Abstract
Abstract
Introduction
Three cases of extranodal NHL presenting with signs and symptoms consistent with cancer of the uterine corpus, cervix, and vagina are reported. The associated literature is also discussed.
Cases
Case 1
A 62-year-old woman presented with 1 month postmenopausal bleeding and lower abdominal pain. She did not report having fever, night sweats, weight loss, or fatigue (“B” symptoms). A physical examination revealed pallor and hepatosplenomegaly with no peripheral lymphadenopathy. Pelvic examination disclosed a bulky uterus. Pelvic ultrasonography confirmed the enlarged uterus and showed a heterogeneous uterine mass. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node biopsy were performed. Macroscopic examination revealed a diffuse infiltration of the endometrium and the myometrium with extension to the isthmus and the internal cervix. The external cervix and the vagina were not involved. The uterine cavity was free at the cut. The myometrial infiltration was grayish white in color, resembling “flesh fish.” Microscopic examination revealed a large-cell diffuse infiltration with cytonuclear atypia and numerous mitoses. A diagnosis of large B-cell NHL was made. Immunohistochemistry revealed the tumor to be positive for leukocyte common antigen (LCA) and negative for pan cytokeratin and cluster of differentiation 20 (CD20), confirming the diagnosis. A complete staging workup revealed a general disease: bilateral pleural effusion and hepatosplenomegaly. According to Ann Arbor classification, the tumor was stage IV. A combination chemotherapy including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) was started in January 2011. The patient received four cycles and it was well-tolerated. As of her last follow-up in January 2012, the patient was free of NHL.
Case 2
A 38-year-old woman was seen in 2000, complaining of menorrhagia and vaginal discharge. Her Papanicolaou smear was reported as showing inflammation. Physical examination did not reveal lymphadenopathy or hepatosplenomegaly. At gynecologic examination, there was an exophytic tumor arising from the cervix. The parametrium was not indurated and the rectal mucosa seemed uninvolved. Vaginal ultrasound revealed a cervical mass measuring 50×50 mm in diameter. Histology of a cervical biopsy revealed a diffuse large B-cell type NHL. Staging workup including CT scan, routine blood work, and bone marrow biopsy was negative. The tumor was classified as stage IE according to Ann Arbor classification. The patient was treated with three courses of combination chemotherapy including CHOP, followed by external beam radiotherapy to the pelvis (50.4 Gy in 28 fractions). At the end of the radiation, the patient had a complete clinical response. She has been followed up for 10 years without any relapse.
Case 3
A 34-year-old nulligravida presented with a 3-month history of irregular vaginal bleeding and pelvic pain. She did not present “B” symptoms. Physical examination did not revealed lymphadenopathy or splenomegaly. A vaginal examination revealed a 30 mm hemorrhagic mass confined to the vagina. Pelvic magnetic resonance imaging (MRI) showed this mass, which extended up to the bladder wall. Biopsy of the lesion demonstrated a diffuse lymphoma and immunohistochemical staining demonstrated that the tumor was of a large B-cell type NHL CD20+. A complete staging workup did not demonstrate any additional sites of disease; bone marrow biopsies were negative for lymphoma. In conformity with the Ann Arbor staging system for extranodal lymphomas, the tumor was considered a stage IE. The patient was treated only with six cycles of combination chemotherapy rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with a complete clinical and histologic response. This chemotherapy was well tolerated and completed without adverse effects. After 1 year of follow-up, the patient remained well without any evidence of disease.
Results
As noted above all three patients remain well as of this writing.
Discussion
Primitive lymphomas are unexpected in the female genital tract, accounting for 1.5% of extra-nodal NHL. 4 The incidence of NHL, especially extranodal lymphoma, has increased in recent decades. It could be explained by the spread of infectious agents such as HIV, immunosuppressive therapies, environmental exposure to pesticides and pollutants, and improved diagnostic techniques. 4
Kosari et al. 5 reported in a study of 186 malignant lymphomas of the female genital tract, that the most common primary sites were, in decreasing order: adenxa (47%), uterine corpus (12%), cervix (9%), vagina (6%), portio (5%), and vulva (4%). 5 Lymphomas occuring in the female genital tract affect all age groups. In the literature, the patients were between 7 months and 89 years of age. 5
The presentation of primary pelvic lymphoma may include findings suggestive of gynecologic malignancy. 4 Clinical symptoms of lymphoma involving the uterus or vagina, are often pelvic pain, abnormal vaginal/uterine bleeding or discharge, or a bulky mass.3,4 Contrary to systemic lymphomas, fever, night sweats, weight loss, and fatigue have been reported rarely. 6 However, the rapid onset of new signs and symptoms favors a diagnosis of lymphoma. 7 In addition, magnetic resonance imaging can be helpful for detecting gynecolgic lymphoma. Diffuse involvement, lack of clear margination, preservation of uterine architecture, normal endometrial enhancement, and tumoral homogeneity are the characteristic MRI features of uterine and cervical lymphoma manifesting on T2-weighted images as a mass with increased signal intensity. 8
Because clinical features and imaging findings are generally not characteristic, tissue diagnosis is mandatory. The accurate diagnosis is based on histopathologic examination of the lesion. The Papanicolaou smear is not a reliable tool for diagnosing lymphomas. 9 Primary cervical lymphomas originate from the cervical stroma, and the overlying squamous epithelium is generally unaffected: therefore, cytology is often normal and multiple and deep biopsies are needed for accurate diagnosis. Adequate fixation, thin sections, good hematoxylin and eosin stains, electron microscopic study, and immunohistochemical analysis have been recommended. 10
The differential diagnosis must include both benign and malignant conditions, such as multiple leiomyomas, corpus cancer, and uterine sarcoma when the entire uterus is involved, or, conversely, cervical fibroids, chronic inflammation, sarcomas, poorly differentiated carcinoma, and melanoma when the mass is limited to the cervix or vagina.3,4
Diffuse large B-cell lymphoma is the most common histologic type in cases of primarily involvement of uterus or of the vagina, 7 with immunochemistry staining positive for CD20. In a large review of lymphomas of the female genital tract reported by Kosari et al., 5 the other less-common lymphomas of the female genital tract included follicular lymphomas and Burkitt's lymphoma.
Appropriate treatment depends on the stage of disease; therefore, a complete staging workup, including a body computed tomography scan and a bone-marrow biopsy is recommended. 10 Recently, positron emission tomography scanning has been used for staging, surveillance, and response to treatment. 11 According to the literature and Ann Arbor classification, stage IE and IIE are the predominant stages, representing 73% and 24% of extranodal NHL, respectively. 10
The management strategy of female genital lymphomas has not been clearly defined bcause of the low incidence of the disease and limited experience in the literature. According to several case reports and a few case series, chemotherapy alone, radiotherapy alone, or radiotherapy combined with either chemotherapy or surgery are the available strategies for their management. 6 However, surgery is excessively used to treat gynecologic lymphoma, and combination chemotherapy alone may represent an option for the patient who desires to preserve her fertility. 12 These tumors are extremely responsive to systemic chemotherapy and CHOP regimen with a minimum of three cycles, or six cycles for bulky disease, including rituximab when CD20+is the standard chemotherapy treatment. 7
Prognosis for extranodal lymphomas is usually poorer than that for nodal lymphomas because of inaccurate or delayed diagnosis. 4 However, if the pelvic lymphomas are diagnosed at earlier stages, prognosis may be excellent compared to that for other gynecologic malignancies, 13 with a 5-year survival rate ranging between 70 to 90%. 3
Conclusions
Because of their low incidence of lower genital tract lymphomas, gynecologists will rarely encounter these tumors,, and routine screening for such a diagnosis may not be justified. In such cases, biopsy can be extremely valuable and should be considered in any patient with unusual clinical or radiologic features, if the clinical scenario is suggestive of a primary nodal process, or even if significant medical comorbidities exist and increase the patient's risk of needing surgery. Furthermore, biopsy of an easy accessible site should be preferred and performed whenever it is possible (e.g., in cases of palpable groin node and tumor of the ovary) to establish the accurate diagnosis and avoid major surgery. Moreover, a correct diagnosis with a complete workup leads to the appropriate therapy, and improves prognosis. For these reasons, it is important to include pelvic lymphomas in the differential diagnosis of some patients.
Footnotes
Disclosure Statement
No competing financial conflicts exist.