Gynecologic Tract Lymphomas: A Clinicopathological Analysis of a Single Institution Case Series

Abstract

Background

Lymphomas involving gynecologic organs often occur in the ovaries, and uterine cervix. Uterine corpus, vagina, and vulva are less common locations involved. Although female genital tract lymphomas are uncommon, it is important for the gynecologists and pathologists to be aware of this entity as it potentially could be the first presenting location of lymphoma or involved secondarily.

Methods

Pathology of lymphomas first diagnosed in and secondarily involving gynecologic organs from January 2005 to January 2024 were retrieved from our institution's pathology databases, and their clinicopathological features were reviewed.

Results

A total of 19 patients with lymphomas involving the gynecological organs were identified with 17 patients being first-time diagnosed with lymphomas on gynecologic surgical pathology specimens and 2 patients with prior history of lymphoma. The average age of patients with lymphoma diagnosed initially in the gynecologic tract was 59.2 years (range 20-83 years). The two patients with prior lymphoma histories had diffuse large B-cell lymphomas (DLBCL) with one transformed from prior retroperitoneal low-grade follicular lymphoma. The cervix was the most frequent location of first-time diagnosed lymphomas, comprising 8 of 17 specimens (47%), followed by bilateral ovaries and fallopian tubes (41%), endomyometrium (12%), and vagina (6%). The types of first diagnosed gynecologic lymphomas were DLBCL (65%), follicular lymphoma (18%), lymphoplasmacytic lymphoma (6%), Burkitt lymphoma (6%) and extranodal marginal zone B-cell lymphoma (MZBCL) (6%). When the criteria of defining primary gynecologic lymphomas were applied, 7 of 17 first-time diagnosed lymphomas in the gynecologic tract were actually primary gynecologic lymphomas without distant disease, peripheral blood or bone marrow involvement, including 5 cervical primary, one endometrial primary and one vaginal primary lymphoma.

Conclusion

Our study confirmed that the most common lymphomas involving the gynecologic tract were DLBCL and follicular lymphoma, with rare incidence of Burkitt lymphoma, extranodal MZBCL and lymphoplasmacytic lymphoma. Misdiagnosing gynecologic lymphomas as high-grade/undifferentiated carcinoma or sarcoma is a real risk for surgical pathologist, especially during frozen sections.

Keywords

primary gynecologic lymphoma secondary gynecologic lymphoma lymphoma of ovary lymphoma of uterus lymphoma of vagina

Introduction

Non-Hodgkin lymphomas (NHL) are common hematological malignancies which can arise from lymph nodes (nodal) or lymphatic cells located in solid organs (extranodal). Extranodal lymphomas account for about 25% to 35% of all NHL lymphomas. Primary extranodal NHL lymphomas most commonly arise in the gastrointestinal tract (30-40%), followed by the skin (10%) and the central nervous system (2-4%).¹ Primary lymphomas of female reproductive tract are extremely rare, representing only 0.2 to 1.1% of extra-nodal NHL.² The most common lymphomas that can involve gynecologic tract included diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Burkitt lymphoma according to published studies.³ Lymphomas involving gynecologic organs often occurred in the ovaries, and uterine cervix, with uterine corpus, vagina, and vulva as less common locations.³ Patients with early-stage lymphomas are often asymptomatic, and common symptoms of advanced diseases included vaginal bleeding or discharge, abdominal pain, distension, and pelvic pain.⁴ In clinical practice, patients with gynecologic lymphomas usually seek medical attention to their primary gynecologists which can lead to misdiagnosis and treated as gynecologic epithelial or mesenchymal malignancies. Cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone with rituximab is the most used chemotherapy regimen for gynecologic lymphomas, which completely differs from treatment regimens for other gynecological malignancies. Therefore, it is important to establish the diagnosis of gynecologic lymphomas early and to distinguish from gynecologic primary epithelial and mesenchymal neoplasms.

To expand our current knowledge in the characteristics of gynecologic lymphomas, we conducted this retrospective study to review the clinicopathologic features of primary and secondary lymphomas of the gynecologic tract.

Materials and Methods

Study Population

After obtaining the Institutional Review Board's approval, we conducted a retrospective study of patients with lymphomas diagnosed in the gynecologic organs, including bilateral ovaries, fallopian tubes, myometrium, endometrium, cervix, and vagina. The patients included in the study were diagnosed between January 2005 and January 2024 at Rush University Medical Center in Chicago, USA. A total of 19 patients were identified and studied for their clinicopathological features.

Study Design

The study group was identified in our institutional electronic surgical pathology archives based on Systematized Nomenclature of Medicine-Clinical Terms (SNOMED) code search in CoPath Plus (Cerner Corporation, North Kansas, USA). Clinical and pathologic materials were reviewed by two pathologists. All relevant clinical information including age, past medical history, surgery records, histopathologic and cytopathology results were retrieved from patients’ electronic medical records in EPIC (Epic Systems Corporation, Madison, USA). Histology slides were prepared with hematoxylin and eosin stain. Intraoperative touch-prep and cytology smears were prepared using air-dry method and with Diff-Quik stain.

Statistics

Frequencies and percentages were calculated for categorical variables. χ² analysis was used to compare the association between categorical variables and outcomes. The continuous variables were compared with unpaired t-test. A P-value < .05 was considered significant and all statistical analyses were conducted using GraphPad Prism 7 (GraphPad Software, San Diego, USA).

Results

A total of 19 patients with lymphomas involving the gynecological organs were identified with an average age of 61.2 years. In total, 17 of 19 (90%) patients were first-time diagnosed with lymphoma on gynecologic surgical pathology specimens and had no prior history of lymphoma. The average age of first-time lymphoma patients was 59.2 years (range 20-83 years). Two of 19 patients had prior known history of lymphoma and now presented with recurrence/spread to gynecologic organs (11%). The average age of patients with prior lymphoma history was 78.5 years and appeared to be older than patients with first-time lymphomas but did not reach statistical significance (P = .085). One patient had prior history of retroperitoneal Grade 1 follicular lymphoma 7 years ago which was treated with chemotherapy and maintenance immunotherapy. Now patient presented with abnormal uterine bleeding and enlarged uterus on imaging. Endometrial biopsy showed DLBCL, germinal center type, transformed from the patient's prior low-grade follicular lymphoma. Histologic section demonstrated fragments of endometrium with lymphoid infiltrate in a hemorrhagic background. The lymphoid infiltrate was obscured by crush artifact, however, focal area showed intermediate to large-sized atypical lymphoid cells with readily identified apoptotic bodies (Figure 1). The other patient had a history of DLBCL diagnosed on urinary bladder biopsy a year ago and was status postchemotherapy. During follow-up, patient presented with a left adnexal mass on PET-CT imaging. Bilateral salpingo-oophorectomy was performed and final pathology showed DLBCL, nongerminal center type involving the left ovary.

Cervix was the most frequent location of first-time diagnosed lymphomas in gynecologic system, comprising 8 of 17 first-time diagnosed patients in our study (47%) (Table 1). The lymphomas arising in the cervix included five DLBCLs including three germinal center subtypes and two unknown subtypes, two Grade 1 follicular lymphomas and one lymphoplasmacytic lymphoma. Four of eight patients were symptomatic with two having vaginal bleeding and two patients with pelvic pain or distension. Three patients were found with cervical mass on routine examination and one patient was incidentally diagnosed after hysterectomy for other indications. Four patients were diagnosed with lymphomas on cervical biopsies and two of four also received concurrent endometrial curettage. One of the two endometrial curettages showed endometrium involvement by cervical follicular lymphoma. The rest of the patients (4/8) with cervical lymphomas were diagnosed on hysterectomy specimens. One of the four lymphomas diagnosed on hysterectomy involved multiple gynecologic sites, including bilateral ovaries, fallopian tubes, myometrium and peritoneal mesentery tissue (DLBCL). Elevated serum CA-125 level was present in this patient. The histology of cervical lymphoplasmacytic lymphoma showed a dense infiltrate of small lymphocytes within the deep cervical stroma. Occasional plasmacytoid cells were present. The lymphocytes were positive for CD20, BCL2 and negative for CD10, CD3, and CD5, ruling out other mature B-cell lymphomas. In total, six cervical lymphomas were limited to the uterine cervix and the other two involved more than one gynecologic site. When the criteria of defining primary gynecologic lymphomas were applied, five of eight lymphomas were considered primary gynecologic lymphomas with no distant involvement or lymphoma cells in peripheral blood or bone marrow. Three of eight patients were considered to have systemic lymphomas with two tumors showing bone marrow infiltrates on follow-up bone marrow biopsies and one patient had concurrent mesentery lymphoma deposit.

Table 1.

Lymphomas First Diagnosed in the Gynecologic Tract and Secondary Lymphomas in Gynecologic Organs.

Lymphomas first diagnosed in the gynecologic tract			17/19
	Uterine cervix
		DLBCL	5/8
		Follicular lymphoma	2/8
		Lymphoplasmacytic lymphoma	1/8
	Ovary and fallopian tube
		DLBCL	5/7
		Follicular lymphoma	1/7
		Burkitt lymphoma	1/7
	Endometrium
		Extranodal marginal zone B-cell lymphoma, MALT type	1/1
	Myometrium
		DLBCL	1/1
	Vagina
		DLBCL	1/1
Secondary lymphomas involving gynecologic organs			2/19
		DLBCL	2/2

Abbreviations: DLBCL, diffuse large B-cell lymphoma; MALT, mucosa-associated lymphoid tissue.

Bilateral ovaries and fallopian tubes were the second most common locations of first-time diagnosed lymphomas in the gynecologic tract, comprising 7 of 17 patients (41%). The lymphomas involving adnexal tissue were all high-grade lymphomas including 5 DLBCLs with two germinal center subtypes, two unknown subtypes and one DLBCL transformed from high-grade follicular lymphoma (Table 2). Other high-grade lymphomas were one Grade 3a follicular lymphoma and one Burkitt lymphoma. All seven patients initially presented with pelvic pain or abdominal distension and were found to have a pelvic mass on imaging. Four patients were diagnosed on hysterectomy with bilateral salpingo-oophorectomy, two patients received salpingo-oophorectomy only and one was diagnosed on ovarian mass biopsy. The histology of Burkitt lymphoma showed medium to large-sized atypical lymphoid cells completely replacing normal ovarian tissue. The malignant cells had large nuclei, coarse nuclear outlines, vesicular chromatin, multiple distinct nucleoli, and scant basophilic cytoplasm. Numerous mitoses and apoptotic bodies were present, reflected in a “starry-sky” pattern. On the touch preps, a rim of basophilic cytoplasm was easily appreciated, and many cells showed cytoplasmic vacuoles. Ki67 mitotic index was more than 90%, compatible with Burkitt lymphoma (Figure 2). The histology of a Grade 3a follicular lymphoma showed CD20+ neoplastic nodular infiltrate of medium-sized cleaved cells with scant cytoplasm (centrocytes) and larger intermixed cells with vesicular chromatin and round to oval nuclei (centroblasts) with focal distinct diffuse component (Figure 3). Because of the high-grade nature of ovarian lymphomas, they frequently involved adjacent uterine bodies (4/7 patients), (Figure 4) adjacent lower gastrointestinal tract (5/7 patients), pelvic lymph nodes (2/7 patients) and even spread to omentum and mesentery tissue in 5 of 7 patients. Serum CA-125 level was elevated in 3 of 4 patients with available CA-125 test results. Only one lymphoma was limited to the ovary without involvement of extraovarian tissue. Interestingly, none of the seven first-time diagnosed ovarian lymphomas were considered primary gynecologic lymphoma when the criterias were applied. Three tumors showed mesentery tissue involvement, two lymphomas involved omental tissue, and one lesion showed adjacent colon involvement. In addition, one patient showed bone marrow lymphoma infiltrates on following-up bone marrow biopsy. As a result, all seven first-time diagnosed ovarian lymphomas were considered systemic disease with gynecologic organ involvement. Ovarian high-grade lymphomas need to be distinguished from high-grade serous carcinoma, solid pattern adult granulosa cell tumor, poorly differentiated neuroendocrine carcinoma with small cell morphology, ovarian small cell carcinoma of hypercalcemic type, intra-abdominal desmoplastic small round cell tumor, Ewing sarcoma, and malignant germ cell tumors, such as yolk sac tumor. A panel of immunostaining markers, such as keratin, PAX8, EMA, FOXL2, WT1, Synaptophysin, Chromogranin, INSM1, CD3, CD20, FLI1, ERG and SALL4 can usually help narrow the scope of differential diagnoses.

Table 2.

Types of Lymphomas First Diagnosed in the Gynecologic Tract.

Lymphomas first diagnosed in the gynecologic tract		17 patients
DLBCL		11/17
	Germinal center type	5/11
	Nongerminal center type	1/11
	Transformed from follicular lymphoma	1/11
	Not subtyped	4/11
Follicular lymphoma		3/17
	Grade 1	2/3
	Grade 3	1/3
Burkitt lymphoma		1/17
Lymphoplasmacytic lymphoma		1/17
Extranodal marginal zone B-cell lymphoma, MALT type		1/17

Abbreviations: DLBCL, diffuse large B-cell lymphoma; MALT, mucosa-associated lymphoid tissue.

Endometrium and myometrium were rarely involved in gynecologic lymphomas, only 2 of 17 (12%) patients. One patient initially presented with nausea, vomiting, and fatigue. Imaging study found a uterine mass and patient received hysterectomy. Final pathology revealed a high-grade malignant neoplasm involving the myometrium and uterine serosa. The tumor featured large cells with multiple prominent nucleoli and brisk mitoses, many of which were atypical. CD20 immunostain was diffusely positive with only focal CD3 positivity, compatible with DLBCL (Figure 5). The patient with endometrial lymphoma had a history of vaginal prolapse for which she underwent a hysterectomy and sacrocolpopexy. On the hysterectomy specimen, she was incidentally noted to have a clonal lymphocytic infiltrate limited to an endometrial polyp. On immunostains, the clonal lymphoid infiltrate was positive for CD20, CD43, and negative for CD5 and Cyclin D1. CD21 highlighted reactive follicular dendritic cell meshwork. The immunoprofile was consistent with extranodal marginal zone B-cell lymphoma (MZBCL), mucosa-associated lymphoid tissue (MALT) type. The patient with DLBCL showed bone marrow infiltrates on follow-up bone marrow biopsy and considered systemic disease with myometrium involvement. The MZBCL was considered primary gynecologic lymphoma with no distant or marrow disease. Lymphoma first diagnosed in vagina was only seen in one patient (5.8%) who initially sought medical attention for vaginal discharge and growing vaginal lump. Vaginal biopsy revealed high-grade malignant neoplasm positive for CD20, CD10, BCL-6, BCL2, MUM1 and negative for keratin 8/18, AE1/AE3 and Epstein-Barr encoding region (EBER) in situ hybridization, compatible with DLBCL germinal center type (Figure 6). The lymphoma showed no distant involvement or peripheral blood or marrow disease and was considered primary gynecologic lymphoma.

In total, 7 of 17 first-time diagnosed lymphomas in the gynecologic tract were primary gynecologic lymphomas without distant disease, peripheral blood or bone marrow involvement, including five cervical primary, one endometrial primary and one vaginal primary lymphoma. The types of primary gynecologic lymphomas included four DLBCLs, two follicular lymphomas and one MZBCL. Interestingly, all the ovarian lymphomas were systemic disease with ovarian involvement, but patients presented with pelvic mass on initial clinical encounter with no prior history of lymphoma (Table 3). To summarize, 2 of 19 patients with lymphomas in gynecologic organs in our study had prior history of systemic lymphomas (11%) and 17 of 19 patients were first-time diagnosed with lymphomas (90%). Among patients with first-time diagnosed lymphomas, about 41% (7/17) were primary gynecologic lymphomas and about 59% (10/17) were gynecologic presentation of systemic disease with either bone marrow or distant organ involvement.

Table 3.

Primary Gynecologic Lymphomas with no Distant, Peripheral Blood or Bone Marrow Involvement.

		7/17
Uterine cervix
	DLBCL	3/5
	Follicular lymphoma	2/5
Endometrium
	Extranodal marginal zone B-cell lymphoma, MALT type	1/1
Vagina
	DLBCL	1/1

Abbreviations: DLBCL, diffuse large B-cell lymphoma; MALT, mucosa-associated lymphoid tissue.

Discussion

Definition of primary lymphomas of the female reproductive tract has been a subject of controversy for years. It is a challenge to distinguish between primary gynecologic lymphomas and systemic lymphomas involving gynecologic organs, especially in patients with both nodal and extranodal involvement. Several diagnostic criteria have been proposed to define gynecologic primary lymphomas. They include tumor confined to gynecologic organs and regional lymph nodes, absence of tumor cells in the peripheral blood or bone marrow, and a long interval between the primary gynecologic lymphoma and distant involvement.^5,6 Since the treatment regimen for primary gynecologic lymphomas is similar to that for systemic lymphoma, the diagnosis of primary lymphoma carries more prognostic value than treatment value, since primary gynecologic lymphomas are more likely to be early-stage diseases. As the focus of our study was on the initial diagnosis of gynecologic lymphomas on surgical pathology specimens, we also introduced the term lymphomas first diagnosed in gynecologic organs alongside of primary gynecologic lymphomas which require further investigation of peripheral blood, bone marrow histology and absence of distant organ involvement. A study on lymphomas detected in the female reproductive tract from the Kiel Lymphoma Registry showed that 37% of lymphomas were gynecologic presentation of systemic disease while 63% were primary gynecologic lymphomas.⁷ In the current study, about 41% of first-time diagnosed lymphomas were primary gynecologic lymphomas and about 59% were gynecologic presentation of systemic disease with either bone marrow or distant organ involvement. Possible explanations for our observed lower percentage of primary gynecologic lymphomas, 41% versus 63% in Kiel Lymphoma Registry, include relatively smaller sample size compared to Kiel registry (19 patients vs 186 patients) and increased awareness of systemic lymphomas involving gynecologic organs among clinicians which lead to earlier diagnoses of systemic disease with bone marrow biopsy or imaging guided biopsy of peritoneal mass/nodules. Previous literature reported that the onset age of gynecologic primary lymphomas ranged from 20 to 80 years with a median age of 54-67.^8,9 In this study, the onset age ranged from 20 to 83 years, with an average age of 59 years. Multiple previous studies showed that ovary and cervix were the most common locations involved by gynecologic primary lymphomas, while uterus and vagina were rarely involved, consistent with our finding of 47% lymphomas in the cervix and 41% ovarian lymphomas.^10,11 As mentioned in other published studies, DLBCL was the most common gynecologic lymphoma followed by follicular lymphoma, similar to our finding of 65% DLBCLs and 18% follicular lymphomas.

Most patients in this study were postmenopausal or perimenopausal, whose age of onset was like that of other gynecologic cancers. The symptoms of gynecologic lymphomas included abnormal vaginal bleeding/discharge, abdominal distension, pelvic pain, and pelvic mass on imaging, which were very similar to cervical, endometrial or ovarian cancers as well. It was reported that patients with gynecologic lymphomas rarely presented with typical “B” symptoms of nodal NHLs, such as fever, night sweats, and weight loss.^12,13 Consequently, it is not easy to differentiate gynecologic lymphomas from other malignancies without histologic examination. Furthermore, differentiation from certain high-grade malignancies with predominantly small round cell morphology can be challenging, such as poorly differentiated/undifferentiated carcinoma, small cell neuroendocrine carcinoma and high-grade sarcomas, especially for pathologists who are not specialized in hematopathology or during intraoperative frozen sections. As a result, a definitive diagnosis of lymphoma eventually relies on other diagnostic methods such as flow cytometry, cytogenetics, immunohistochemistry, and molecular testing. In our study, intraoperative frozen section was done in 7 patients, including 5 ovarian masses, 1 cervical mass and 1 uterine mass. Six frozen sections were correctly interpreted as lymphoma at the time of intraoperative consult. One frozen section on a uterine mass was misinterpreted as undifferentiated carcinoma and the patient underwent staging surgery and tumor debulking as a result. Final pathology revealed uterine DLBCL.

The etiology and pathogenesis of cervical lymphomas remain unclear and may be related to a combination of immunodeficiency, immune escape, chronic inflammation, and HPV infection.^14,15 On imaging study, cervical lymphomas typically show bulky lesions infiltrating the cervical stroma with circumferential enlargement, submucosal, or fungating mass. Other studies on cervical lymphomas reported that the majority were DLBCL (85%) while follicular lymphoma was the second most common type, similar to our finding in this study. DLBCLs are all high-grade malignancies and may exhibit cohesive growth, marked nuclear pleomorphism, hyperchromasia, irregular nuclear contour, prominent nucleoli, mimicking high-grade carcinomas (Figure 7a). In addition, DLBCL may be difficult to differentiate from small cell neuroendocrine carcinoma, melanoma, and high-grade sarcomas. The distinction between these entities sometimes depends on careful evaluation of Diff-Quik stained smears for cytological features, such as dispersed cells, lymphoglandular bodies, and crush artifact which suggests malignant lymphoma instead of high-grade carcinoma or sarcoma. As a result, the histology, cytology smears, immunostains, and molecular studies should all be taken into consideration to achieve the final diagnosis. Cervical follicular lymphoma needs be differentiated from chronic lymphocytic cervicitis. Neoplastic follicles in follicular lymphoma usually infiltrate the deep cervical stroma and are densely compacted, while benign reactive follicles are located in the superficial cervix and loosely arranged. BCL2 immunostaining and lymphocyte clonal analysis are helpful for making a definitive diagnosis.¹⁶ Occasionally, follicular lymphoma may not display clear follicular nodularity, instead shows small clusters of mature appearing small lymphoid cells in a sclerotic cervical stroma as shown in our cervical lesion (Figure 7b). Lymphoma-like lesions, also called florid-reactive lymphoid hyperplasia, is a major differential diagnosis to lymphoplasmacytic lymphoma. It was reported in one study that lymphoplasmacytic lymphoma was usually restricted to the lower gynecologic tract and occurred in women over 60 years of age.⁷ The patient with lymphoplasmacytic lymphoma in our study was 58 years old at the time of diagnosis. The histology of lymphoma-like lesion usually shows a polymorphous infiltrate of large and small lymphoid cells, including immunoblasts mixed with plasma cells and neutrophils. Immunostaining reveals a mixture of B-cells, T-cells, and polytypic plasma cells. The prognosis of cervical primary lymphomas is reported to be poorer than that of the more common nodal lymphomas.¹⁷

In this study, the lymphomas first diagnosed in the ovaries were DLBCL (71%), a Grade 3a follicular lymphoma (1/7 patients) and Burkitt lymphoma (1/7 patients). Burkitt lymphoma is a malignant lymphoma associated with the translocation between MYC and immunoglobulin heavy (IGH) locus (in 80% of tumors), with the most common variant t(8;14)(q24;q32) or, less commonly, to the immunoglobulin lambda (IGL) locus and immunoglobulin kappa (IGK) locus by the t(8;22)(q24;q11) and t(2;8)(q12;q24) translocations, resulting in constitutive MYC expression. Burkitt lymphomas are subtyped into EBV-associated Burkitt lymphoma and EBV-negative Burkitt lymphoma by the latest fifth edition WHO classification of hematolymphoid tumors.¹⁸ The traditional subtypes of endemic (Epstein-Barr virus related), sporadic (in young adults) and immunodeficiency-associated (related to HIV, organ transplant or primary immunodeficiency) are no longer recommended. The traditional sporadic subtype is more likely to be found in the abdominal cavity and soft tissue, including ovary, testis, and breast.¹⁸ The patient with ovarian Burkitt lymphoma in our study was 20 years old and negative for EBER, HIV or immunodeficiency, suggestive of the traditional sporadic subtype/EBV-negative Burkitt lymphoma. The histology of Burkitt lymphoma showed monotonous infiltrate of medium-sized blastic cells with round nuclei, clumped chromatin, and multiple conspicuous nucleoli. Numerous mitotic figures and macrophages containing apoptotic bodies were readily identified, reminiscent of a “starry-sky” pattern. Immunostains showed positivity for CD20, CD10, negative BCL2, and high Ki67 index (more than 90%). Burkitt lymphoma is a rapidly progressive disease with an aggressive clinical course. High-risk factors include higher stage, bone marrow infiltration, cerebral manifestation, elevated lactate dehydrogenase (LDH) or tumor mass greater than 10 cm.¹⁹ In addition, women with Burkitt lymphoma were reported to be younger (median age, 30 years) than those with other lymphomas and had worse 5-year cancer-specific survival than those with DLBCL or follicular lymphoma.²⁰ Differential diagnoses to ovarian lymphomas include poorly differentiated/undifferentiated carcinoma, dysgerminoma, small cell neuroendocrine carcinoma, solid pattern granulosa cell tumor, Ewing sarcoma, rhabdomyosarcoma, and desmoplastic small round cell tumor. Intraoperative frozen section evaluation of small round cell tumors is difficult and has relatively low accuracy. Careful examination of Diff-Quik-stained touch prep and smears for cytologic features, such as dispersed singly cells, lymphoglandular bodies and crush artifacts, can help rule out ovarian lymphoma and avoid unnecessary debulking and staging surgeries (Figure 8). Communication between gynecologists and pathologists during intraoperative consultation can help with the situation as well. If a pathologist can be informed of lymphoma as a potential diagnosis during the present illness, the chance of misdiagnosing ovarian lymphoma as other malignancies will be significantly reduced.

Lymphomas that could happen in endomyometrium reported by other studies were DLBCL, follicular lymphoma, extranodal MZBCL, NK/T-cell lymphoma, small lymphocytic lymphoma, and T-lymphoblastic lymphoma.²¹ In this study, we observed one DLBCL in the myometrium and one extranodal MZBCL in the endometrium. It was reported that extranodal MZBCL occurred exclusively as primary lesions in the uterine mucosa by other published study.⁷ MZBCL usually shows expansile sheets of small round to slightly irregular lymphoid cells that diffusely infiltrates the stroma. The lymphoid cells tend to spare the overlying epithelium, but there can be focal lymphoepithelial lesion. A minor population of larger cells and reactive lymphoid follicles can be seen. The neoplastic cells are usually positive for CD20, BCL2, light chain restriction and negative for CD5, CD10, BCL6, and cyclin D1. In above mentioned study, all primary lymphomas involved vagina were DLBCL, compatible with our finding in this study.²¹ In their study, 50% of patients presented with vaginal bleeding. Pelvic examination usually found a mass that involved the vagina with a bulky pelvic distribution, including multiple other contiguous nonvaginal structures. Uterine and vaginal high-grade lymphomas need to be distinguished from basaloid squamous cell carcinoma, poorly differentiated neuroendocrine carcinoma with small cell morphology, rhabdomyosarcoma and malignant germ cell tumors, such as yolk sac tumor. A panel of immunostaining markers, such as keratin AE1/AE3, p63, p16, synaptophysin, chromogranin, INSM1, CD3, CD20, Desmin, Myogenin, and SALL4 can usually help narrow the scope of differential diagnoses. Prognostic factors for uterine and vaginal lymphomas include stage at diagnosis which is the most critical predictor of outcome. Early-stage lesions tend to have significantly better prognosis. Histologic subtypes also matter in term of prognosis. DLBCL is most common in vaginal lymphomas which tend to be more aggressive but still respond well to treatment. The primary vaginal lymphomas were reported to have a five-year survival rate of 80% to 90% if the diagnosis was made early and therapy was adequate.²² The five-year survival rate was reported to be about 83% for low-stage primary uterine lymphomas.²³ However, outcomes became less favorable when uterine lymphomas were diagnosed at advanced stages with reported three-year survival of 57.9%.²⁴ No lymphoma involving vulva was found in our study. According to published study, lymphomas involving vulva included DLBCL, mycosis fungoides (MF) and peripheral T-cell lymphoma. Interestingly, the incidence of DLBCL was significantly higher than MF in their study, raising the possibility of bias in the selection of biopsy sites since MF often involved many other accessible skin sites that were more likely to be biopsied.²¹

In conclusion, our study confirmed that the most common lymphomas involving the gynecologic tract were DLBCL and follicular lymphomas (both low grade and high grade). Other rare lymphomas included Burkitt lymphoma, extranodal MZBCL and lymphoplasmacytic lymphoma. Some of these rare gynecologic lymphomas appeared to be site-specific, such as Burkitt lymphoma in the ovary and extranodal MZBCL in the uterus.²⁰ Misdiagnosing gynecologic lymphomas as high-grade/undifferentiated carcinoma or sarcoma is a real risk for surgical pathologists, especially during intraoperative frozen sections. An unfortunate misdiagnosis can cause harm to the patients since the treatment regimens for gynecologic lymphomas are completely different from those for carcinomas and sarcomas. Unnecessary tumor staging and debulking procedure can cause trauma to patients as well because of misinterpreted frozen section result.

Supplemental Material

sj-pdf-1-ijs-10.1177_10668969251362445 - Supplemental material for Gynecologic Tract Lymphomas: A Clinicopathological Analysis of a Single Institution Case Series

Supplemental material, sj-pdf-1-ijs-10.1177_10668969251362445 for Gynecologic Tract Lymphomas: A Clinicopathological Analysis of a Single Institution Case Series by Melika Forooshani, MD, John Findley, MD, Lucas Yan, Ruonan Zhang, MD, Summer Dewdneym, MD, Andras Ladanyi, MD and Lei Yan, MD in International Journal of Surgical Pathology

Footnotes

ORCID iD

Lei Yan

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental Material

Supplemental material for this article is available online.

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