Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy worldwide, and the lymph nodes are the primary sites of involvement [1]. Diffuse large B-cell lymphoma (DLBCL) is a subtype of NHL that is estimated to account for approximately 30% of all NHL cases. Furthermore, it is classified into germinal center B-cell (GCB), activated B-cell (ABC), and unclassified subtypes according to the cell of origin, which can be identified by gene expression profiling [2]. Approximately 20% of all NHL cases develop outside the lymph nodes, most often in the gastrointestinal tract or skin. NHL can also occur in the female genital tract, such as the vulva, cervix, or ovaries, accounting for approximately 1.5% of all NHL cases [3]. Many physicians have difficulty diagnosing or treating vulvar DLBCL because of its extremely low prevalence; approximately 12 cases have been reported over the last two decades [4,5].

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP regimen) is the preferred regimen for vulvar DLBCL, similar to that used for common DLBCL, and localized radiation can also be administered according to each patient's condition. For the prognosis of DLBCL, the 2-year progression-free survival rate is approximately 69%, and 2-year overall survival (OS) rate is approximately 78% with the R-CHOP regimen [6].

In this article, we report a case of primary vulvar DLBCL managed with the R-CHOP regimen and localized radiation therapy. We also review the related literature for the diagnosis, treatment, and prognosis of this rare disease.

A 55-year-old woman presented with a 1-week history of a solid mass on the right side of the vulva. Pelvic magnetic resonance imaging (MRI) performed at an outside hospital demonstrated an approximately 3.3 cm, well-marginated, enhancing mass confined to the subcutaneous fat layer of the right ventral side of the vulva with surrounding subcutaneous swelling (Fig. 1). No significantly enlarged lymph nodes were observed in the inguinal region. Inflamed tissue, such as an abscess or ruptured epidermal cyst, was suspected; differential diagnoses of atypical hemangioma, lymphoma, and synovial sarcoma were also considered. The patient was referred to our hospital for further treatment. The vulvar mass was mobile, and the patient complained of slight tenderness. She was scheduled to undergo excisional biopsy at our institution on April 28, 2020. There were no specific findings on her medical history, laboratory examinations, chest radiograph, and electrocardiogram. DLBCL was diagnosed on the basis of histological examination by a pathologist. Immunohistochemical staining was positive for CD20, Mum-1 protein, C-myc, CD79a, and Ki67 LI, and negative for CD3, CD10, CD30, Bcl-2, Bcl-6, cyclin D1, and CD138. According to the Hans algorithm, the lesion was diagnosed as non-GCB subtype [7] (Fig. 2). The patient was referred to a hematologic oncologist at our institution for further management. Bone marrow aspiration and biopsy revealed normocellular marrow. There was no lymphadenopathy on the neck, chest, or abdomen by computed tomography (CT) or F-18 fluorodeoxyglucose positron emission tomography/CT, except for a reactive change in the right inguinal lymph node.

The disease stage was classified as IE according to the Ann Arbor staging classification. The patient received four cycles of chemotherapy with an R-CHOP regimen beginning on May 26, 2020: rituximab, 375 mg/m²; cyclophosphamide, 750 mg/m²; doxorubicin, 50 mg/m²; vincristine, 1.4 mg/m²; and prednisolone, 100 mg for 5 days. One month after the last chemotherapy treatment, localized radiation therapy (36 Gy in 20 fractions) was administered to the pelvic region for consolidation. She showed complete remission on CT in November 2020 and maintained this status on the latest CT scan performed in May 2022.

Few cases of primary vulvar DLBCL have been reported to date. Our case provides insight into the management of this rare disease. Table 1 shows information about the cases of primary vulvar DLBCL that have been reported previously, including the disease-free survival (DFS) rate, response to first-line treatment, and other clinical factors, such as patient age and disease stage [3-5,8-14]. No comparative studies have been conducted on the prognosis between primary vulvar DLBCL and typical DLBCL originating in the lymph nodes due to the small number of cases. According to a previous study of stage I to IV DLBCL, the GCB subtype showed a longer DFS and OS with an R-CHOP regimen than the other subtypes [8]; in particular, the ABC subtype had a significantly poor prognosis.

There are too few cases of stage IE or IIE vulvar lymphoma to evaluate prognosis, including DFS and OS. Thus, we reviewed previous reports of primary lymphoma of other organs, including mucosa-associated lymphoid tissue (MALT) lymphoma and thyroid lymphoma. We could not find a previous study comparing the prognosis between stage IE or IIE and stage I or II. A previous comparative study of 70 cases of stage IE or IIE primary MALT lymphoma was conducted between 1989 and 1998. With regard to the ratio of response to treatment, complete remission was found in 95.7% of cases and partial remission occurred in 4.3%. The 5-year DFS and OS rates were 76% and 96%, respectively. Among the five patients who underwent surgical treatment, only two showed local recurrence, whereas eight of 62 patients who received radiotherapy (30–35 Gy) experienced recurrence. Localized MALT lymphomas have an excellent prognosis after moderate-dose radiotherapy [9]. In another study of primary thyroid lymphoma, 1,408 patients were included, of whom 56% had stage IE disease at diagnosis. The median OS with rituximab-based chemotherapy and radiation was 9.3 years, and the 5-year OS rate was 66%. For thyroid DLBCL subtypes, the 5-year DFS rate was 75% [10].

Gynecologists may find it challenging to suspect vulvar lymphoma when encountering a vulvar mass because of low disease prevalence. Therefore, gynecologists should consider including many benign diseases as well as other malignant tumors of the vulva, such as lipoma, leiomyoma, Bartholin gland cyst, or abscess, in the list of differential diagnoses. Pelvic MRI is the most useful imaging modality for this purpose [15,16]. Vulvar lymphoma shows some characteristic features similar to lymphoma in other female genital organs, such as the uterine cervix, uterine corpus, or ovaries [16].

On MRI, vaginal lymphoma typically appears as a homogeneous enhancing, hypovascular mass with preservation of the mucosa on T2-weighted images [16-18]. It also shows low signal intensity on T1-weighted images, intermediate signal intensity on T2-weighted images, and homogeneous enhancement [16,19]. In contrast, CT imaging shows a well-defined mass with a density similar to that of muscle [16,20]. Similarly, vulvar cancer typically appears as a hypointense to isointense mass on T1-weighted images, and as an enhancing mass with intermediate hyperintensity (“evil gray”) on T2-weighted images. Diffusion-weighted images may be useful for detecting a lesion because of their better tumor-to-normal tissue contrast compared to T2-weighted images [15,19]. In vulvar lipoma, the lesion appears as a well-demarcated and hyperintense mass on turbo spin-echo (TSE) T2-weighted images. The signal intensity of vulvar lipomas is similar to that of the subcutaneous fat. Signal loss from the tumor on fat-saturated TSE T2-weighted images demonstrates the presence of internal fat content within the vulvar mass [15]. Vulvar leiomyomas are hypointense on TSE T2-weighted images. In addition, the mass shows uniform enhancement on T1-weighted images [15]. A Bartholin gland cyst appears as a hyperintense mass in the vaginal introitus on T2-weighted images. Subtraction imaging in T1-weighted images typically shows T1 hyperintensity without internal enhancement after contrast administration. This finding may indicate the presence of hemorrhage or proteins within the cyst [15]. On T2-weighted images, a Bartholin gland abscess typically appears as a hyperintense lesion with thickened, uneven borders, and internal debris. On T1-weighted images, the thickened rim of the abscess is enhanced, whereas the central area is not [15].

In conclusion, gynecologists should rule out lymphoma and other benign tumors as the cause of a vulvar mass. The patient with a subcutaneous tissue-confined mass was diagnosed with non-GCB-type vulvar DLBCL in this study. The patient showed a generally good response to an R-CHOP regimen with radiotherapy after local excision of the vulvar mass.