High grade non-Hodgkin's lymphoma (NHL), Kaposi's sarcoma and invasive cervical cancer, are the AIDS defining cancers in HIV infected populations, although several other malignancies occur with increasing frequencies in HIV patients. Plasmablastic lymphoma (PBL) is a rare NHL variant specifically associated with HIV and constitutes __% of all HIV related lymphoma (1,2). It expresses well-differentiated plasma cell markers like CD138, bright CD38, MUM1, instead of conventional B-cell markers like CD20, CD3, S100, HMB45 (3). Plasmablastic lymphoma is reported to have a predilection for unusual sites like oral cavity, orbit and oesophagus, and has poor survival rates (4).
We reviewed 6 cases of plasmablastic lymphoma in HIV postitive patients who had been diagnosed and treated at the departments of Medicine and Medical Oncology, Medical College, Kolkata, India, over an 18 month period from June 2010 to December 2011. Interestingly, all 6 patients had involvement at sites other than the oral cavity, which has been reported to be the most common site of occurrence of PBL (3). We discuss the diverse clinical presentation and organ involvement by PBL in these 6 patients and their histopathological and immunohistological properties. We also report on the response to standard chemotherapy and the survival rates of these study subjects on short term follow up basis.
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Out of the HIV positive patients who attended the HIV Referral Clinic at Medical College, Kolkata between June 2010 to December 2011, 6 were diagnosed to be suffering from plasmablastic variant of non-Hodgkin's lymphoma. All of them were admitted to the Department of Medicine, where they underwent clinical examinations and relevant investigations, including radiological and histopathological examinations. The various imaging modalities were undertaken and analysed by the same radiologist; similarly, the histopathogical and immunohistological slides were reviewed by the same oncopathologist, before a diagnosis of plasmablastic lymphoma was ascertained. The patients were subsequently transferred to the department of Medical Oncology, where they received chemotherapy and supportive treatment, and reviewed regularly on follow up upto 12 months.
The average age of the 6 patients was 50.8 ± 3.8 years, all of whom were male. All of them were known to be HIV positive; the average duration of seropositive status being 25.3 months (range 3.5 to 46 months). Mean CD4 count at presentation was 125.5 ± 71.1 cells/μL. 5 of the patients were on highly active antiretroviral therapy (mean duration 26.2 months), while one patient who had been diagnosed HIV seropositive 3.5 months ago had refused the HIV Referral Center's offers for antiretroviral therapy The most common symptom at presentation was fever (4/6, 66.7%), followed by chest heaviness and weight loss (2/6, 33.3% each) and 1 patient each with weakness of both lower limbs, cessation of urination and eye swelling.
Each patient is described in brief with regards to clinical and radiological findings:
47 year old male patient who had presented with fever, shortness of breath and right sided chest heaviness of 3 months duration. He was found to have pallor, lymphadenopathy and a right sided pleural based mass, from which a CT-guided biopsy was obtained.
46 year old male who had progressively decreasing urine output over 1 week, developed uremic symptoms after admission along with anuria and steadily rising serum creatinine. A large pelvic mass was palpated, which was confirmed on ultrasonography and was responsible for complete obstruction of both ureters, leading to bilateral hydronephrosis and obstructive renal failure. A CT guided biopsy of the pelvic mass was obtained, followed by bilateral ureteral stenting for relief of obstruction. The patient succumbed to renal failure in spite of stenting and hemodialysis, and the biopsy findings were obtained post mortem.
53 year old male with generalised lymphadenopathy who developed sudden onset double vision and a rapidly progressive painful proptosis in the right eye. CT scan of his brain and orbit revealed a right sided retroorbital mass which was responsible for the proptosis and was also compressing the right optic nerve. He refused consent for a guided fine needle aspiration to be performed on the retroorbital mass. An excision biopsy was performed from his cervical lymph node. He refused consent for a guided fine needle aspiration to be performed on the retroorbital mass.
55 year old alcoholic suffering from pain abdomen, fever and weight loss, was found to have a large (10 X 8 cm) suprarenal mass, which was compressing the liver as well as encasing the great vessels. A guided trucut biopsy was obtained from the suprarenal mass.
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50 year old male smoker who presented with fever, pallor and lymphadenopathy and who was subsequently diagnosed to be having a solid mass in the left lower lobe of lung, accompanying pleural effusion and mediastinal lymphadenopathy.
54 year old patient with history of defaulting on antiretroviral therapy presented with fever for 4 months and a spastic paraplegia slowly progressing over 2 weeks, along with bowel and bladder involvement. Magnetic resonance imaging of his spine revealed a soft tissue mass in lower thoracic region causing compressive myelopathy. A CT guided trucut biopsy was performed subsequently.
All the biopsy specimens were subjected to histopathological and immunohistochemical studies at the oncopathology laboratory of the department of Medical Oncology, and were opined on by the same histopathologist. In all the biopsy samples obtained from different sources ( lymph node-1, pleural mass-1, lung mass-1, suprarenal mass-1, pelvic mass-1, paraspinal mass-1), the predominant histopathogical picture was sheets of monomorphic population of large lymphoid cells with prominent nucleoli, scant to moderate deeply basophilic cytoplasm and frequent mitotic figures, suggestive of diffuse large B-cell lymphoma. Immunohistochemical studies revealed that the lymphoma cells in all biopsy samples phenotypically expressed the plasma cell markers MUM-1/IRF4, CD38, CD138/syndecan and were negative for B-cell markers (CD3, CD20, CD30, CD79A, ALK-1, BCL-6, PAX-5). Among other cell markers, CD56, CD10, CD4 and Bcl-2 were positive in 4 (66.7%), 4 (66.7%), 2 (33.3) and 1(16.7%) patients respectively. Serological testing for presence of Epstein Barr virus was performed in all patients except patient 2; out of the 5 of them, 3 (60%) demonstrated the presence of IgG antibodies to Epstein Barr viral capsid antigen.
The 5 surviving patients were instituted with chemotherapy for lymphoma (Regime: cyclophosphamide, doxorubicin, vincristine, prednisone) under the aegis of the department of Medical Oncology. All of them attained partial remission ( meaning _________) after ___ cycles. Subsequently, 3 out of 5 patients were started on infusional EPOCH therapy, out of whom 2 patients attained near total regression after __ months/__ cycles of chemotherapy, while 1 patient succumbed to chemotherapy related complications(___________). The 2 patients who opted to remain on conventional CHOP therapy were having stable disease at the completion of 6 monthly cycles of chemotherapy.
Lymphomas occurring specifically in HIV-positive patients include primary effusion lymphoma (PEL) and plasmablastic lymphoma (PBL) (1). Of these, PBL occurs most commonly in young HIV infected adult males, the most common site of occurrence being the oral cavity(3). Other rarer sites like orbit and oesophagus have also been reported in various case reports (5,6). Orbital involvement includes extraocular muscles, optic nerve as well as retinal and uveal layers.
In our case series, the average age of presentation of the all male patient cohort was 50.8 ± 3.8 years, which was higher when compared to the average age of 38 years reported in the only large study on PBL done till date (3). In the patients described above, PBL was found to have nodal as well as atypical extranodal distribution in the form of orbital, adrenal, pleuropulmonary as well as spinal involvement. This represents a significant deviation from earlier case reports and case series where the eye, oral cavity and gastrointestinal tract were the principle organ/ organ system to be involved (3,5,6). To the best of our knowledge, we believe that patients 2 and 4 represent the first instances of PBL patients presenting with post-renal renal failure and adrenal involvement respectively in world literature.
A distinguishing feature of PBL is a poor expression for B-cell markers like CD20, CD3, S100, HMB45 and cytokeratins and a strong reactivity for well-differentiated plasma cells markers, such as CD138 and CD38.
In our case series, immunohistochemistry of all the biopsy specimens revealed expression of plasma cell markers MUM-1/IRF4, CD38, CD138/syndecan and uniform absence of B-cell markers (CD3, CD20, CD30, CD79A, ALK-1, BCL-6, PAX-5); indeed, it was this phenotypical and immunological peculiarity which enabled us to confirm plasmablastic lymphoma as the diagnosis in all the patients. There was variable expression of the other cell surface markers like CD56, CD10, CD4 and Bcl-2. EBV coinfection stood at 60% in comparison to 52 to 74% in other studies (2,7).
HIV associated non-Hodgkin's lymphoma has been known to be an aggressive tumor class, especially plasmablastic lymphoma, which has reported mortality rates of 53- 60% and median survival of 6-15 months (3,4). Available literature regarding treatment of PBL suggests that combining anticancer treatment with antiviral drugs may offer the best outcome in terms of better chemotherapy tolerance, an improved complete remission (CR) rate, a significant improvement of disease-free survival (DFS) and a significant decrease in the number of deaths due to HIV related complications (1,8,9).
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Our experience in treatment of PBL showed a partial remission rate of __% at 6 months of CHOP regimen, a near total remission rate of __% with infusional EPOCH regimen and an overall mortality of 33.3%. However, the extremely small cohort size does not allow for comparison between the relative efficacies and benefits of the two regimens.