Exceptionally Rare Lymphoma Entity: Primary Uterine Marginal Zone Lymphoma in a Patient with Rheumatoid Arthritis

Péter Rajnics¹, Ádám Kellner¹, Zoltán Tóth², Mariann Moizs¹, Zoltán Tóth³, Krisztina Takács⁴, Timea Stromájer-Rácz⁴, Miklós Egyed^1* and Péter Rajnics^4
*Correspondence: Miklós Egyed, Department of Hematology, Kaposi Mór Teaching Hospital, Hungary, Tel: +36-30-9021-067, Email:

Introduction

According to the Connecticut tumor registry the incidence of nonHodgkin’s lymphoma (NHL) has risen steadily [1]. Primary NHLs of the uterus and cervix are rare, comprising only 0.54%–0.64% of all extranodal NHLs, most occurring in the cervix [2]. Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) of the uterus is exceptionally rare, with only few cases reported in the literature [2]. These cases were diagnosed mostly after hysterectomy. Etiology and pathogenesis of primary genital tract NHLs are unknown, although there might be a possible association between chronic inflammation and lymphomas [3]. In the past decades, a higher incidence of lymphomas has been reported in patients with autoimmune rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (SS), psoriatic arthritis, and dermatomyositis. It is still uncertain whether disease specific determinants or phenotypic or treatment related characteristics increase likelihood of lymphomagenesis in these patients [4].

The most useful diagnostic methods were computed tomography (CT) and magnetic resonance imaging (MRI) in the lymphoma staging [5, 6]. Unfortunately both tools have low specificity, therefore new, more accurate methods were investigated. The positron emission tomography associated with low dose CT (PET/CT) is more frequently used in staging nowadays.

Because of the low incidence, few data are available about primary extranodal uterine lymphoma treatment. Radiation therapy alone or irradiation with either surgery or chemotherapy may be found in the literature [7-11]. We present a case with Ann Arbor stage IE MALT lymphoma of the uterus, treated by chemoimmunotherapy alone.

Case Presentation

A 73-year-old woman with a 4-month history of postmenopausal vaginal bloody discharge was referred to the department of obstetrics and gynecology.

Patient had rheumatoid arthritis, mild fibrosis of the lung and chronic renal insufficiency. RA was treated with low dose (4mg daily) methylprednisolon.

Fractionated curettage was made according to the national protocols. Histologically, the infiltrate was homogenous; the main elements were mature lymphocytes with pale scant cytoplasm and centrocytes. The immunohistochemical analysis showed an evidence of massive LCA and PAX5 positivity (Figure-1) and B-cell markers including CD20. The specimen was BCL-2, CD43 positive and showed Kappa monoclonality on the cell-surface and somewhere intracellular. Cyclin D1 and CD5, CD10, CD23, and IgD expression were negative. These findings established the diagnosis of a marginal zone lymphoma.

Blood test revealed elevated creatinine and blood urea nitrogen values and hypochromic anemia (Hb:111 g/L, MCH:26 pg); Staging procedures included whole body PET/CT scan and bone marrow biopsy. Bone marrow biopsy was normal; the whole body PET/CT scan showed enlarged uterus with intensive pathologic FDG accumulation (SUVmax:5.9) without any invasion to the parametrium, or other lymphadenopathy (Figure 2 A).

The patient had low-intermediate risk according to the international prognostic index (IPI).

The patient were treated with rituximab-CHOP (rituximab dose was 375 mg/m2 , cyclophosphamide dose was 750 mg/m2 , doxorubicin dose was 50 mg/m2 , and vincristine dose was 1.4 mg/m2 in the first day of cycle and prednisone 100 mg orally in first to fifth days of each cycle) chemoimmunotherapy in 21 days of cycles.

Eight cycles of chemoimmunotherapy (R-CHOP) were administered. Complete remission was achieved after eight cycles according to the restaging PET/CT (Figure 2 B, C) and repeated fractionated curettage. The patient is disease-free since 20 months.

PET/CT scan shows good therapeutic response. C. Restaging PET/CT scan after 8 cycles of RCHOP treatment shows complett remission of lymphoma.

Discussion

The name, primary extranodal lymphoma, means that the lymphoma involves extranodal organ without lymph node involvement. We could observe a more rapid increase in the incidence of extranodal lymphomas, compared to the nodal in the past two decades [12-14].

However only few cases of primary NHL of the uterus can be found in the literature. The most common histological subtype is DLBCL [15] in the uterus, but other subtype, such as marginal zone B-cell lymphoma may occour [15, 16].

Direct association between chronic inflammation and lymphomagenesis has been observed by epidemiological studies The infectious etiology of gastric MALT lymphoma has been well documented and chronic colonisation of Helicobacter pylori in gastric mucosa can trigger gastric MALT lymphoma development. Other infectious agents, such as Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), hepatitis C virus (HCV), and human Tcell lymphotropic virus-1 (HTLV- 1), can play role in lymphomagenesis in human [17].

The pathomechanism of lymphoma development in chronic imflammation is probably complex. The chronic antigen stimulation may contribute to inflammatory responses by attracting neutrophils, which release reactive oxygen species (ROS). ROS are genotoxic and may cause a wide range of genetic abnormalities. Moreover the chronic inflammation triggers a prolonged proliferation of B cells, and the risk of DNA damage increase in this condition.

EBV can persist in infected B cells and incorporates in the host DNA by which transform these cells [17].

Link between chronic non-infectious imflammations, such as autoimmune diseases and lymphomas has been observed in the past. Severity of autoimmunity and higher degree of inflammation have consistently been associated with increased risk of lymphoma [18]. The exact pathomechanism of lymphoma genesis is unknown in these conditions. Immune dysregulation, received immunosuppressive drugs, such as methotrexate may be responsible for lymphomagenesis. Other risk factors such as smoking or unknown environmental factors can contribute to the development of lymphoid malignancies in rheumatic patients [4, 19].

Prognosis of extranodal lymphomas is usually poorer than nodal lymphomas because of inaccurate or delayed diagnosis [20]. Ann Arbor stage, size, and extent of disease, age, number of extranodal sites, performance status, serum lactate dehydrogenase values, and grade of lymphoma are significant prognostic features.

The most frequent symptoms are abnormal uterine bleeding, postmenopausal or postcoital bleeding, pelvic pain in uterine lymphoma [21, 22]. These symptoms are not specific, therefore clinicians must differentiate the lymphoma from benign inflammatory and other malignant diseases such as cervical or corpus carcinomas, sarcomas, and lymphoma like lesions [15, 23, 24]. For a definitive diagnosis a deep biopsy or fractionated curettage with histopathological evaluation and immunophenotyping are required [23, 24].

There is no evidence-based treatment protocol for primary extranodal uterine MALT lymphomas in our day. Radiotherapy, chemotherapy, and surgery, either alone or in combination are available and documented treatments [21, 22, 25, 26, 27]. Rituximab plus CHOP therapy, which is the standard and effective management in DLBCL [28, 29], may be useful in other CD20 positive B-cell lymphomas. Total abdominal hysterectomy, salpingo-oophorectomy, pelvic node dissection, radiotherapy are controversial.

Rituximab was the first monoclonal antibody, registered for the treatment of B-cell lymphomas. The use of rituximab has been rapidly incorporated in clinical practice because of its significant clinical activity and few adverse effects [30]. Rituximab is also used for treatmentof primary NHL of the cervix [31].

Our case demonstrated one possible cause of lymphoma origin: the chronic imflammation or immunosupressive therapy in autoimmune rheumatoid arthritis may be linked to lymphoma genesis. The PET/CT scan contributed to the primary and follow-up staging. The PET/CT scan was a reliable diagnostic tool in uterine lympoma.

Finally, the R-CHOP chemoimmunotherapy was a good and tolerable treatment option in elderly patient. Hysterectomy was not needed and patient is disease free nowadays. A multicenter analysis is necessary to evaluate the accurate location of chemoimmunotherapy in these rare extranodal lymphoma entities.

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