Malignant lymphomas constitute a biologically heterogeneous group of diseases resulting from the clonal expansion of lymphocytes (1) and they are categorized based on their presumed cell of origin (either B-cell or T-cell), their morphology (Hodgkin or non-Hodgkin), and their level of cell differentiation (2). Approximately one fourth of all lymphomas originate from extranodal tissues, with the gastrointestinal tract and skin being the most common sites (3). Lymphomas that arise from the gynecological tract are less common, representing around 1% of extranodal lymphomas. Of these, less than 1% emerge from the uterine cervix (4).

The symptoms of primary lymphoma of the uterine cervix (PLUC) often mimic those of cervical epithelial tumors. A notable number of patients present with atypical symptoms such as bleeding and pain, and pelvic exam usually reveals cervical oedema. Since PLUC tend to develop in the cervical stroma rather than the mucosa, it has been suggested that cytology cannot serve as a reliable diagnostic tool, which creates a diagnostic challenge for clinicians (5). This characteristic limits the utility of traditional cytological screening methods, such as the Pap smear, which are designed to detect epithelial abnormalities. As a result, cytology often produces false negatives in PLUC cases and therefore has limited efficacy as an initial diagnostic tool. Given this, reliance on histopathological examination through biopsy and the use of imaging modalities, such as MRI and CT scans, is crucial for accurate diagnosis (6). PLUC bear histopathological resemblance to lymphomas that occur in other anatomical sites. However, the characterization of the malignancy as primary can be difficult because the disease often involves contiguous sites including the uterus and the vagina (6).

The optimal therapeutic management of patients with female genital tract lymphomas and PLUC comprise another matter of debate due to the rarity of the disease, the presence of different histopathological subtypes that respond differently to treatment and the lack of prospectively designed studies on the disease. According to a body of evidence which is mainly based on case reports and series, treatment options may encompass surgery, chemotherapy, radiotherapy, or various combinations of the above (7). Multidisciplinary co-operation between gynecologists, pathologists, hematologists and medical oncologists has been strongly recommended for the management of patients diagnosed with the disease.

Given the limited clinical data on PLUC, we sought to thoroughly review the existing literature and summarize the reported cases. Our focus was on the clinicopathological features, diagnosis, and treatment approaches associated with this condition.

In this systematic review of the literature, we identified cases of primary lymphoma of the uterine cervix and examined their clinicopathological characteristics, diagnosis and therapeutic management. Our study included 213 reports which comprised 339 patients diagnosed with primary lymphoma of the uterine cervix. Our findings revealed that most patients presented with non-specific symptoms including vaginal bleeding and discharge with a mean age of 48.5. The menopausal status of the patients varied and most of them were diagnosed at an early stage, according to the Ann Arbor staging system. The follow-up period ranged from 4 weeks to 246 months and the absolute 5- and 10-year survival rates were 86.1 and 85.4%, respectively. Although a higher concentration of cases was noted in Asia and Europe in terms of geographical distribution, the small volume of case reports and series analyzed does not allow the identification of any geographical variations or patterns. Broader studies on extranodal lymphomas suggest that factors such as genetic predispositions, environmental influences, or differences in healthcare systems and diagnostic practices may contribute to regional distribution patterns (3).

The existence and recognition of primary genital tract lymphomas was initially widely debated in the literature (3) until the identification of normal lymphoid tissue in female reproductive tract (17) and the reporting of patients with malignant lymphomas located exclusively in gynecological organs (18). While the exact causes and mechanisms behind these lymphomas remain elusive, chronic inflammation is suggested as a potential triggering factor (19). However, further mechanistic studies are required to elucidate the aforementioned theory. The increase in the incidence of extra-nodal lymphomas in different body sites, during the last decades has been also linked with the increase in immunosuppressive therapies, environmental toxins as well as, improved diagnostic techniques (20).

Despite the presence of published cases of primary lymphomas of the female genital tract in the scientific literature their definition remains a matter of controversy. A number of investigators have discussed cases of lymphomas in different parts of the female reproductive tract without presenting specific criteria to define primary tumors (5,21–23). Others have applied either the Fox and More criteria for uterine lymphoma (24) or the Harris and Scully modification of the Ann Arbor staging system for ovarian lymphomas (25). Currently, different staging systems are used for PLUC, which may contribute to inconsistencies in diagnosis and treatment planning. Developing a standardized staging and diagnostic framework specifically for PLUC would reduce this variability and facilitate more consistent management of the disease across clinical settings (26,27). Regarding PLUC, the definition that has been proposed by Kosari et al is the most comprehensive and includes the following criteria: i) Lymphomas confined to the cervix at the time of initial diagnosis, ii) lymphomas that are localized in the cervix without any evidence of involvement of other body parts on full investigation, and iii) the absence of abnormal cells indicating leukemia in the peripheral blood and bone marrow (28).

The presentation of the disease usually involves vaginal bleeding or discharge as cervical lesions can easily become ulcerated and/or infected (29), a phenomenon described in different histopathological types of cervical malignancies (30). In line with the results of our study, the presence of ‘B’ symptoms is considered uncommon and affects only a relatively small number of patients with PLUC (31), while cases of asymptomatic patients have been also reported. Despite the fact that clinical presentation of PLUC is very similar to other cervical tumors, the disease is considered to be human papillomavirus (HPV)-independent and distinct compared to cervical epithelial malignancies (32–36). While the co-existence of PLUC with other synchronous histological types of cervical cancer is pathophysiologically feasible, in this review, we only identified sporadic cases.

As far as diagnosis is concerned, histopathology plays a pivotal role while cytology cannot be utilized reliably as PLUC mainly affects the stroma rather than the epithelium of the uterine cervix. This was also reflected in our results, with only one fifth of the investigators using cytology as the first modality for diagnosis. The histopathological diversity within PLUC, with DLBCL as the most common subtype, mirrors patterns observed in other extranodal lymphomas (27,37). The range of subtypes suggests that while broad treatment protocols may be effective, subtype-specific approaches may be beneficial for optimizing outcomes. Less common subtypes, such as lymphoma-like lesions, further underscore the need for careful diagnostic differentiation, as histopathology plays a critical role in guiding treatment decisions (38). Future research should focus on identifying and characterizing genetic profiles in PLUC, as this could lead to more tailored and effective treatment options, similar to the advancements seen in other lymphomas.

Immunohistochemistry is another important diagnostic tool and lymphoma markers used for other types of lymphocyte malignancies can be also found consistently in PLUC. These marker include among others CD20 and Ki-67 for B-cell and CD3 and CD20 for T-cell lymphomas (37). Although such markers are widely used in diagnosing PLUC, variability in their expression across cases can impact diagnostic accuracy. This variability likely stems from the biological diversity of lymphomas, with different lymphocyte subtypes displaying distinct immunophenotypic profiles (26). Genetic mutations and the tumor microenvironment also contribute to these differences, highlighting the need for a more comprehensive marker panel to improve accuracy (38).

In the analysis it was evident that premenopausal women had better oncological outcomes when compared to the postmenopausal women. Although such an outcome could have been expected as premenopausal status could be associated with a younger, healthier population, the actual reasons for this disparity remain unclear. Potential factors may include differences in hormonal status, comorbidities, or variations in treatment response. Further research is necessary to investigate the underlying mechanisms and how they may influence survival outcomes in PLUC (38,39).

Due to the rarity of the disease, a consensus regarding therapeutic management has not been established. Older reports utilized radiotherapy as monotherapy. However, more recent approaches included either surgery (115/309), with or without neo-adjunctive or adjunctive therapy, chemotherapy alone (109/309), or a combination of chemotherapy and radiotherapy (62/310). In our analysis, there was no statistically significant difference in the overall survival when surgery alone was compared with chemotherapy alone. However, the longest calculated median survival was for those who received neo-adjuvant chemotherapy (15 patients, median survival 72 months, range 36–156). Additionally, surgery followed by adjunctive chemotherapy resulted in similar overall survival when compared to surgery alone. The question is whether PLUC should be managed in accordance with treatment guidelines for lymphoma of other sites (26), or whether it should be site-specific; an anatomical site such as the uterine cervix is feasible to remove surgically with relatively little morbidity. Our study does not provide sufficient evidence to confirm the idea that PLUC should be managed non-surgically. Based on the extremely limited present data, which may also be influenced by the age of some of the studies and geographical variation, there is possibly a tentative suggestion that a combination of neo-adjuvant chemotherapy and surgery may represent a reasonable treatment option.

Current guidelines for the management of non-Hodgkin lymphomas typically recommend chemotherapy as the first-line approach. Specifically, for diffuse B-cell lymphomas, it is preferable to utilize a doxorubicin-based regimen, such as a course of six to eight cycles of R-CHOP (rituximab, cyclophosphamide, vincristine, prednisolone) (40). In contrast, when dealing with indolent B-cell lymphomas, such as marginal zone lymphomas, there is no single standardized regimen that is universally recommended. Treatment options vary, ranging from rituximab alone to more intricate and complex combinations like R-hyper C-VAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine) (41). The consideration of radiotherapy as a treatment option is typically reserved for instances of very low-stage lymphomas that exhibit localized characteristics and can be easily targeted. For example, this approach may be appropriate for early-stage follicular lymphoma, as indicated in the NICE guidelines (42). Treatment guidelines for squamous cell carcinoma or adenocarcinoma of the cervix recommend surgery in cases where the disease is at an early stage (43). In our study the overall survival was not significantly different in patients treated with chemotherapy alone. It is possible that chemotherapy alone represents a safe treatment option for younger premenopausal patients diagnosed at an early stage who wish to retain their fertility. Del Valle-Rubido et al published the only case included in this study where the patient received fertility-sparing management; a 28-year-old woman received ‘CHOP’ chemotherapy, after transplantation of the ovaries; this patient went on to survive at least 10 years and was still alive at the time of writing (9). However, the results of our analysis in this study, including the lack of difference in survival between management options, should be interpreted with caution considering the potential limitations associated with the analysis including the low number of patients, the heterogeneity between the included studies and the scarcity of events.

To the best of our knowledge, our study is the most comprehensive review on the reported cases of PLUC. Our findings present pooled data from 328 patients and highlight published data with quality assessment of included studies.

However, several limitations should be acknowledged. The inclusion of low-quality case reports and case series limits the validity and generalizability of our conclusions. These studies inherently carry a significant risk of bias, being particularly susceptible to overinterpretation and selection bias. Although many of the studies were rated as low risk of bias according to our assessment tool, their fundamental design flaws make them prone to publication bias, especially since negative findings are rarely reported. Consequently, the data presented, while potentially insightful, may not accurately reflect real-world outcomes. Additionally, although this study identifies various subtypes of PLUC, the limited data available restricts our ability to thoroughly examine the treatment response and prognosis for each subtype, as also reflected in the lack of statistical power of the Kaplan-Meier graphs. Given the rarity of PLUC and its subtypes, further research is needed to understand these subtype-specific outcomes, including recurrence rates and disease-free survival, which may guide more tailored treatment strategies. Quality of life metrics are also essential for providing insight into the impact of PLUC treatments in the long-term. Therefore, data from larger, prospectively designed studies are essential for drawing more reliable conclusions about optimizing diagnostic and therapeutic strategies for patients with PLUC.

A further limitation in the classification of PLUC arises from the concurrent use of the Ann Arbor staging system, which is traditionally used for lymphomas, and the FIGO staging system, which is applied to cervical cancers. The use of these two distinct staging systems can create inconsistencies and challenges in classification, which may impact treatment decisions and hinder efforts to further develop comparative studies. Developing a unified staging system specifically tailored to PLUC could improve clarity in both clinical practice and research, allowing for a more standardized approach to diagnosis and treatment planning.

Another notable limitation is our inability to estimate the effect size of outcomes and quantify uncertainty. It is noteworthy that a majority of clinical cases lack sufficient information for concentrating study results into a mean, median, or proportion with a confidence interval. This underscores the significance of initiatives aimed at standardizing and enhancing the quality of information reported in case reports. Overall, a pooled integrated analysis of case reports and series cannot replace evidence provided by clinical trials. Therefore, subject recruitment in rare diseases and personalized medicine represents a critical task in clinical research (40,41,43,44).

Finally, the conclusions drawn from our integrated analysis are inevitably constrained by the small number of patients included, the difficulty to assess homogeneity between studies and the inherent rarity of the events under investigation. Statistical significance is typically determined by observing patterns or outcomes that are unlikely to occur by chance alone (45). However, in the context of rare events, the occurrence itself is infrequent, making traditional measures of statistical analysis and significance less applicable. The late crossover of survival curves observed in some of the supplementary sensitivity analyses highlights a statistical manifestation of this key limitation. Overall, the scarcity of events can lead to challenges in sample size, limiting the statistical power to detect meaningful differences or associations (46–47).

In conclusion, malignant lymphomas can arise at unconventional anatomical sites. In the cervix uteri, the tumor appearance can vary and thus may be misdiagnosed with a primary epithelial malignancy. Although primary malignant lymphomas of the uterine cervix are infrequent, early detection, optimal therapeutic management, and multidisciplinary involvement may provide benefits to patients developing the disease. The knowledge of the rare occurrence of malignant lymphoma in the cervix, its unique characteristics and the increased awareness of clinicians can prevent clinical misdiagnoses and ultimately improve the clinical outcomes of patients developing this uncommon disease. While evidence on this condition remains limited, leveraging international registries could significantly strengthen the body of knowledge surrounding this rare malignancy.