of lymphomas.⁵ Common differential diagnoses for chest wall masses include benign lesions such as haematoma, lipoma, abscess, elastofibromas and malignant lesions such as rhabdomyosarcoma, Ewing’s sarcoma, liposarcoma, chondrosarcoma, plasmacytoma and lymphoma in immunocompetent individuals. Kaposi sarcoma and NHL are the most common neoplasms that afflict the musculoskeletal system in patients with HIV.^{7 8} Psoas muscle and lower extremities are the most common sites for muscle-associated lymphomas and DLBCL is the most common histological subtype.⁸ Chest wall lymphomas commonly arise in the setting of pyothroax (pyothorax-associated lymphomas) or as a result of seeding during needle aspirations.⁹ Lymphomatous involvement of chest wall in the setting of HIV with no history of pyothorax or needle aspirations is extremely rare, particularly for HIV-associated BL. Marotta et al previously described a case of HIV-associated DLBCL of shoulder that was treated with a surgery followed by radiotherapy.¹⁰ Corti et al described four cases of HIV-associated NHL of chest wall among which one case was BL while two were plasmablastic lymphomas and one was DLBCL.¹¹

HIV-associated BL is classified into three subtypes: the classic type that accounts for approximately 30% of all HIV-associated lymphomas and morphologically resembles classic BL encountered in HIV-negative patients, BL with plasmacytoid differentiation and the third subtype referred to as ‘atypical’ BL. Epstein–Barr virus (EBV) positivity ranges from 30% in classic BL to 50%–70% in BL associated with plasmacytoid differentiaton.² HIV-associated BL originates from a germinal centre that is closely related to c-myc rearrangement and infection with the EBV. The characteristic morphological findings of sheets of monomorphic medium-sized B-cells with basophilic cytoplasm, numerous mitotic figures and admixed macrophages (‘starry-sky pattern’) are not specific because lymphoblastic lymphoma, DLBCL, plasmablastic lymphoma and even a high-grade T-cell lymphoma can have this picture. The tumour cells are positive for B-cell–associated antigens such as CD19, CD20, CD22 and CD79a, and express surface immunoglobulins (SIgs) with light chain restriction and the germinal centre cell markers CD10 and bcl-6. The tumour cells are negative for CD5, CD23 and terminal deoxynucleotidyl transferase (TdT), and usually negative for bcl-2; however, bcl-2 can be expressed in 10%–20% of cases.⁵

The prognosis of HIV-associated lymphomas including BL has improved from a 5 year overall survival of 28%–47% in the pre-HAART era to 62%–78% in the current era with HAART and chemoimmunotherapy.⁴ The treatment of HIV-associated BL remains controversial and several studies have shown that cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) regimen is highly suboptimal. Cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate / ifosfamide, etoposide, high-dose cytarabine (CODOX-M/IVAC), Fractionated Cyclophosphamide, Vincristine, Adriamycin, and Dexamethasone (Hyper CVAD) and short-course EPOCH–R regimens are known to confer an overall survival of up to 90% in patients of HIV-associated BL in combination with HAART.¹² While the intensive regimes are associated with a lesser risk of CNS relapse, they are poorly tolerated with a 80% incidence of grade three febrile neutropenia and 45% incidence of grade 3 mucositis as compared with short-course EPOCH-R regimen where the incidence of grade 3 febrile neutropenia is 22%.¹³ Considering the patient’s age, superior tolerability and feasibility of EPOCH-R regimen in the resource-limited settings, the same was opted in our patient after ruling out CNS involvement. He achieved CR with six cycles of EPOCH-R therapy with intrathecal methotrexate and continues to be in remission at 18 months from diagnosis.

Learning points.

• The risk of lymphomas remains high in HIV patients on highly active antiretroviral therapy (HAART) despite adequate virological suppression and immune reconstitution.

• Burkitt’s lymphoma must be considered in the differential diagnosis of chest wall tumours in HIV patients.

• Combination of HAART and intensive chemoimmunotherapy can lead to favourable outcomes today in most patients of HIV-associated Burkitt’s lymphoma.

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