Bilateral ovarian metastatic squamous cell carcinoma arising from the uterine cervix and eluding the Mullerian mucosa

A 48 year old P4L4 visited the Gynecology outpatient department with chief complaints of heavy vaginal bleeding for 10 days following an eight-month period of amenorrhea. Progestin therapy was initiated as there was no relief of menorrhagia with tranexamic acid. Apart from severe backache for which she was undergoing an orthopedic consult, there was no other significant contributory history.

General physical and breast examination was unremarkable. The cervix and vagina appeared normal with no focal lesions and bimanual palpation disclosed an enlarged uterus corresponding to 14-16 weeks’ size. Ultrasonography revealed a bulky uterus with thickened endometrium. The ovaries were enlarged (right: 53 × 34 × 37 mm; left: 42×32×29 mm) but had a normal echotexture. At hysteroscopy, the endometrium appeared mildly hyperplastic and there was no abnormality in the cervical canal.Papanicolaou smear was initially reported as negative for intraepithelial lesions and malignancy (Figure 1a,b,c) while a simultaneously performed endometrial biopsy showed secretory endometrium, post ovulatory day 3 with concomitant exogenous hormone induced changes (Figure 1d). There was no evidence of endometritis, granulomas, hyperplasia, atypia or malignancy in the endometrial biopsy. Despite the availability of alternative treatment modalities such as oral progestins, endometrial ablation and Mirena levonorgestrel-intrauterine system, the patient opted for the removal of uterus. Consequently, total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed.

The uterus was received bisected (9.0 × 6.0 × 5.0 cm, 356.0 gm) with an essentially normal endometrial lining and thickened myometrium (Figure 2a). The exocervix (1.5 × 1.5 cm) had focally irregular mucosal surface. The endocervix (2.5 cm in length) was unremarkable. Small nodules varying in diameter from 0.5 to 1.0 cm were noticed near the fimbrial ends while the tubal lumina were patent without mucosal thickening. The right ovary had a convoluted external surface which upon sectioning demonstrated near complete replacement of the ovarian parenchyma by a grey white lesion (3.9 × 2.3 × 0.7 cm) (Figure 2b). There was no hemorrhage or necrosis. The left ovary had a convoluted external surface and the parenchyma showed two grey white well demarcated lesions (2.0 × 1.0 cm and 1.0 × 1.0 cm) and a single smooth walled cortical cyst (Figure 2c). After overnight fixation in 10% formalin and processing, the tissues were embedded in paraffin. Multiple 3 to 5 micron sections were cut and stained with hematoxylin and eosin. Immunohistochemical study was performed by Dako’s envision method.Microscopically cervical intraepithelial neoplasia grade 3 was detected over the surface epithelium while the deeper stroma exhibited islands of moderately differentiated SCC (Figure 3). The endometrium was weakly proliferative, completely uninvolved by tumor. Both the fallopian tubes showed hydrosalpinx and the lumina were devoid of tumor deposits (Figure 4a). There was ubiquitous presence of lymphovascular tumor emboli within the cervical stroma, myometrium and the tunica muscularis (Figure 4b). Both the ovaries showed well circumscribed nodular tumor deposits of moderately differentiated SCC (Figure 4c,d). Contiguous ovarian parenchyma showed normal stroma, corpora albicantes and thick walled vessels. The left ovary additionally showed a follicular cyst.The endophytic cervical lesion, the lymphovascular channels within the endomyometrium and the tubes, and the ovarian lesions demonstrated strong positivity to p63 and high molecular weight cytokeratin CK5/6 immunohistochemistry (IHC) markers (Figures 5a, b, 6a,b, 7a,b). Squamous differentiation is characterized by strong nuclear staining with p63 and cytoplasmic staining with CK5/6, and the positive staining of these markers corroborated with the neoplastic foci seen on hematoxylin and eosin sections. Significant negative markers included CK7/CK20 (Figures 5c,d, 6c,d, 7c,d), leukocyte common antigen, gross cystic disease fluid protein, CD117 and inhibin.

Morphology and IHC evaluation concluded that the bilateral ovarian metastases, ubiquitous tumor emboli in the lymphovascular channels of the fallopian tubes and endomyometrium, and the endophytic cervical lesion were all squamous and originated in the exocervical epithelium. Despite liberal sampling the mucosal involvement of the endometrium or the tubes could not be demonstrated. A review of the cervical cytology smears ascertained that neoplastic cells had been misinterpreted as reactive endocervical cells by a trainee neophyte pathologist.