Lymphoma of the cervix: A diagnostic pitfall on cervicovaginal smear.

Malignant lymphoma that secondarily involves the cervix is a rare condition and may be difficult to distinguish from follicular cervicitis and small cell carcinoma. Cervical lymphoma is sometimes misdiagnosed on cervicovaginal cytology due to its rarity. We report a case of a cervical lymphoma in a 65-year-old woman, which was diagnosed as a squamous cell carcinoma on cervicovaginal cytology.

Introduction

Lymphoma of the cervix is a relatively rare tumor with an overall incidence of less than 1% among all cervical malignancies. The most common clinical presentation is abnormal uterine bleeding, although occasionally atypical lymphoid cells on a routine cervical smear have led to detection.[12]

While cervicovaginal cytology is neither a screening nor a diagnostic test for cervical lymphoma, in some cases, an atypical clinical presentation may be suggestive of lymphoma. The cervical lymphomas may be misdiagnosed on Papanicolaou (Pap) smears by the pathologist because lymphomas are unexpected at this site and may be confused with other types of malignant neoplasms or inflammatory processes. Herein, we describe a case of cervical lymphoma which was diagnosed as squamous cell carcinoma on cervicovaginal cytology.

Case Report

A 65-year-old woman presented to the urogynecology clinic in our institution with a month history of urinary incontinence and menometrorrhagia. Her past medical history was not significant. Cervicovaginal cytology was performed, and a diagnosis of “possible small cell non-keratinizing squamous cell carcinoma” was made. A computed tomography (CT) of the abdomen and pelvis revealed the presence of diffuse, heteregeneous uterine cervical mass and hypoechoic enlarged iliac lymph node. A biopsy was immediately conducted and the histopathological examination revealed large cell lymphoma infiltration beneath the epithelium. The neoplastic cells lacked tropism for the overlying epithelium [Figure 1a]. Malignant cells involving the cervix were monomorphic, mainly dispersed singly, with little cytoplasm and marked hyperchromasia [Figure 1b]. Immunostaining was performed by the avidin-biotin complex immunoperoxidase technique on a Dako autostainer PLUS with FLEX Envision chemistry (Dako, Autostainer Plus, Denmark) using pancytokeratin (MNF 116, Dako, 1:200), CD20 (L26, Biogenex, 1:50), CD45 (UCHL-1, Dako, 1:50), CD23 (SP23, Dako, FLEX Ready-to-Use), CD3 (Polyclonal Rabbit Anti-Human, Dako, FLEX Ready-to-Use), CD5 (Clone SP19, Dako, FLEX Ready-to-Use), CD10 (56C6, Dako, FLEX Ready-to-Use), Cyclin D1 (NCL-L-Cyclin D1-GM, Leica Microsystems, 1:25) as the primary antibody and 3-amino; 9 ethyl-carbazole (AEC) as the chromogen.

Figure 1

(a) Section showing dispersed atypical cells invading stroma of the uterine cervix under the normal squamocellular epithelium of the exocervix (H and E, ×200). (b) Malignant lymphoid cells which have rounded to irregular nuclei (H and E, ×400). Inset. Tumor cells showing strong CD2 immunoreactivity (IHC, ×400)

On the immunohistochemical analysis, these cellular elements were negative with pancytokeratin, CD3, CD5, CD10, CD23, Cyclin D1 but showed diffuse positivity with CD45 and B-cell markers including CD20 [Figure 1 (inset)]. These findings established the diagnosis of diffuse large B-cell lymphoma (DLBCL). Consequently, re-evaluation of the cervicovaginal smear was found to be consistent with lymphoma, which was supported by clinical information and tissue biopsy confirmation. On review cervicovaginal smear showed the epithelial cells surrounded by loose cell aggregates or isolated atypical small round cells [Figure 2]. The cells had scant, delicate cytoplasm, with relatively high nuclear/cytoplasmic (N/C) ratio and hyperchromatic nuclei with irregular nuclear membrane. These features supported the diagnosis of lymphoma. Bone marrow trephine biopsy did not reveal any lymphoma deposits. The patient received eight courses of R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) and achieved complete remission.

Figure 2

Cervical smear showing a round, loosely arranged lymphoid cells with scanty cytoplasm (H and E, ×100) Inset: Dispersed small cells with scant cytoplasm and hyperchromatic nuclei (Pap, ×200)

Discussion

Malignant lymphoma rarely arises in the cervix, accounting for less than 0.5% of extranodal lymphomas. Most cervical lymphomas represent secondary involvement in generalized disease. The tumors occur in middle-aged women, the age at presentation ranges from 20 to 80 years, with the median age varying from 40 to 59 years. Clinical signs are abnormal uterine bleeding, abdominal or pelvic discomfort, dyspareunia, back pain, or vaginal discharge.[1-4]

It is important to recognize the cytological features of cervical lymphomas because these lesions can mimic primary cervical carcinoma clinically and radiographically. Although Pap smear is a safe, accurate, and popular method for evaluating cervical lesions, primary cervical lymphoma is uncommonly diagnosed, with less than 60 cases reported in the medical literature.[56] The cytological specific diagnosis of cervical lymphoma is usually not possible on Pap smears. In most cases the cervical smear is negative, which is probably due to the fact that these tumors infiltrate the cervical stroma, and the squamous and glandular epithelial lining is initially preserved. In study of Dursun et al.[5] 41% of women with primary cervical lymphoma had abnormal cervical cytology.

Because the vast majority of cervical neoplasms are primary carcinomas, recognition of nonglandular malignant elements on Pap smear should raise the suspicion of a hematologic malignancy. A monomorphic pattern of dispersed single cells is a clue for lymphoma of the cervix. Although rare, lymphomas of the uterine cervix should be included in the differential diagnosis of small cell neoplasm cytological abnormalities of the cervix in the Pap smear. Poorly differentiated and small cell carcinomas that present as dispersed atypical cells may mimic lymphoid proliferations. However, poorly differentiated carcinomas show some degree of cohesion or nuclear molding as evidence of their epithelial nature. An advantage of liquid-based preparations is the ability to perform immunophenotypingon the residual material to distinguish an epithelial lesion from a lymphoid lesion.[6]

Cervical lymphoma can be misdiagnosed as carcinoma on cervicovaginal cytology due to its rarity. In our case, the reason of the false diagnosis as squamous cell carcinoma was the presence of small cells with high N/C ratio which were interpreted as small cell nonkeratinizing variant of squamous cell carcinoma. Therefore, awareness of this potential diagnostic pitfall is of great importance in order to avoid misdiagnosis as carcinoma on cervicovaginal cytology. The possibility of lymphoma should be kept in mind while dealing with small cell neoplasms or poorly differentiated tumors in this location. To render a cytological diagnosis of lymphoma is important because it prompts immediate treatment and avoids overtreatment.