Plasmablastic lymphoma (PBL) has been described initially as a rapidly progressive and almost invariably fatal diffuse largecell lymphoma with plasmablastic features. Immunohistochemical findings show CD20 antigen negative and VS38c, CD138 and MUM-1 positives. This neoplasm is described almost exclusively involving the jaw and oral mucosae in HIV-positive patients. However, most recently, the clinical spectrum of the disease has been expanding, with a number of single case reports in HIVnegative patients and with extra-oral manifestations.
Keywords: Plasmablastic lymphoma; Oral cavity; AIDS; HIV
PBL: Plasmablastic Lymphoma;
DLBCL: Diffuse Large B Cell Lymphoma;
HIV: Human Immunodeficiency Virus;
HAART: Highly Active Antiretroviral Therapy
AIDS: Acquired Immunodeficiency Syndrome;
LDH: Lactate Dehydrogenase;
CT: Computed Tomography;
PCR: Polymerase chain reaction;
EBER: Epstein-Barr virus-encoded RNA;
EBV: Epstein-Barr Virus;
PCR: Polymerase Chain Reaction;
HHV-8: Human Herpes Virus 8;
CNS: Central nervous System
PBL is described as a subtype of the DLBCL commonly seen in patients with HIV infection. Is a rare and aggressive subtype of lymphoma that was initially described arising the soft tissue of the oral cavity and the jaw in HIV-seropositive patients . PBL is generally associated with a poor prognosis and a shorter survival after diagnosis. The poor overall prognosis of HIV-associated PBL is not modified favorably by the intensive chemotherapeutic regimens in the HAART era .
A 40-year old male with diagnosis of HIV infection since 1994 was admitted to our HIV/AIDS Department with 3 months history of fever, weight loss (10 kg in this period), night sweats and abdominal mild pain. He had diagnosis of AIDS because he had history of subacute disseminated histoplasmosis in 2004 and disseminated disease due to Mycobacterium avium Complex in 2009. He received HAART between 2009 to 2012 with a good clinical, virological and immunological response. Since 2013 it was his own decision to stopped HAART.
Physical examination revealed a tumoral intraoral mass involving the hard palate and the gingiva with painfull swelling over the left upper maxilla (Figure 1). A large left submandibular lymph node was palpable. Abdominal examination revealed hepatosplenomegaly. Significant laboratory findings include hematocrit 33%, hemoglobin 11 g/dL, erythrocyte sedimentation rate 52 mm/h, white blood cells 6 500/mm3, platelets 385 000/mm3, LDH: 3212 U/L (N: 230-460 U/L). Renal and liver function were normal and hepatitis B and C antibodies were negative. The CD4 T-lymphocytes count was 104 cells/μL (7%). CT scan of the maxillofacial area revealed a heterogeneous mass with areas of necrosis involving the left upper jaw. An excisional biopsy of the gingival lesion was performed. The samples were initially fixed in formalin, processed routinely and embedded in paraffin. It was stained with hematoxylin and eosin (H/E). Histopathological examination of the biopsy smears of this lesion using H/E showed a diffuse and dense proliferation of atypical lymphoid cells with extensive areas of necrosis involving the oral mucosae (Figure 2). Immunohistochemistry (IHC) was performed; the antigen retrieval with low and high pH solution (VECTOR) following the protocol. The markers were CD20 (Clone L26) (DAKO); CD3(Monoclonal Mouse Anti-Human) (DAKO); Vs38C (DAKO) MUM1 (Clone MUM1p) (DAKO); Ki 67(Clone MIB-1) (DAKO) and Bcl6 protein (Clone PG-B6p)(DAKO). The detection methods include LSAB+ with diaminobencidine (DAKO). The percentage of the cells with Ki67 was counted ten fields per high-power field (HPF). In situ hybridization (ISH) for Epstein-Barr Virus genome (EBER) PNA Probe/Fluorescein (DAKO) was performed.
Figure 1. PBL with a typical clinical appearance of the lesion: a large, non-fluctuant, gingival lesion located at the left upper jaw including the gingiva and the palate.
Figure 2. Oral mucosae biopsy showing a diffuse and dense proliferation of atypical lymphoid cells.
IHC examination revealed that neoplastic cells were strongly positive for the plasma cells markers MUM1 (Figure 3), VS38c (Figure 4) with expression of CD45 (Figure 5). All other negative markers include CD3, CD10, CD20, BCL6 and AE1/ AE3. The Ki67 index was high (90% expression). Excision biopsy of submandibular lymph node revealed a similar histopathological pattern and IHC characteristics of the intraoral cavity lesion. Based on the histopathological morphology and the plasma cell immunophenotype, the final diagnosis of primary PBL of the oral cavity was made. ISH revealed extensive positive for EBER (Figure 6). PCR was negative to detect HHV-8 genome. Bone marrow biopsy was negative for neoplastic infiltration.
Figura 3. MUM1 (IHC 400X) expression in the neoplastic cells.
Figure 4. VS38c expression (IHC 100X) in the atypical cells.
Figure 5. CD45 expression (IHC 400X) in neoplastic cells.
Figure 6. ISH positive for EBV genome in the atypical cells.
PBL is a rare and rapidly progressive variety of DLBCL that accounts for approximately 2,6% of all AIDS-related lymphomas [3,4]. In a large review of 228 cases of PBL, 69% affected HIVpositive patients and 31% were HIV- seronegative . Also, in the group of seronegative patients, a third have other causes of immunosuppression, generally solid organ transplantation or immunosuppressive therapy [6,7]. However, 92% of oral PBL described in the medical literature were in HIV-infected patients . The majority of HIV-infected patients with PBL of the oral cavity are young males, less than 40 years, with severe immunosuppression [9,10]. PBL was the initial manifestation of the HIV infection in approximately 5% of the cases .
Most recently, PBL was described in other sites, different of the oral cavity, such as lymph nodes, subcutaneous soft tissue, liver, bones and the anorectal region [11,12,13]. More than 20% of extra-oral PBL involve the lymph nodes .
The most significant clinical feature of PBL is its affinity for the oral cavity. In the oral cavity, PBL presents with large and painless oral masses, generally ulcerated, involving the gingival and the palate and, frequently, including various tooth and the jaw [1,15]. Additionally, some patient presents with typical “B” symptoms as prolonged fever, night sweats and weight loss . “B” symptoms have been reported in 33% of HIV-positive and in 50% of HIV-negative patients at diagnosis .
Other of the most important characteristics of PBL is the infiltration of the bone marrow tissue. The higher frequency of bone marrow involvement in patients with PBL confirms the aggressive nature and the poor prognosis of this subtype of lymphoma .
Histopathologically, PBL is characterized by a minimal or absent expression of leukocyte common antigen (LCA/ CD45), epithelial markers and B-cell antigens (CD20 and CD79a), but is immunoreactive for plasma cell markers such as CD138 [5,17]. Also, PBL shows many cytological and immunophenotypical features similar to plasma cell myeloma. EBERs positive is favorable to the diagnosis of PBL . Another histopathological finding in PBL is a diffuse pattern with a high mitotic index .
EBV infection is strongly associated with the pathogenesis of PBL in AIDS patients and has been observed in 74% of the published cases [4,5,9]. The role of HHV-8 is uncertain [9,19].
MYC translocations may contribute with the pathogenesis and the naturally aggressive clinical presentation of PBL.
Extensive local invasion, rapid disseminated disease, and resistance to chemotherapy characterized HIV-associated PBL with a high rate of relapse and death.
Treatment of PBL have not been established; therapeutic regimens include CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CHOP-like regimens or CVAD or hyper-CVAD are the most widely used regimens . The occasional use of radiotherapy has been also described. CNS chemoprophylaxis should be routinely employed in the management of patients with PBL, especially those with disease progression that typically involves the CNS . In some studies the addition of HAART to the chemotherapy has a favorable impact on the survival of HIV-associated PBL [5,17]. However, other studies describe a poor-free survival and overall survival despite HAART and intensive chemotherapeutic regimens . Actually there is no curative treatments for advanced PBL; autologous or allogeneic stem cell transplantation is a therapeutic option for relapsed or refractory disease [20,22]. Castillo JJ et al  analyzed retrospectively 70 patients with HIV-associated PBL treated with chemotherapy. In this series, the mean of CD4 + T cell counts was 165 cells/μL, the overall response rate to chemotherapy was 77% but only 46% of the patients presented complete response. The overall survival rate was 14 months and 72% of patients died for lymphoma progression. In this study, the use of regimens more intensive than CHOP did not associated with a better survival.
This case is peculiar and represent a very interesting contribution to the otolaryngologists in the clinical practice.
In conclusion, PBL show a high prevalence in immunocompromised patients, especially in HIV-positive and in those undergoing solid organ transplantation. HIV infection should be suspected in all patients with diagnosis of oral or extra-oral PBL.