The present state of primary ovarian lymphoma: a case report and twenty years of analysis

doi:10.21203/rs.3.rs-4170305/v1

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Case Report

The present state of primary ovarian lymphoma: a case report and twenty years of analysis

https://doi.org/10.21203/rs.3.rs-4170305/v1

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Objective

To analyze the clinical and imaging characteristics of primary ovarian lymphoma (POL) from the perspective of radiologists.

Materials and Methods

The clinical and imaging data of a 52-year-old patient diagnosed with POL was retrospectively analyzed in this study. A review and summary of similar cases reported in English over the past twenty years, as available in the PubMed database, were also conducted.

Results

The occurrence of POL is not limited by age but is more commonly observed in the forties years old. Clinical manifestations of POL are often nonspecific, presenting as an abdominal mass, abdominal pain, and ascites. The most prevalent histological subtype of POL is diffuse large B cell lymphoma. Imaging features are helpful for diagnosis, such as “ovarian retention sign”, “large ovaries touching each other”, and “vascular floatation”.

Conclusion

Imaging plays a crucial role in the diagnosis of POL, with radiologists serving as a pivotal role in furnishing essential diagnostic data to assist clinicians in devising suitable treatment strategies, preventing unnecessary surgical interventions.

Primary ovarian lymphoma

imaging features

diffuse large B cell lymphoma

Primary extra-nodal non-Hodgkin lymphoma in the female genital system is a rare disease, accounting for 0.5% of NHL and 1.5% of all ovary neoplasms^[1]. Due to its non-specific presentations, it can often be mistaken for other ovarian neoplasms, leading to potential delays in diagnosis or misdiagnosis. The definitive diagnosis of primary extra-nodal non-Hodgkin lymphoma mainly relies on pathological^[2] and immunohistochemical analysis. Despite the challenges posed by ambiguous clinical and imaging features, this study aims to enhance comprehension and awareness of POL by the case report and reviewing similar cases documented in existing literature.

The study was approved by the ethics committee of our hospital (approval NO: K2023068). The requirement for written informed consent was waived.

Case report

A 52-year-old woman, presented with intermittent abdominal pain of unknown etiology, and a protuberant mass resembling an egg at the left lower abdomen that can be spontaneously touched by herself since July 2022. The mass exhibited progressive growth over one month, extending to encompass the entire lower abdomen. Subsequently, the patient presented at our institution seeking further medical intervention. The ultrasound suggested a solid cystic mass measuring 13.88×10.36×11.45 cm was identified in the pelvic cavity, which had a clear boundary and regular shape, and a blood flow signal could be seen inside (Fig. 1A). An unenhanced computed tomography (CT) scan of the abdomen, revealed a soft tissue density mass with non-uniform internal density measuring approximately 13.5×10.3 cm in its largest cross-section, along with pelvic effusion (Fig. 1B). Throughout the course of the illness, the patient exhibited symptoms of insomnia, decreased appetite, and a weight loss of 5 kg.

Previous surgical history included an abdominal subtotal hysterectomy for adenomyosis in 2014.

The laboratory examination revealed elevated Lactate dehydrogenase (LDH) of 1800 U/L (normal range: 120-250 U/L), as well as neuron-specific enolase (NSE) of 82.88ng/ml, Cytokeratin-19-fragment (CYFRA21-1) of 2.37ng/ml, and CA125 at 198.04 u/ml (Table 1). Other laboratory tests were normal.

Table 1

Review of the laboratory test data of case one.
	Preoperative	Postoperative immediately	F/U 6 months	F/U 1 year	Reference
CA-125 (U/mL)	198.04↑		9.18	9	< 24.0
CYFRA21-1 (ng/mL)	2.37↑		1.84	7.3	< 2.08
NSE (ng/mL)	82.88↑		15.09	12.55	< 25.00
LDH (U/L)	1800↑	328↑	191	160	120–250
D-Dimer (mg/L)	4.72↑	2.41↑	1.04↑	0.12	<0.5
hypersensitive C-reactive protein，hs-CRP (mg/L)	8.9↑	73↑	0.4	0.8	0–3
Abbreviations: CA-125, carbohydrate antigen 125; CYFRA21-1, cytokeratins 19 fragment antigen21-1; NSE, neuron specific enolase; LDH, lactate dehydrogenase; CRP, C-reactive protein; F/U, follow-up.

Abdominal pelvic MRI scans revealed a solid soft tissue mass with heterogeneous signal, as well as marginal cystic water signal shadows in the pelvic cavity, displaying slightly isointense signal on T1WI, mixed isointense to high signal on T2WI, and heterogeneous high signal on DWI with varying low signal on ADC, the mean ADC value of the lesion was 1.868×10^-3 mm²/s (Fig.1C-E). The right ovarian was enlarged significantly, resulting in the physical contact between two ovaries within the body, ies contact each other due to enlargement, which was called “large ovaries touching each other”.

Enhanced MRI demonstrated moderate delayed enhancement of the lesion. Meanwhile, the arterial phase indicated that the tumor artery originated from the internal iliac artery, and the blood vessels normally walked within the tumor, referred to as “vascular floatation”. The delayed phase showed that he right ovarian vein appeared thickened and tortuous, with an indistinct boundary with the lesion. Small lymph nodes and pelvic effusion were also observed in the pelvis. (Fig.1F、G).

The surgical operation was conducted with the patient's informed consent. The surgical procedure disclosed an enlargement of the right ovary by a diameter of 14cm, adhering to the right bladder and pelvic wall.

The resection tissues were then pathologically examined and subsequently tested with hematoxylin-eosin (H&E) and immunohistochemical (IHC) staining techniques. Notably, no tumor cell was detected in the left ovary and fallopian tube. The IHC results of the tumor tissues in the right ovary revealed positive expression of CD19, CD20, CD45, CD79a, Bcl-6, Bcl-2, MUM-1, INI-1, and Brg-1. The positivity rates of C-Myc, P53, and Ki-67 were 20%, 80%, and over 90% respectively.

Through analysis of the pathological examination, researchers identified the tumor as high-grade aggressive malignant B-cell lymphoma, namely diffuse large B-cell lymphoma (DLBCL), which could be classified into two subtypes: germinal center B-cell-like (GCB) and non-GCB, distinguished by the expression of immune markers CD10, BCL-6, and MUM-1. Combined with the Hans classification and IHC results, the definitive pathological diagnosis of the case was DLBCL (GCB subtype) with a better prognosis than DLBCL (non-GCB subtype)^[3].

After surgery, the patient was treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, resulting in complete remission. Now the patient was discharged and followed up.

Literature Review

In order to achieve a thorough comprehension of POL from diverse viewpoints, we have synthesized the characteristics of patients reported in the last twenty years, focusing solely on English language literature available on PubMed. Cases were classified as POL if the initial site of disease presentation was the ovary, with the exclusion of patients presenting with evidence of disseminated disease^[4].

We researched 56 cases of POL documented in the literature over the preceding two decades. The predominant subtype was DLBCL (n=41), followed by Burkitt lymphoma (n=7). Supplement Table 1 presents a detailed analysis of DLBCL. According to premier articles which summarized that the majority of patients of POL were relatively young, with a median age ranging from 42 to 47 years^[5,6]. In our analysis, the age ranged from 5 to 75 years, with a mean age of 42.1 years and a median of 45 years. The involvement of both ovaries in POL was common^[7]. And bilateral ovarian involvement might be indicative of an advanced stage and serve as an adverse prognostic factor^[8]. The affected ovary would enlarge with varying degrees, with the right ovary being more susceptible than the left^[1]. But in our review, 28 cases were unilateral (15 involving the left and 13 involving the right), 9 cases were bilateral and 4 cases were not mentioned.

Symptoms including fever, night sweats, and weight loss were reported in 10% to 33% of patients.^[9] The most prevalent symptom was abdominal pain, followed by abdominal distension, fatigue, irregular menstrual cycles, constipation, and frequent urination. A majority of patients exhibited B symptoms. The identified neoplasms generally exhibited a size exceeding 10 cm, manifesting as either an abdominal mass or an enlarged ovarian. Elevated levels of LDH and CA 125 were frequently observed, aiding in the diagnostic process and subsequent monitoring^[10]. Other laboratory parameters and tumor markers generally were normal.

In reviewing cases, the imaging performance of POL was simple, only described as enhancement with uneven dense/signal abdominal mass, sometimes accompanied by ascites. In our case, we would elaborate in detail on the imaging findings of POL. Most of the cases underwent surgical resection and chemotherapy, but debulking of the tumor was not considered to be related to good prognosis^[11]. CD20 and LCA were frequently positive in POLs. Fox et al. reported a mean survival time of 60 months for Ann Arbor Stage IIE POL^[12], with one patient even surviving for over 7 years.

Until now, the lack of lymphoid tissue in normal ovaries has contributed to a lack of consensus regarding the tissue origin and pathogenesis of POL^[10]. Some researchers hypothesize that chronic inflammatory stimulation of the ovary may play a role in the development of POLs, while others speculate that the lesions may arise from the lymphoid component of teratomas or malignant transformation of primitive reticular cells in the ovarian stroma^[6,13]. In their investigation of 37 oophorectomy specimens, Skodras et al. confirmed the presence of scattered lymphocytes and small lymphoid aggregates through IHC analysis. ^[14]

In this case, the patient underwent a comprehensive series of examinations, yielding valuable information that may help other radiologists in the future. To our best knowledge, whether using CT or MRI, the imaging presentations of POLs were lack of specificity. Radiologists need to be careful and familiar with subtle imaging findings.

Upon review of prior cases, as Ferrozzi et al^[15]described in their review, POLs typically manifest as a huge solid mass, with heterogeneous enhancement on contrast-enhanced CT. When using MRI, POL is more likely to be presented as homogeneous high signal intensity on T2WI than other ovarian solid tumors^[16,17] . Furthermore, the presence of ovarian retention sign, large ovaries touching each other and vascular floatation, are significant distinguishing features of POL. Although the characteristic called vascular floatationa can also observed in lymphomas occurring in other anatomical locations^[18].

Enlargement of the ovary with preserved architecture and peripheral cysts may also indicate the presence of ovarian torsion. However, this manifestation is typically unilateral and is commonly accompanied by severe pain.

Although our case presented with all three of these distinguishing imaging features, our radiologist still made a misdiagnosis, suspecting it was a fibrogenic tumor. If solid masses involve bilateral ovaries, with the key radiologic features described above, POL should be considered in the differential diagnosis, especially when patients have certain acquired conditions, such as rheumatoid arthritis and AIDS^[12,19–21].

POL presents with common symptoms such as abdominal pain, distention, and ascites, which are comparable to those seen in ovarian cancer^[9]. This similarity poses a challenge in accurately diagnosing POL as it can mimic other ovarian entities. Unlike other ovarian neoplasms that typically require surgical intervention, POL can be effectively treated with chemotherapy^[14]. Therefore, it is crucial to differentiate POL from ovarian neoplasms of interstitial origin to provide appropriate treatment.

In instances of bilateral solid ovarian tumors, it is imperative to distinguish them from metastatic carcinoma by judiciously integrating the patient's clinical background. When tumors occur unilaterally in the ovaries, other ovarian neoplasms need to be distinguished from the following:

1. Secondary ovarian lymphoma

The first consideration for differential diagnosis is lymphoma with secondary ovarian involvement, as POL exhibits a higher 5-year survival rate than secondary lymphoma^[4,22–24]. Therefore, accurate differentiation between the two is crucial^[4]. Fox et al. have proposed the following criteria for diagnosing primary ovarian non-Hodgkin lymphoma (PONHL)^[25]: (1) At the time of diagnosis, the lymphoma is clinically confined to the ovary and a complete investigation fails to reveal evidence of lymphoma elsewhere. However, an ovarian lymphoma can still be considered primary if it has spread to immediately adjacent lymph nodes or structures. (2) The peripheral blood and bone marrow should not contain any abnormal cells. (3) If further lymphomatous lesions occur at sites remote from the ovary, then at least several months should have elapsed between the appearance of the ovarian and extra ovarian lesions.

Adenopathy, splenomegaly, or both would be expected in such circumstances. PET-CT^[26,27], abdominal and chest CT^[28]/MR imaging are valuable tools for determining disease stage and evaluating postoperative response.

2. Ovarian fibroma

Ovarian fibroma typically presents as a solid mass with low signal intensity on both T1WI and T2WI. The presence of cysts at the periphery is indicative of ovarian lymphoma, which is not typically observed in fibromas. Additionally, fibromas demonstrate slower growth rates compared to lymphomas, which have the fastest doubling time of any tumor^[10]. Rapid growth is a distinguishing feature more commonly associated with lymphoma than other ovarian neoplasms.

Radiologists must correlate patients' clinical history with the presence of positive staining for LCA in histological specimens to differentiate malignant lymphoma from non-lymphoid neoplasms^[29].

3. Dysgerminoma

As a type of germ cell tumor that is commonly found in the ovaries, dysgerminomas usually manifest in individuals aged 20-30 years. These tumors are predominantly solid and unilateral masses, and characteristic fibrovascular septa can be observed in most lesions^[11]. Besides, the mean ADC value in dysgerminomas (0.830 ± 0.154 × 10-3 mm²/s) is lower than POL (1.868×10-3 mm²/s). Dysgerminomas typically exhibit elevated levels of LDH and alkaline phosphatase (ALP), whereas POLs are usually associated with elevated LDH only. Lymphomas do not stain for dysgerminoma markers such as placental alkaline phosphatase (PLAP)^[20].

Limited-stage DLBC (conventionally defined as Ann Arbor stages I-II,10 cm maximum tumor dimension) is excellent with a 10-year overall survival of at least 70% to 80%[28]. However, when primary ovarian DLBCL is diagnosed late due to delays or inaccuracies in diagnosis, the prognosis is significantly worse, with a survival rate ranging from 0 to 36% [30]. In summary, as imaging plays a central role in diagnosing POL, radiologists need to accurately differentiate POL from other tumors, particularly in the early stages, to assist clinicians in developing suitable treatment strategies and enhancing patient prognoses.

Author Contribution

Wei Liu&Houyun Xu are co-first authors because they did most of the work together, including data collection and analysis, writing, and reviewing the manuscript. Jibo Hu& Junjie Zhou helped to describe the imaging of this case. Xiping Yu interpreted the pathological part. And Hongjie Hu polished the writing of this manuscript. All authors have reviewed the manuscript for submission.

Institutional Review Board Statement

The study was carried out in compliance with the 2013 revised Declaration of Helsinki and received approval from the Committee on Human Subject Research and Ethics at The Fourth Affiliated Hospital of Zhejiang University School of Medicine (Approval NO: K2023068).

Conflicts of Interest

The authors declare no conflicts of interest.

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No competing interests reported.

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The present state of primary ovarian lymphoma: a case report and twenty years of analysis

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Objective

Materials and Methods

Results

Conclusion

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INTRODUCTION

Materials and Methods

RESULT

DISCUSSION

CONCLUSION

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Author Contribution

REFERENCES

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