A Case Report of an Unusual Cause of Abnormal Uterine Bleeding: Primary Cervical Lymphoma Misdiagnosed As Hormonal Dysfunction

A 44-year-old G2P2 woman presented with a four-month history of persistent vaginal bleeding. She denied pelvic pain, fever, night sweats, weight loss, or any other associated symptoms. After the first month of symptoms, she consulted a gynecologist, who initially suspected AUB secondary to ovulatory dysfunction. This preliminary diagnosis was based on the patient's age (fourth decade of life), a recent transvaginal ultrasound showing an anteverted uterus with normal size, shape, and contours, measuring 9.2 × 4.5 × 5.7 cm (estimated volume: 122.7 cm³). The myometrium demonstrated homogeneous echotexture, and the endometrium was centrally located, echogenic, and measured 9.3 mm in thickness. The right ovary measured 3.7 × 2.6 × 3.7 cm (estimated volume: 19.7 cm³) and contained a 2.8-cm dominant follicle. The left ovary measured 2.6 × 1.9 × 2.2 cm (estimated volume: 5.9 cm³) and showed normal morphology and echogenicity. No free pelvic fluid was identified. Overall, the ultrasound findings were unremarkable, with the only notable finding being a dominant follicle in the right ovary. No sonographic evidence of a cervical or pelvic mass, or any other significant gynecologic abnormality, was observed. Furthermore, according to the patient's medical history, her previous treating physician had informed her that a Pap smear performed a few months earlier had been reported as normal. Based on these findings, the patient was advised to remain under observation and return if her symptoms persisted or worsened (Table 1 ). AUB: abnormal uterine bleeding, Pap smear: Papanicolaou smear, MRI: magnetic resonance imaging, DLBCL: diffuse large B-cell lymphoma, PET/CT: positron emission tomography/computed tomography, R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, IHC: immunohistochemical Because the vaginal bleeding persisted, she returned for reassessment four months after symptom onset. A follow-up transvaginal ultrasound demonstrated a solid, well-defined, pelvic nodular mass that was slightly heterogeneous, predominantly hypoechoic, measuring approximately 7.7 × 4.9 × 3.8 cm, and exhibiting marked vascularity on Doppler imaging. Both ovaries remained normal in size and echotexture. Subsequent pelvic MRI demonstrated an anteverted uterus measuring 11.7 × 5.2 × 6.0 cm (estimated volume, 189.8 cm³). The junctional zone showed focal posterior thickening with a small T1-hyperintense cystic lesion in the right lateral wall, suggestive of adenomyosis. A previous cesarean section scar with an isthmocele measuring 0.7 × 0.5 cm and a residual myometrial thickness of 0.2 cm was identified. A circumferential cervical mass measuring 8.5 × 5.1 × 6.7 cm was observed, with approximately 7.0 cm of longitudinal vaginal extension involving the lower third of the vagina. Bilateral parametrial involvement, more pronounced on the right, was present without distal ureteral involvement or hydronephrosis. The fat plane between the lesion and the rectal wall was preserved. The endometrium measured 10 mm and demonstrated normal signal intensity. Both ovaries were normal in size and morphology, with a 1.6-cm corpus luteum cyst in the left ovary. The urinary bladder was adequately distended, with smooth walls and homogeneous contents. The rectum and perirectal fat planes were preserved. No pelvic lymphadenopathy or fluid collections were identified, and only a small amount of free pelvic fluid was present. Based on these imaging findings, the radiological impression was locally advanced cervical carcinoma with bilateral parametrial extension and involvement of the lower third of the vagina. This represented the leading radiological differential diagnosis prior to histopathological confirmation (Figure 1 ). Pelvic MRI demonstrating a large solid cervical mass measuring approximately 8.5 × 6.7 × 5.1 cm, with diffuse enlargement of the cervix. The lesion exhibited relatively homogeneous signal intensity on T2-weighted images and restricted diffusion on diffusion-weighted imaging, findings that initially raised radiological suspicion for locally advanced cervical carcinoma. MRI: magnetic resonance imaging On physical examination, the patient was in good general condition. Speculum examination revealed an edematous cervix with hyperemia, marked friability, and diffuse bleeding. These clinical findings were also considered highly suggestive of advanced cervical carcinoma. Consequently, the patient underwent colposcopy with a deep multi-site cervical biopsy (seven tissue fragments) performed in the operating room owing to excessive bleeding and marked cervical friability. Histopathological examination revealed a high-grade malignant neoplasm composed predominantly of atypical, poorly differentiated small- to intermediate-sized cells, accounting for approximately 90% of the evaluated specimen. No tumor necrosis, lymphovascular invasion, or perineural invasion was identified. The morphological findings suggested a high-grade lymphoproliferative neoplasm, and IHC analysis was requested to establish a definitive diagnosis (Figure 2 ). Hematoxylin-eosin staining (100×) demonstrating a dense subepithelial infiltrate of atypical small-to-intermediate-sized lymphoid cells beneath the cervical squamous epithelium, which shows only reactive changes. The IHC panel demonstrated diffuse positivity for CD20, CD10, BCL6, and BCL2, with a Ki-67 proliferative index of approximately 90% (Figure 3 ). Diffuse strong membranous CD20 positivity highlighting the neoplastic B-cell infiltrate (100×). The immunophenotypic profile supported the diagnosis of DLBCL. DLBCL: diffuse large B-cell lymphoma, IHC: immunohistochemical These findings established the definitive diagnosis of DLBCL of the uterine cervix, germinal center B-cell-like subtype, according to the Hans algorithm. Fluorescence in situ hybridization analysis demonstrated no rearrangements involving MYC, BCL2, or BCL6. Following histopathological confirmation, whole-body PET/CT was performed for disease staging and treatment planning. The examination demonstrated a large hypermetabolic cervical lesion with diffuse thickening of the vaginal walls, obliteration of the vaginal fornices, and inferior extension to the vaginal introitus. The lesion measured approximately 8.4 × 5.1 × 9.3 cm and demonstrated a maximum standardized uptake value of 55.9. Based on these findings, the patient was classified as Ann Arbor stage IE. The planned treatment consisted of six cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

Primary lymphoma of the uterine cervix is an extremely rare malignancy, accounting for only 0.008% (approximately 8 of every 100,000) of all cervical neoplasms [ 1 ]. Lymphomas comprise a heterogeneous group of hematopoietic malignancies, and the uterine cervix is an exceptionally uncommon site of primary involvement. The most common clinical manifestation of primary cervical lymphoma is abnormal uterine bleeding (AUB) [ 2 ]. AUB is one of the most frequent complaints in gynecological practice, affecting more than 50% of women during their reproductive years [ 3 ]. The PALM-COEIN classification, established by the International Federation of Gynecology and Obstetrics (FIGO) in 2011, categorizes the causes of AUB into structural causes (polyp, adenomyosis, leiomyoma, and malignancy) and non-structural causes (coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) [ 4 ]. Within the malignancy category, AUB is most commonly associated with ovarian, endometrial, and cervical carcinomas [ 4 ]. Among cervical malignancies, squamous cell carcinoma (82.72%) and adenocarcinoma (12.18%) are the predominant histological subtypes [ 5 ]. These epithelial tumors are strongly associated with human papillomavirus (HPV) infection and can usually be detected by Papanicolaou (Pap) smear cytology and HPV molecular testing [ 6 ]. In contrast, primary cervical lymphoma is a lymphoid rather than an epithelial malignancy. Unlike common cervical carcinomas detected by routine Pap smear screening, it originates within the deep cervical stroma and typically spares the superficial epithelium. Consequently, exfoliative cytology and HPV-based screening frequently fail to detect this disease [ 1 , 7 - 9 ]. This combination of extreme rarity and negative routine screening results represents a major diagnostic challenge. Consequently, when patients present with persistent AUB despite negative cervical cancer screening and unremarkable initial imaging studies, the diagnostic evaluation is often directed toward more common non-structural causes, particularly ovulatory dysfunction [ 4 ]. Definitive diagnosis, therefore, relies on histopathological examination combined with immunohistochemical (IHC) analysis, which remains the diagnostic gold standard [ 9 ]. Delayed recognition may postpone appropriate treatment and adversely affect patient prognosis [ 10 ]. Here, we present the case of a 44-year-old woman with persistent AUB whose initial transvaginal ultrasonography and cervical cancer screening were unremarkable, leading to a presumptive diagnosis of ovulatory dysfunction. Owing to persistent symptoms, further investigation revealed a rapidly enlarging cervical mass initially suspected to represent locally advanced squamous cell carcinoma. The definitive diagnosis of primary cervical diffuse large B-cell lymphoma (DLBCL) was established only after histopathological and IHC evaluation.

Primary cervical lymphoma is an exceptionally rare malignancy that predominantly affects women in their fourth decade of life, with persistent AUB representing its most common clinical manifestation [ 1 , 3 , 9 ]. Less frequently, patients may present with pelvic pain, a sensation of pelvic pressure, or a palpable pelvic or vaginal mass, often mimicking locally advanced cervical carcinoma [ 2 ]. Although uncommon, constitutional ("B") symptoms such as fever, drenching night sweats, and unexplained weight loss may also occur [ 3 ]. The principal differential diagnoses include squamous cell carcinoma, cervical leiomyoma, sarcoma, adenomyosis, endometriosis, and chronic cervicitis [ 1 , 9 ]. In the present case, the patient's age, persistent AUB, a recent transvaginal ultrasound demonstrating normal pelvic findings, and a reportedly normal Pap smear initially supported a diagnosis of ovulatory dysfunction, one of the most common causes of AUB in perimenopausal women [ 4 ]. The availability of the original ultrasound report documenting normal findings before symptom progression illustrates the rapid clinical evolution of this lymphoma. Although the original cervical cytology report was unavailable, the previous treating physician had informed the patient that the Pap smear result had been normal. Diagnosing primary cervical lymphoma remains particularly challenging because conventional screening methods for epithelial cervical malignancies, including Pap smear cytology and HPV molecular testing, are not designed to detect lymphoid neoplasms and therefore frequently yield negative results [ 1 , 9 ]. This diagnostic limitation reflects the disease's biological behavior rather than a failure of the screening methods themselves. Unlike epithelial cervical cancers, DLBCL originates within the deep cervical stroma while typically sparing the superficial squamous epithelium, making exfoliative cytology and even superficial biopsies potentially non-diagnostic [ 7 , 8 ]. Consequently, definitive diagnosis depends on obtaining adequate deep-tissue samples for histopathological examination and IHC analysis, which remains the diagnostic gold standard [ 9 ]. This diagnostic challenge is illustrated by the report of Koyanagi et al., who described an unusual case of primary cervical lymphoma detected through routine cervical cytology [ 11 ]. Although rare, that case demonstrates that cytological detection is possible when lymphoma cells involve the superficial epithelium. Nevertheless, histopathological confirmation with immunohistochemistry was still required to establish the diagnosis [ 11 ]. In the present case, persistent symptoms despite initially reassuring investigations prompted further evaluation with repeat imaging. The subsequent ultrasound and pelvic MRI demonstrated a rapidly enlarging cervical mass, leading to the preliminary radiological diagnosis of locally advanced cervical carcinoma. This interpretation was clinically reasonable because squamous cell carcinoma is by far the most common cervical malignancy [ 5 ], and primary cervical lymphoma is well recognized as a frequent radiological and clinical mimic of advanced cervical carcinoma [ 7 , 9 ]. However, imaging findings alone were insufficient to establish the diagnosis. A definitive diagnosis was made only after histopathological examination, and IHC characterization confirmed the diagnosis of DLBCL. Following pathological confirmation, PET/CT was performed for disease staging and treatment planning rather than for diagnostic confirmation. The patient was subsequently classified as Ann Arbor stage IE, providing the basis for therapeutic decision-making. Because primary cervical lymphoma is exceptionally uncommon, standardized treatment guidelines are lacking. Nevertheless, systemic chemotherapy remains the preferred treatment modality and is associated with excellent remission rates and effective control of occult systemic disease [ 1 , 7 , 9 ]. The R-CHOP regimen is currently one of the most widely accepted therapeutic protocols [ 7 , 9 ]. In selected patients, radiotherapy or immunotherapy may also be considered as individualized treatment strategies, particularly in recurrent disease [ 1 , 2 , 12 ]. Patient prognosis depends largely on disease stage and established prognostic factors, including the International Prognostic Index. Cross-sectional imaging, particularly CT and PET/CT, plays an essential role in disease staging and treatment planning [ 9 ]. The Ann Arbor classification remains the most commonly used staging system for primary cervical lymphoma [ 9 ]. Although the FIGO staging system may also be applied in selected cases [ 2 ], its concurrent use with the Ann Arbor staging system may create classification discrepancies because these systems were developed for different disease processes. Early recognition and prompt initiation of chemotherapy are associated with favorable outcomes. A systematic review by Kechagias et al. reported five-year and 10-year overall survival rates of 86.1% and 85.4%, respectively [ 2 ].

Primary cervical lymphoma should be considered in the differential diagnosis of persistent AUB, particularly when routine cervical cancer screening results are negative and symptoms persist despite an initially unremarkable evaluation. Because this malignancy originates within the cervical stroma, conventional cytological screening methods may fail to detect the disease. Consequently, persistent clinical suspicion should prompt further investigation, including deep cervical biopsy with histopathological and IHC analysis, which remain the diagnostic gold standard. Although primary cervical lymphoma is exceptionally rare, early recognition is essential to avoid delays in appropriate treatment and to optimize patient outcomes.