Lymphomas are malignant hemopathies characterized by the clonal proliferation of lymphoid cells. A distinction is mainly made between Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (B, T, NK) [1] . Extranodal lymphoma is defined as all the manifestations related to the infiltration of non-nodal lymphoid tissue by lymphoma cells [1] . Its frequency is variable, between 24% and 48%, according to the data available in the literature [2] . In sub-Saharan Africa, the frequency was globally estimated at 18.6% [3] , reaching 80% in AIDS patients [4] . Extranodal lymphoma can affect any organ. Digestive lymphomas are the most frequent extranodal sites, representing 30% - 40% of NHLs [5] . The presentation of extranodal lymphomas is polymorphic with various sites: cutaneous, central nervous system, ENT, pleuropulmonary, etc [5] . Diffuse large B cell lymphoma (DLBCL) account for about one-third of extranodal involvement [1] [6] . Moreover, during certain NHLs, extranodal localizations of the disease are specific. MALT (Mucosa Associated Lymphoma Tissue) lymphomas have been described with digestive, thyroid, cutaneous and ocular involvement [1] . Treatment options are represented by chemotherapy sometimes associated with immunotherapy, surgery and radiotherapy. A poor outcome has been reported with extranodal localizations of lymphomas, with less overall survival (p = 0.003) despite the same progression free survival (p = 0.8) [7] . Data on the extra-nodal manifestations of lymphoma are patchy and have not been specifically studied in sub-saharan patients particularly in Senegal. Thus, we conducted this study with the objective of assessing the management and outcomes of patients with extra-nodal lymphoma.

Concerning socio-epidemiologic data (Table 1), a total of 52 patients were included (28 men and 24 women), with a sex-ratio of 1.2. The mean age (Table 1), was 44.25 ± 17.6 years (extremes: 18 - 80 years) for all patients, and 32 ± 11 years (extremes: 18 - 65 years) for HL patients. Toxic exposure was seen with chemical fertilizers (13.4%), long-term phytotherapy (5.8%) and hydrocarbons (3.8%). Comorbidities were diabetes (11.5%), hypertension (5.7%) and HIV infection (3.8%).

Looking at the diagnostic aspects, the mean time from the first symptoms to the confirmation of the diagnosis was 9.4 ± 4.8 months. According by ECOG PS score, 65.4% of patients had a score of more than 2. The signs of lymphoma progression, also called B symptoms, were present in 71.2% of cases. We observed a total of 63 extranodal sites in our patients of whom 82.3% were isolated and 17.7 % were multiple.

The extranodal manifestations (Figure 1) were digestive (19%), cutaneous

NHL: Non Hodgkin Lymphoma, HL: Hodgkin Lymphoma; M: man, W: Woman; HIV: Human Immunodeficiency Virus; ECOG PS: Cooperative Oncology Group Performance Status.

(17.5%), pleuropulmonary (17.5%). Some patients presented with bone marrow (4.8%), thyroid (1.6%), parotid gland (1.6%) and breast (1.6%) involvements. The clinical presentation was site dependent. Other findings related to the lymphoma were tumoral lymphadenopathies, splenomegaly and hepatomegaly respectively in 64.4%, 11.5% and 7.7% of cases.

For blood count abnormalities, we found anemia in 75.6% of cases, with an average hemoglobin level of 11 ± 2 g/dl. It was present in all digestive location and all bone marrow involvements. The average of white blood cell count was 20 ± 25 G/l and the average platelet count was 325.4 ± 152.9 G/l.

According to histologic subtypes (Table 2), NHL was predominant with 80.8% of cases, involving B cells (53.9%) and T cells (26.9%). HL was found in 19.2% of cases (10 cases), all presenting as the classic form on histology. Extranodal location was primary in 73.1%, and secondary as part of a disseminated lymphoma in 26.9%.

Tumor assessment according to Ann Arbor classification, noted that patients were at stage IV (60.9%), stage III (12 %), stage II (10.1%) and stage I (17%). For gastrointestinal tract MALT lymphomas (n = 4), patients were all at advanced stages: IIE (25%) and IV (75%). The other sites of MALT lymphomas were the thyroid gland (1 case) and parotid gland (1 case). The entities being multiple, and different prognostic scores are summarized in Table 3. Advanced stages are observed in DLBCL (50%), FL (50%), T-cell NHL (42.9%) and HL (60%) (Table 3).

N: Total number; n: effectif concerned, DLBCL: Diffuse Large B Cell lymphoma; MALT: Mucosa Associated lymphoïd Tissue; B-cell NHL: B-cell non Hodgkin Lymphoma; T-cell NHL: T-cell non Hodgkin Lymphoma; HL: Hodgkin lymphoma.

N: Number evaluated, n: effectif concerned, aa-IPI: Age Adjusted International Prognostic Index; FLIPI: Follicular Lymphoma International Pronostic Index; MIPI: Mantle Cell lymphoma International Prognostic Index; IPI T: International Prognostic Index for T-Cell NHL, EORTC: (European Organization for Research and Treatment of Cancer), IPS: International Pronostic Score. DLBCL: Diffuse Large B Cell lymphoma; Mantle NHL: Mantle Cell lymphoma; T-cell NHL: T-cell non Hodgkin Lymphoma; HL: Hodgkin lymphoma.

Regarding the treatment, conventional chemotherapy was used in 24 cases of NHL and 9 cases of HL. Immunotherapy with Rituximab was given in 13 cases of NHL and 1 case of HL. Adjuvant treatment involved surgical resection in 8 cases of digestive localizations, radiotherapy in 2 cases of spinal localizations and decompressive laminectomy in 1 case.

During the follow-up, we noted 29.7% complete remission (n = 11), 67.6% partial remission (n = 25) and 30.7% with no remission. The mortality rate was 38.5% in our study.

The median overall survival in our study was 20.5 months [18.7 - 72.2 months]. According to the Kaplan Meier curve, the probability of survival at the end of the study was, 48% for HL patients and 20% for NHL patients. In analytical study, the median survival was 25.1 months [23.5 - 34.1 months] during HL and 20.5 months [18.7 - 72.2 months] (p: 0.14) (Figure 2).

Among socio epidemiologic aspects, extranodal involvement is not uncommon, and some authors have published a frequency reaching 40% [2] [13] . This observation is also made in our study on patients who have comorbidities, especially

diabetes and HIV, which may explain in part the extra nodal presentation [3] ; which is comparable to the results found by Niang [14] in the same unit. In a large sub-Saharan multi-regional serie, a lower frequency (18.6%) of extranodal localization of the lymphoma could be linked to the inaccessibility of the radiological assessment [3] . In Africa, the diagnosis of extranodal lymphoma is made in patients in their fifties [3] [4] , which is younger than the Western population [13] . There are no particularities of the age of onset of extra nodular lymphoma compared to the nodal form. Thus, our patients with HL were younger than those with NHL, consistent with data of lymphomas in sub-Saharan Africa [3] .

Diagnosis was mainly suspected by the presence of suggestive signs, related to the location. At diagnosis, more than half of the patients had advanced deterioration and progressive symptoms of the disease, as described in the African series where patients traditionally consult late [3] . The main extranodal localizations were digestive, cutaneous, pleuropulmonary [1] [2] in our study. Although the authors agree that the digestive and cutaneous locations are the most frequent during extranodal involvement of lymphomas. The frequency varies for the different localizations in the different studies [15] [16] . Parotid, thyroid and breast involvement were rare [7] . Extranodal location was more frequent in primary (73.1%) than disseminated form of lymphoma (26.9%). However, the difficulty of clearly differentiating the primitive form or a secondary location remains a reality [2] [3] [4] .

According to the subtype of lymphomas, the extranodal localizations of HL are less frequent, being around 5% to 15%, whether advanced stages or not [3] [17] . In our study, we observed only classic classic form of HL. On the other hand, NHL can be up to 8 times more common, with a frequency around 30 to 40%. In this group of hemopathies, approximately one-third of patients with DLBCL present extranodal involvement regardless of the stage of the disease [1] [6] [7] . The preferred localizations of DLBCL are bones, bone marrow, nervous system and gastric [5] . MALT lymphoma is associated with gastric, but also thyroid and parotid locations [1] .

Most of our patients were at an advanced stage (59.6%) and the prognosis was unfavorable in 56% (23 cases) above the value (46%) found By Alshemmari in Kuwait [7] . The high prevalence of adenopathy and the long time to diagnostic may explain this situation.

On biology aspects, anemia was the most common cytopenia seen in digestive involvement and was present in all patients with bone marrow involvement. This is a very frequent situation in lymphomatous pathologies. Its etiologies are multiple, can be central or peripheral, related to bone marrow infiltration, inflammatory and immunological phenomena, reduced intake and sometimes blood loss. They often combine, leading to a significant decrease in hemoglobin levels [18] .

During the follow-up of our patients, around one-third reached CR. However, obtain CR in our setting is difficult due to the lack of diagnosis tools and access to drugs. We found a high prevalence of advanced stages like Mezger [3] who reported 78% in a multicentric sub-Saharan study. Therefore, the overall survival is shorter in associated extranodal lymphoma [7] . In our setting, the survival of patients followed for extranodal HL is better than that observed in patients with NHL, although this is not statistically significant. Survival remains low in our series of extranodal HL, because it is associated with poor prognostic factors. A better median survival of 34.2 months is reported in a Senegalese study that included observations of nodal and extranodal HL [19] . However, the survival profile is disparate with a better evolution in digestive MALT lymphoma (overall survival at 3 years: 5%) than in DLBCL (overall survival at 5 years in Ear Nose Throat: 45%) [5] .

Limitations of the study are related to those of retrospective work responsible for the loss of documents, the unavailability of positron emission tomography to assess patients, and the lack of access to standardized treatment protocols. financed by the health authorities, in order to follow patients’ survival.

Extranodal involvement of lymphomas is found in various sites, sometimes associated, and often diagnosed at advanced stages. Extranodal form of lymphoma, is frequent in B cell lymphoma, particularly DBLCL, it is also seen in T cell lymphoma. These lymphoma entities are particular in their aggressiveness and poor outcome, especially in our practice where the therapeutic options are limited.

The authors declare no conflicts of interest regarding the publication of this paper.

Fall, S., Camara-Tall, M.L., Niang, E.H.D., Sarr, K., Ndiaye, A., Ciss, M.M., Dakono, A., Thiam, A. and Ndiaye, F.S.D. (2023) Extranodal Locations of Lymphoma: Presentation and Evolutionary in Senegalese Patients. Open Journal of Blood Diseases, 13, 1-10. https://doi.org/10.4236/ojbd.2023.131001