Spontaneous Regression of an Oral Manifestation of Plasmablastic Lymphoma: Literature Review and Commentary about the Phenomena

Plasmablastic Lymphoma (PBL) is a hematolymphoid malignant disease that has a predilection for the oral cavity and jaw. The aim of this paper is report a total resolution of oral manifestation of PBL without any oncological treatment; this process is extremely rare and we discuss the mechanism which can occur. We present a case of PBL in left maxilla and oral mucosa in a woman HIV-positive patient. After an incisional biopsy an unusual outcome of spontaneous regression of the disease occurred, we reported the diagnostic process, the management and the Case Study follow up of case. We revised the similar cases reported in the literature and we will discuss the hypotheses how the phenomenon can occur. Although the PBLs are aggressive lesions, with questionable prognosis, the spontaneous regression can occur and the patient should be monitored for the risk of metastases and possible recurrence of the disease.


INTRODUCTION
Some neoplasias are classified as Acquired Immunodeficiency Syndrome related cancers, especially Kaposi's sarcoma, high-grade B-cell non-Hodgkin's lymphoma and invasive cervical cancer [1]. Plasmablastic Lymphoma (PBL) is an aggressive form of diffuse large B-cell lymphoma, composed of large cells with morphology of immunoblasts and a plasma cell. History of immunodeficiency especially caused by HIV infection is common in patients with PBL. [2]. Some cases of this disease occurs at extranodal sites, especially in the oral cavity [3].
Even though prognosis is poor, a complete remission of disease without treatment can occur. This finding was reported initially in HIV+ patients that start the use of highly active antiretroviral therapy (HAART) [4,5,6] or yet which interrupted this therapy [7]. This phenomena has been seen in PBL in HIV+ patients with undetectable viral range and with immune system stable after the performance of an incisional biopsy [8,9]. Besides have been reports of spontaneous regression (SR) an HIV negative patient in absence of anti-neoplastic treatment [10,11]. The literature review reported eight cases of PBL SR without anti-neoplastic treatment (Table 1), we herein describe more one case of intraoral PBL that spontaneously regressed in the absence of any anti-neoplastic treatment.

PRESENTATION OF CASE
A 66-years-old woman was referred to our Oral Pathology Department showing a nodular lesion involving the maxillary region associated with painful symptoms with a history of approximately Intraoral inspection showed an exophytic erythematous nodule with ulcerated areas on the maxillary left ridge, measuring approximately 3x4 cm. On palpation the lesion had a fibrous consistency and the superior left first molar presented increased mobility (Fig. 1A). The panoramic radiograph revealed bone resorption in the left side of maxilla probably due to periodontal disease in the superior left first molar (Fig. 1B). During the clinical evaluation no lymphadenopathy was detected. On the basis of these findings the clinical diagnoses were: malignant neoplasia or deep fungal infection. An incisional biopsy was performed. During the surgical procedure, the tissue was bleeding and friable.
The specimen was submitted to histopathological analysis, which revealed a diffuse proliferation of large, round to oval cells, with typical plasmablastic features (i.e., immunoblastic morphology with abundant basophilic cytoplasm, occasional paranuclear hofs and prominent central nucleolus). Frequent apoptotic bodies and mitotic figures were seen (Fig. 2). Immunohistochemistry identified expression of CD138, CD38 and MUM1 by the neoplastic cells.
No staining was seen with CD20, TDT, PAX-5, HHV8 and EMA (Table 2). Proliferative index accessed by Ki-67 reached more than 95% of the tumor cells. With these histopathologic and immunophenotypical findings the diagnosis of a plasmablastic lymphoma was established. The patient was referred to an oncologic center for appropriate treatment.
During the hospital admission, a fine biopsy was performed by a general oncologist and the diagnosis of PBL was confirmed. The patient was then referred to a hematolymphoid   During follow-up period, the patient underwent upper left first molar extraction with uneventful healing (Fig. 3). Fig. 4 shows the correlation between serological examination, the clinical lesion (appearance and regression) and the HAART therapy of the patient. The patient showed no recurrence of the oral lesion for 12 months. However, in medical follow PET-Scan, it was diagnosed tumor bone metastasis (bilateral humerus, right frontal region, costal arcs with pathological fracture of femur and radius) and the patient started chemotherapy (three courses of EPOCH chemotherapy).

DISCUSSION
Plasmablastic Lymphoma affects, predominantly, males in their fourth decade of HIV-positive patients. PBL commonly affects extranodal sites, predominantly the oral cavity, gastrointestinal tract and the skin Contrasting, in the present case, our patient is a female patient and had a more advanced age than most seropositive patients. The best prognosis is associated with younger patients, early stage of the disease and no lymph node involved [12].
The literature proposes that a SR of tumors can be related to the efficiency of the immune system. This behavior may act by different ways: blocking cell growth or proliferation, inducing apoptosis and activating natural killer cells One hypothesis to explain SR of lymphomas is that the local trauma caused by the incisional biopsy triggers the local immune system t healing response, and to resolve the tumor The radiation hypothesis suggests that doses received by the patient from imaginologic procedures can contribute to SR of PBL our case the patient was submitted to a single digital panoramic radiograph with an average dose of 100 mGy. Furthermore, the patient reported the use of phytotherapic ointment: olive oil and Malva sylvestris topically, several times. These substances act as anti agents contributing with the lesion regression [16,17].
PBL resolution without any form of intervention such as surgery, radiotherapy, chemotherapy is rare. In the few cases reported of PBL SR (Table 1) it was not possible to pro profile, even when considering multiple viral infections (EBV, HHV8 and HIV) to try predicting this phenomenon.
HAART can present a dual behavior in seropositive patients regarding the manifestation of PBL. Reported cases describing high viral load and decompensated immune system with PBL; after HAART, they regularized CD4/CD8 rates and the spontaneous resolution of the neoplasia occurred. A possible explanation is immune function reconstitution and the viral load control [4,5]. On the other hand, the use of HAART might trigger the Immune Reconstitution Inflammatory Syndrome, [18] and this phenomenon results in the uncontrolled production of inflammatory cells leading to development of PBL [5,19]. In the present case, ; Article no. BJMMR.33683 Plasmablastic Lymphoma affects, predominantly, males in their fourth decade of life, usually in positive patients. PBL commonly affects extranodal sites, predominantly the oral cavity, rointestinal tract and the skin [3]. Contrasting, in the present case, our patient is a female patient and had a more advanced age eropositive patients. The best prognosis is associated with younger patients, ease and no lymph node The literature proposes that a SR of tumors can be related to the efficiency of the immune act by different ways: blocking cell growth or proliferation, inducing activating natural killer cells [13]. One hypothesis to explain SR of lymphomas is that the local trauma caused by the incisional biopsy triggers the local immune system to the ponse, and to resolve the tumor [14]. The radiation hypothesis suggests that doses received by the patient from imaginologic res can contribute to SR of PBL [15]. In our case the patient was submitted to a single digital panoramic radiograph with an average dose of 100 mGy. Furthermore, the patient reported the use of phytotherapic ointment: olive oil and Malva sylvestris topically, several times. act as anti-inflammatory ting with the lesion regression PBL resolution without any form of intervention such as surgery, radiotherapy, chemotherapy is rare. In the few cases reported of PBL SR (Table 1) it was not possible to propose a patient profile, even when considering multiple viral infections (EBV, HHV8 and HIV) to try predicting HAART can present a dual behavior in seropositive patients regarding the manifestation of PBL. Reported cases describing -patients with high viral load and decompensated immune system with PBL; after HAART, they regularized CD4/CD8 rates and the spontaneous resolution of the neoplasia occurred. A possible explanation n and the viral On the other hand, the use of HAART might trigger the Immune Reconstitution [18] and this phenomenon results in the uncontrolled production of inflammatory cells leading to In the present case, the clinical lesion appearance and SR occurred after the HAART, when the viral load was undetectable and the patient immune system was already reestablished (Fig. 4).
Differential diagnosis of ulcerated swelling at oropharyngeal mucosa in immunosuppressed patients (post-transplant or HIV positive) may consider lymphoproliferative disorders as EBVpositive mucocutaneous ulcers. Histologically shows lymphocytes, immunoblasts plasma cells, histiocytes and eosinophils with atypical large Bcell blasts, plasmacytoid apoptotic cells, with immunopositivity for CD20+, CD79a+, PAX5+, Oct-2+ and Bob.1+ [20]. Complete remission of this disease when immunosuppressant were reduced or when immune system are recovered are reported in the literature [21]. The reported case is negative for EBV and for CD20 and the patient was immunocompetent since the appearance of the oral lesion, thus we discarded the EBV driven lesion diagnostic.
Metastases can occur after the complete remission of primary tumor; in our case the patient presented metastasis of the oral PBL in bones with femur and radius fracture; other case report related oral metastasis in breast and bone marrow after 2 months [22]; for this reason the PBL patient's follow-up is mandatory. The metastatic appearance may be identified by MMP value study as also by computerized tomography imaging (CTi) and colonoscopy in abdominal cases [23,24], in our case report, the metastasis was diagnosed by PET-scan exam.

CONCLUSION
Lymphomas are common in seropositive patients, but SR of these hematopoietic tumors, especially PBL, remains a dilemma. The mechanism involved includes factors that host co-infections and immune system recovery. A bigger number of cases may contribute to clarify possible associations. There are no defined protocols to manage these patients yet, even though there is a consensus which recommends a long term follow-up because of a recurrence risk and possibility of distant metastases.

CONSENT
All authors declare that 'written informed consent was obtained from the patient for publication of this case report and accompanying images.

ETHICAL APPROVAL
As per international standard or university standard, written approval of Ethics committee has been collected and preserved by the authors.