Primary non-Hodgkin’s lymphoma of the vagina (PNHLV): a gynaecologist’s enigma!

Abstract

Primary lymphoma of the female genital tract is very rare, particularly those presenting primarily in the vagina are even rarer. We report a case of a 60-year-old woman who presented with generalised abdominal pain, vaginal discharge and a thickening of the posterior vaginal wall. Prompt radiological investigations and biopsy led to early diagnosis and appropriate treatment. Complete metabolic remission was obtained with three cycles of chemotherapy and radiotherapy. This case highlights the need for increasing the awareness about lymphomas presenting as vaginal lesion(s) and for clinicians to keep an open mind when working up such patients.

Background

Haematological malignancies very rarely present with gynaecological symptoms. Although rare, clinicians/gynaecologists need to be aware of such possibilities and should be able to diagnose them and refer them to a haematologist for further management. We present one such case of primary non-Hodgkin’s lymphoma of the vagina (PNHLV).

The female genital tract as a primary site for lymphoma is rare, with less than 1% originating in the female genital tract.¹ The incidence of the genital tract being involved as a secondary site is much higher in upto 30% of cases with disseminated disease.² Primary vaginal lymphoma is so rare that in a large series of 9500 women with malignant lymphoma, only 4 arose from the vagina.²

The aim of this report is to bring to everyone’s attention the need to stay vigilant and think out of the box for uncommon diagnoses in patients that present with vague symptoms like generalised abdominal pain and vaginal discharge.

Case presentation

A 60-year-old postmenopausal woman presented with non-specific and generalised abdominal pain of 4 months’ duration along with watery, non-foul smelling discharge. She also complained of increased frequency of micturition, but gave no medical history of haematuria, urinary incontinence, weight loss, fever and night sweats.

Her cervical smears were normal. She was a para 3, all three children were born vaginally.

Medical history of note included asthma, temporomandibular joint dysfunction and irritable bowel syndrome. She had a normal colonoscopy a year before presentation.

On vaginal examination, the cervix felt normal. However, there was a firm, non-ulcerated thickening palpable on the posterior vaginal wall. It was 4–5 cm in length extending down to the mid portion of the vaginal canal up to a depth of 2–3 cm from the introitus. It was separate and not involving or breaching the rectal mucosa. There was a streak of blood on the glove after examination, but no complaints of subsequent per vaginal bleeding. Per rectal examination was normal.

Investigations, differential diagnosis

On transvaginal ultrasound, there was a 3 cm mass on the left adnexa arising from the uterus, diagnosed as a pedunculated fibroid. Uterus and right ovary were normal on ultrasound. However, vaginal thickness could not be evaluated on ultrasound. Cancer antigen (CA) 125 was 17.

MRI of the pelvis was arranged to better delineate the vaginal mass. The MRI confirmed the findings of a vaginal mass (figure 1) with an abnormal 3 cm pelvic node, likely secondary to a vaginal malignancy.

Figure 1.

MRI T2 image of the pelvis showing a vaginal mass on the posterior vaginal wall.

Further workup for a possible vaginal malignancy was initiated. An examination under anaesthesia was performed along with hysteroscopy, colposcopy, vaginoscopy and deep biopsies of the vaginal mass. An endometrial biopsy was also obtained. Colposcopy and hysteroscopy were normal.

The vaginal biopsy confirmed a diffuse large B cell non-Hodgkins lymphoma (NHL), positive for CD20, CD45, CD79a and BCL6. A bone marrow trephine biopsy was normal. Positron emission tomography (PET) scan showed diffuse uptake at the site of vaginal malignancy and pelvic nodes, however no uptake was seen anywhere else or above the diaphragm. She was diagnosed as a stage II AE diffuse large B cell lymphoma involving the vaginal wall (Ann Arbour).³

Treatment, outcome and follow-up

She was treated with three cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone) followed by involved field radiotherapy with 30 Gy in 15# to the vagina and nodal sites in the pelvis. A PET scan after two cycles of R-CHOP showed complete metabolic response which was sustained on a subsequent PET scan performed 3 months post-radiotherapy. She remains in remission at 30 months follow-up.

She had one episode of grade 4 neutropaenia (absolute neutrophil count—0.35×10⁹/L) following third cycle of chemotherapy, which was complicated by a small patch of cellulitis over the anterior abdominal wall which responded to antibiotics. The only side effect of radiotherapy was grade 1 diarrhoea which resolved spontaneously.

Discussion

PNHLV is a rare haematological malignancy. It can sometimes even mimic gynaecological malignancy.¹ Hence, it is good practice to have a low threshold for investigating such patients and an open mind for accepting such varied diagnoses. It is so rare that out of 9500 women with lymphomas, only six were found to have an initial presentation in the cervix and four in the vagina.² It is reported in a wide age group (26–66 years), the mean age reported in literature is around 42 years of age.⁴

In a retrospective analysis of 186 patients with malignant lymphoma detected in the female genital tract, the most frequent type of lymphoma proved to be diffuse large B cell lymphoma, closely followed by follicular lymphoma, including all three grades of malignancy. Burkitt lymphoma showed a rather similar frequency. Marginal zone lymphoma occurred exclusively as primary lesions in the uterine mucosa. Lymphoplasmacytic lymphoma was restricted to the vulvo-vaginal area and occurred in women over 60 years of age.⁵

Unlike nodal NHL, which usually manifests with prodromal symptoms of fever, night sweats, weight loss or ‘B’ symptoms, genital lymphomas rarely present with these symptoms.⁶ Of the known cases thus far, the most common clinical presentations were vaginal bleeding (34.8%), vaginal mass (23.9%), vaginal discharge (17.4%) and abdominal/pelvic pain (15.2%). About 13% of women were asymptomatic (box 1).⁷

Box 1. Symptoms of primary non-Hodgkin’s lymphoma of the vagina.⁷ .

• Vaginal bleeding.

• Vaginal mass.

• Vaginal discharge.

• Abdominal/pelvic pain.

• Asymptomatic.

The Ann Arbour system is used to stage NHL.³ The staging modifiers are stated as A or B depending on the presence or absence of symptoms such as unexplained weight loss, night seats or fever. Following tissue diagnosis, bone marrow examination completes the investigations with involvement of bone marrow upgrading the staging to 4 (table 1).

Table 1.

Modified Ann Arbour classification for extranodal lymphoma⁹

Stage	Area of involvement
I E	Involvement of a single lymph node region or a single organ.
II E	Involvement of a single extralymphatic organ or site and one or more regional lymph nodes ipsilateral to diaphragm.
II E	Involvement of a single extralymphatic organ or site and regional lymph nodes on both sides of the diaphragm.
IV E	Diffuse involvement or dissemination of one or more extralymphatic sites, with or without the involvement of lymphatic nodes.

In this case, the patient presented post menopausally with a generalised abdominal pain and vaginal discharge. A normal ultrasound and CA 125 made the diagnosis of ovarian/fallopian tube malignancy unlikely. Normal endometrial biopsy ruled out endometrial cancer. Possibility of cervical malignancy was ruled out on colposcopy.

Typically, vaginal cancer presents with an ulcerated lesion in the vagina. However our patient, only had an abnormally thickened posterior vaginal wall which was not ulcerated. Ultrasound of the pelvis was not very helpful in diagnosis as it did not identify the abnormality in the vaginal wall.

MRI suggested possibility of primary vaginal malignancy and helped delineate the extent of disease. However, biopsy obtained after examination under anaesthesia confirmed the histological diagnosis of diffuse large B cell lymphoma.

Tumour markers were normal in our case. However, NHL can sometimes be associated with abnormal CA 125 levels in patients with mediastinal and/or abdominal involvement, bulky tumour, and the presence of effusion. Serial serum CA 125 measurements are useful for monitoring patient response to therapy.⁸ Elevated levels at the time of diagnosis have been associated with a decreased 5 year survival rate.¹

CT of the abdomen and pelvis can also help identify the sites of disease involvement, especially nodal sites. Prior to the advent of CT and PET, chest X-ray was mandatory to look for spread of the disease beyond the diaphragm. Currently, PET-CT is the imaging modality of choice as it shows the extent of metabolically active disease. PET-CT is also useful to track disease regression/progression and recurrence.

Examination under anaesthesia adds to the clinical picture by facilitating better and complete delineation of the lesion. It also provides an opportunity to obtain biopsies. It is important to obtain sufficient tissue material to perform not only conventional histopathological examination, but also for immunohistochemistry, cytogenetics (fluorescent in situ hybridisation) and molecular genetics in order to establish the correct histological subtype of lymphoma. Immunohistochemistry also helps in ruling out other differentials of firm, smooth non-ulcerated vaginal lesions such as Ewing’s sarcoma, mixed Mullerian tumour, melanoma and neuroendocrine tumours.⁶ In our case due to a sufficient biopsy taken, diagnosis was made at first biopsy however as illustrated by a case report diagnosis can be delayed with insufficient biopsy and hence the importance of adequate biopsy.⁴

Prognosis of the disease depends on early diagnosis, stage, size, performance status, histological grade and subtype; with almost an 80%–90% 5-year survival rate associated with early diagnosis and prompt treatment.⁴ The therapeutic value of surgery is limited to providing a histological diagnosis.⁸ Chemotherapy along with radiotherapy is the mainstay of treatment and have shown excellent responses, as with our case. Awareness of the disease and preoperative diagnosis can be beneficial, as the patient may be able to avoid unnecessary staging operations and disease cytoreduction.¹

Learning points.

• Primary non-Hodgkin’s lymphoma of the vagina is a rare condition.

• The diagnosis of a pelvic lymphoma should always be considered in the differential for a gynaecological malignancy.

• When an abnormal lesion is identified on examination, further radiological and histological investigations should be arrange promptly.

• Early diagnosis and prompt treatment can lead to complete metabolic response and a very good prognosis for the patient.

• Prompt preoperative histological diagnosis can prevent unnecessary surgery.