Primary extranodal marginal zone B-cell lymphoma of the ovary, fallopian tube, and uterus: A rare case report and review of the literature.

A 78-year-old nulliparous female with several year-history of intermittent periodic burning in the vulva managed with topical estrogen, presented to her gynecologist due to acute worsening of vulvar pain. A transvaginal ultrasound was performed revealing a left adnexal tubular mass, measuring 9.2 × 3.2 × 4.5 cm, two endometrial polyps 0.9 × 0.3 cm and 0.5 × 0.3 cm, and a thickened endometrial stripe measuring 4.61 mm. She was then referred to Gynecology Oncology for management. She endorsed some lower back pain and intermittent tenderness to palpation in bilateral lower pelvis and denied any fever, malaise, unintentional weight loss, or night sweats. Pelvic examination was benign, revealing no adnexal or uterine tenderness, fullness, or masses. Preoperative laboratory results, including a complete blood count, liver enzymes, and serum electrolytes were all within normal limits. The patient chose to proceed with total robotic hysterectomy, bilateral salpingo-oophorectomy, with plan for intraoperative frozen pathology of the adnexal mass (see Fig. 1 ). Injection of the uterine cervix was performed at the start of the procedure to enable surgical staging in the event that endometrial carcinoma was identified intraoperatively on frozen section. During the operation, the mapped left sentinel lymph node appeared enlarged and suspicious for pathologic involvement. Intraoperative frozen section of the left fallopian tube mass showed a small blue cell tumor, favoring lymphoma, at which point the decision was made to proceed with staging. An infracolic omentectomy was performed and left pelvic sentinel lymph node were sent for analysis. The patient tolerated the operation well with no complications. Fig. 1 Laparoscopic images of the pelvis. A, Laparoscopic image of the left ovary and fallopian tube (LOF) demonstrating a large solid tumor that extends to the left ovary. B , Small anteverted uterus measuring approximately 8 cm in length (U), bladder (B) normal appearing right ovary (RO) and fallopian tube (RF). Laparoscopic images of the pelvis. A, Laparoscopic image of the left ovary and fallopian tube (LOF) demonstrating a large solid tumor that extends to the left ovary. B , Small anteverted uterus measuring approximately 8 cm in length (U), bladder (B) normal appearing right ovary (RO) and fallopian tube (RF).

Catherine Spencer: Writing – review & editing, Writing – original draft, Visualization, Resources, Investigation, Conceptualization. Samer Z. Al-Quran: Writing – review & editing, Writing – original draft, Visualization, Supervision, Resources, Investigation, Conceptualization, Data curation, Formal analysis, Methodology, Project administration. Mackenzie Dent: . Sarah Todd: . Jenci Hawthorne: Writing – review & editing, Resources. Vijaya Kadam Maruthi: Writing – review & editing, Investigation. Ju-Hsein Chao: Writing – review & editing. Mustafa Al-Kawaaz: Writing – review & editing, Writing – original draft, Visualization, Supervision, Resources, Project administration, Methodology, Investigation, Conceptualization.

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Primary EMZL of the female genital tract is uncommon, with involvement of the fallopian tube and ovary being exceedingly rare, with only a few cases reported (see Table 1 ) ( Cho, 2011 , Ji, 2022 , Nezhat, 2013 , Noack, 2002 , Zhang, 2022 ). To our knowledge, this is only the second case described involving the ovary ( Nezhat, 2013 ). Table 1 Cases of primary EMZL presenting in the fallopian tube or ovary. Study Age Site Presenting symptoms Association Therapy Follow-up Noack, 2002 1 34 Left fallopian tube 3 months of pelvic pain, no B symptoms No autoimmune disease; Swab positive for Acinetobacter species Salpingectomy + gentamicin Disease free at 12 months post-surgery Cho, 2012 2 43 Right fallopian tube 6-months of dysmenorrhea and menorrhagia, no B symptoms Hashimoto’s thyroiditis on thyroid replacement Total laparoscopic hysterectomy Disease free at 12 months post-surgery Zhang, 2022 3 30 Bilateral fallopian tubes Infertility and dyspareunia, no B symptoms Hepatitis B infection on treatment Bilateral salpingostomy Disease free at 3 years post-surgery Ji, 2022 4 26 Bilateral fallopian tubes 2 months of menorrhagia, no B symptoms No autoimmune disease or infection present Bilateral salpingectomy Disease free at 12 months post-surgery Nezhat, 2013 5 47 Right ovary, right fallopian tube, right pelvic sidewall, appendix in the setting of endometriosis Severe dysmenorrhea, no B symptoms No autoimmune disease or infection present; associated endometriosis Total hysterectomy, bilateral salpingo-oophorectomy, appendectomy, and peritoneal biopsies Disease free at 12 months post-surgery Spencer et al, (present case) 78 Left fallopian tube and left ovary, uterus, and left pelvic sentinel lymph node Intermittent tenderness to pelvic palpation No autoimmune disease or infection present Total hysterectomy and bilateral salpingo-oophorectomy Disease free at 12 months post-surgery Cases of primary EMZL presenting in the fallopian tube or ovary. EMZL is an indolent lymphoma which can be asymptomatic on presentation. Among symptomatic cases, the clinical presentation tends to depend on the site of the organ involved ( Cerhan and Habermann, 2021 ). For previously described cases of EMZL involving the female genital tract, presenting symptoms were nonspecific including pelvic pain, dysmenorrhea, or menorrhagia, all lacking typical B symptoms commonly seen in lymphomas, making the diagnosis quite difficult. Our patient had a similar clinical presentation with no B symptoms and only intermittent tenderness to pelvic palpation. Extranodal marginal zone lymphomas are well known to be associated with autoimmune diseases (systemic lupus erythematosus, Hashimoto thyroiditis, or Sjögren syndrome), or with infectious etiologies ( Helicobacter pylori for gastric MALT lymphoma, Borrelia burgdorferi for cutaneous MZL, or Chlamydia psittaci for ocular adnexal MALT lymphoma), HIV, hepatitis C virus, or solid organ transplantation ( Cerhan and Habermann, 2021 ). The only other documented case of primary EMZL involving the ovary was associated with endometriosis ( Nezhat, 2013 ). The authors hypothesized that the inflammatory mediators seen in endometriosis may share similarities with autoimmune diseases and infections in neoplastic transformation pathways through the stimulation of B-cell proliferation ( Nezhat, 2013 ). Our patient was not found to have endometriosis or any of the common associations of autoimmunity or infectious etiology. The immunophenotype of neoplastic cells (CD5-, CD10-) and morphologic findings supported the diagnosis of EMZL in this case. Effacement of the affected tissue by small to medium-sized lymphocytes is seen with EMZL with or without lymphoepithelial lesions ( Bacon et al., 2007 ). Some tumor cells can have abundant pale cytoplasm (so called monocytoid cells). Admixed plasma cells can be seen in the background. The neoplastic cells often surround residual germinal centers (GCs), and can variably colonize them (follicular colonization). Typically, the neoplastic cells are negative for CD10, CD5, CD23, cyclin-D1, SOX11, LEF1 and BCL6. They can show aberrant expression of CD43 and rarely (<5%) they can be CD5(+). The presence of MYD88 p.L265P mutation raised the differential of lymphoplasmacytic lymphoma, which can be difficult to differentiate from EMZL in extranodal sites due to overlapping morphologic features and immunophenotype. MYD88 (Myeloid differentiation primary response 88) is necessary for immune function. Abnormal MyD88 signaling contributes to chronic inflammation-induced cancers. In particular, the L265P mutation is detected in ∼90–95% of cases of lymphoplasmacytic lymphoma /Waldenstrom macroglobulinemia (LPL/WM). However, MYD88 mutation can be seen in a small subset of MZL (4–15%) ( Hamadeh, 2015 , Insuasti-Beltran, 2015 , Varettoni, 2013 ). In addition, the absence of a high titer IgM paraprotein/monoclonal protein (M−spike) and CXCR4 mutation in this case favors a diagnosis of EMZL. CXCR4 mutations are the second most common mutations in LPL/WM identified in ∼30–40% of patients. They represent acquired (somatic) genetic alterations that frequently occur after the acquisition of MYD88 mutations. The presence of CXCR4 mutations is linked to more advanced disease with higher serum IgM levels and increased bone marrow disease burden ( Kaiser et al., 2021 , Treon et al., 2020 ). It is worth noting that upon review of the intraoperative frozen section findings in our case with the provisional diagnosis of lymphoma, the decision was made to excise the sentinel lymph node to potentially provide additional information to our BMT colleagues to guide post-surgical management andtreatment. Examination of histologic sections from the left pelvic sentinel lymph node with immunohistochemical studies confirmed the presence of marginal zone lymphoma with similar morphologic features and immunophenotype to the left ovary. Additionally, should the final pathology differ from the intraoperative assessment, this would ensure representative sampling of lymph nodes from the affected side for further evaluation. Limiting the procedure to the mapped sentinel lymph node also helps reduce surgical morbidity compared with a complete lymphadenectomy. Among the previously documented cases of primary EMZL involving the fallopian tube and ovary, all received surgery as their only treatment, except for one requiring antibiotics for treatment of a concurrent Acinetobacter infection. All patients were managed with surveillance and proved to be disease free for at least 12 months. Likewise, our patient received surgery was monitored with active surveillance with no evidence of disease recurrence at one year. In conclusion, although EMZL of the ovary and fallopian tube is extremely rare, it should be maintained on the differential diagnosis if atypical lymphoid cells or dense lymphoid aggregates are observed in the surgical specimen.

Extranodal marginal zone lymphoma (EMZL) is a type of low-grade B-cell lymphoma that most commonly occurs in gastric tissue; however, many other organs can be affected, including intestine, salivary gland, lung, thyroid, orbit, and skin ( Schreuder, 2017 ). Primary lymphoma of the female genital tract is a very rare condition, accounting for only 0.2–1.1% of extranodal non-Hodgkin lymphomas, with the most common histological subtype being diffuse large B-cell lymphoma ( Shi, 2024 ). Among the cases of EMZL in the female genital tract, majority originate in the uterus ( Kosari, 2005 ); to the best of our knowledge, only five cases have been described in the literature noting primary EMZL of the fallopian tube and only one case involving the ovary ( Cho, 2011 , Ji, 2022 , Nezhat, 2013 , Noack, 2002 , Zhang, 2022 ). Thus, we describe a rare case of extranodal marginal zone B-cell lymphoma, involving the left fallopian tube and left ovary, as well as uterus, and left pelvic sentinel lymph node.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Examination of histologic sections of the ovary revealed effacement of the architecture by a diffuse atypical lymphoid infiltrate composed predominately of small CD20(+) B-lymphocytes, including few with pale cytoplasm. Similar findings were noted in the endometrium, myometrium, serosa, left fallopian tube and ovary, and left pelvic sentinel lymph node (see Fig. 2 ). Immunohistochemical studies showed that the atypical lymphoid cells were positive for PAX-5, and IgM, with low labeling of nuclei by Ki-67 (∼10%). They were negative for CD5, Cyclin D1, LEF1, IgG and CD30. CD3 was positive in small T lymphocytes. In situ hybridization study (ISH) for EBV-encoded RNA (EBER) was negative. Flow cytometric immunophenotyping performed on fresh tissue demonstrated an abnormal population of kappa-restricted, CD20(+), CD19(+), CD79b(+), CD22(+), CD5(−), CD10(−), CD23(−) and CD38(−) small B-cells. The neoplastic cells comprised ∼ 70% of lymphocytes. Molecular testing was positive for MYD88 mutation but negative for CXCR4 mutation. Fig. 2 Permanent sections show a proliferation of atypical small to medium-sized lymphoid cells that efface the architecture of the affected sites. A , The uterus (H&E stained, magnification x 1), showing diffuse lymphoid infiltrate of the endometrium, myometrium, and serosa. B , Left ovary, (H&E stained, magnification x1) showing diffuse lymphoid infiltrate . C, Left ovary, (H&E stained, magnification x20) showing diffuse infiltration of lymphoid cells, contrasted by normal ovarian stroma (top). D , Left ovary (H&E stained, magnification x40) showing neoplastic cells consisting of varying proportions of small lymphocytes with round nuclei and dense chromatin. E-F , Immunohistochemistry shows a dense population of neoplastic cells within the left ovary that are CD20 (E) and IgM (F) positive (magnification x20). G-J, Dot plots of flow cytometric immunophenotyping (FCM) highlight the neoplastic B-cell population (in red) in comparison to the background T-lymphocytes (in blue). G , The neoplastic B-cells show expression of CD20 and are relatively similar in cell size to the small background T-cells, which are CD20-negtaive, based on forward light scatter (FSC) properties. The B-cells are negative for CD38 (H) , CD5 and CD10 (I) and show surface kappa light chain restriction (J) supporting the diagnosis of lymphoma . The background T-cells show normal expression of CD5 (I) . (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Permanent sections show a proliferation of atypical small to medium-sized lymphoid cells that efface the architecture of the affected sites. A , The uterus (H&E stained, magnification x 1), showing diffuse lymphoid infiltrate of the endometrium, myometrium, and serosa. B , Left ovary, (H&E stained, magnification x1) showing diffuse lymphoid infiltrate . C, Left ovary, (H&E stained, magnification x20) showing diffuse infiltration of lymphoid cells, contrasted by normal ovarian stroma (top). D , Left ovary (H&E stained, magnification x40) showing neoplastic cells consisting of varying proportions of small lymphocytes with round nuclei and dense chromatin. E-F , Immunohistochemistry shows a dense population of neoplastic cells within the left ovary that are CD20 (E) and IgM (F) positive (magnification x20). G-J, Dot plots of flow cytometric immunophenotyping (FCM) highlight the neoplastic B-cell population (in red) in comparison to the background T-lymphocytes (in blue). G , The neoplastic B-cells show expression of CD20 and are relatively similar in cell size to the small background T-cells, which are CD20-negtaive, based on forward light scatter (FSC) properties. The B-cells are negative for CD38 (H) , CD5 and CD10 (I) and show surface kappa light chain restriction (J) supporting the diagnosis of lymphoma . The background T-cells show normal expression of CD5 (I) . (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) The patient was seen in bone marrow transplant clinic one month post-operatively. A hepatitis panel and human immunodeficiency virus (HIV) testing were nonreactive and lactate dehydrogenase was within normal limits. Serum protein electrophoresis (SPEP) was obtained and showed no monoclonal protein (M−spike). The serum free kappa light chain was 12.8 (4.2–27.7), with serum free lambda light chain of 9.4 (2.4–20.7), and kappa:lambda ratio of 1.36 (0.22–1.74). All these parameters were within normal limits (reference ranges between parentheses). Given that no IgM monoclonal gammopathy or CXCR4 mutation were detected, a diagnosis of marginal zone lymphoma was rendered. A positron emission tomography scan was obtained which showed no evidence of lymphoma (no lymphadenopathy, hepatosplenomegaly or extranodal disease) after surgical intervention. A staging bone marrow biopsy was not performed in this case due to the absence of lymphocytosis or other abnormalities in the CBC or differential count that indicate bone marrow infiltration. Through shared decision making with the patient, a plan was made to obtain surveillance imaging twice yearly.