Metachronous Cancer of Breast and Adenocarcinoma of Cervix: A Rare Case Report

The occurrence of a second primary cancer in a cancer survivor is well documented. It may be synchronous (within 6 months of diagnosis of first primary cancer) or meta-chronous (more than 6 months of diagnosis of first primary cancer). There may be several factors responsible for development of multiple primary malignancies like genetic predisposition and exposures to carcinogenic substances. Treatment of first primary malignancy may lead to development of second cancer. The improvement in survival after a successful treatment of one cancer itself is a factor which increases the possibility of second primary malignancy. One such metachronous cancer is that of breast and cervix. Incidence of metachronous cancer involving cervix is 0.82% to 1.33%.1 The other organs commonly involved are gastric, colon and lung. The histological type of cervical cancer in metachronous cancer is mostly squamous cell cancer and adenocarcinoma was rare.1 The role of tamoxifen given for breast cancer in development of uterine and cervical cancer have been reported. But tamoxifen does not appear to endorse the pathogenesis of non-squamous cervical cancer.2 On the other hand, the role of human papillomavirus (HPV) in breast cancer have also been reported. We present a case of a woman who received tamoxifen for invasive ductal carcinoma of breast and subsequently developed adenocarcinoma of cervix.

A 48-year-old, para 3 and live 3 (P3L3) attended surgery outpatient department (OPD) in the month of November 2015 with the complaint of lump in the left breast since 3 months. There was no history of associated pain, nipple discharge or trauma. There was no family history of breast cancer or any other type of cancer in the family. She was having amenorrhea since last 6 months. On examination of the breast, a hard lump of approximately 7 × 5 cm, non-mobile, non tender was felt in inner lower quadrant of the left breast with retraction of the skin overlying the mass. The nipple and areola of the left breast was normal with no discharge on expression. The right breast was found to be normal with no palpable axillary nodes on both sides. Supraclavicular nodes were not palpable bilaterally. Complete gynecological examination was done and no abnormality was detected. Pap smear was taken which was negative for intraepithelial lesion and malignancy. Ultrasound revealed normal uterus and bilateral adnexa. Trucut biopsy of the breast lump shows cells suggestive of invasive ductal carcinoma-NOS (Fig. 1). Patient was clinically staged as invasive ductal carcinoma stage T4bN0M0.

Fig. 1
Hematoxylin and eosin at 20× shows cells are arranged in nests and occasional duct like structure and solid clusters suggestive of invasive ductal carcinoma-NOS.

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The patient received 3 cycles of neo-adjuvant chemotherapy with Cyclophosphamide, Epirubicin, 5 fluorouracil. Patient underwent modified radical mastectomy in January 2016. Histopathological examination of the tissue showed invasive cancer of breast-No special type: Modified Bloom Richardson grade I with cancerization of lobules and lymphovascular emboli. Out of the 16 lymph nodes identified in the axillary tail, 11 showed tumor cells. Immuno-histochemistry report

Estrogen receptor-Positive, Allred score 4/8, Progesterone receptor-positive, Allred score 5/8, Her2/neu-negative (1+). Patient received 3 more cycles of chemotherapy after surgery. Patient also received radiotherapy and tamoxifen.

After 6 months of tamoxifen therapy i.e., in the month of November 2016 the patient attended gynaecology OPD with the complaint of bleeding per vaginum. On examination, ulceroproliferative growth approx. 3 × 2 cm seen in the posterior lip of the cervix involving the posterior fornix. Bilateral parametrium was free. The size of uterus was normal. Cervical biopsy shows endometroid variety of endocervical adenocarcinoma (Fig. 2). Magnetic resonance imaging pelvis revealed irregular thickening predominantly of the posterior part of cervix with T2 hyper intense vaginal collection suggestive of cancer of cervix with no parametrial involvement. Patient was diagnosed as second primary malignancy with adenocarcinoma cervix Stage IIa. Patient was advised surgery but she opted for chemo radiation. Patient received chemotherapy with paclitaxel and carboplatin. She completed 3 cycle of chemotherapy. Clinically she is doing well. Size of her cervical growth has also decreased. Patient is presently on radiotherapy.

Fig. 2
Hematoxylin and eosin at 20× shows back to back glandular pattern of tubules, papillae and glands with features of moderately differentiated adenocarcinoma of cervix.

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Tamoxifen, a selective estrogen receptor modulator is a commonly used drug as an adjuvant therapy following surgery for breast cancer. The significant improvement of 10 year survival with tamoxifen in patients with estrogen receptor positive breast cancer patient has been well documented.3 As tamoxifen is strongly associated with development of endometrial hyperplasia and carcinoma; the patients must be well informed regarding the possibility of developing the same. The association of tamoxifen with endometrial carcinoma has been established.4, 5 More than 2 year of tamoxifen therapy increases 2.3 times chance of endometrial cancer.6 The possibility of developing cervical cancer following tamoxifen therapy has also been studied. In patients with HPV infection, tamoxifen is responsible for enhancing the expression of HPV 16 & 18 and also expression of E6 & E7 in cancer cells of the cervix, the molecular mechanism of which has been established.7, 8 In our patient, the cervical cancer screening with Pap smear was negative for intraepithelial lesions and malignancy when she was diagnosed with breast cancer. However, after 6 months of tamoxifen therapy the patient was diagnosed with cervical adenocarcinoma which is a rare occurrence. In one study use of tamoxifen was associated with development of papillary-serous adenocarcinoma of uterine cervix.2

On the other hand, the role of HPV infection in breast cancer has also been considered. The presence of HPV in the tumor tissue and not in the normal breast tissue had been reported by several studies, which suggests the role of HPV in development of breast cancer.9, 10, 11 Henning et al.12 reported the presence of HPV 16 DNA in breast tissue and cervix of patients with breast cancer being treated for cervical intraepithelial neoplasia III. Though the route of infection and transmission is not yet known, the possibility of spread of HPV infection to different organs with subsequent development of carcinoma is a possibility. The role of tamoxifen in cervical cancer and the role of HPV infection in both cancer of cervix and breast cancer have been well documented. In our patient, the adenocarcinoma of cervix (rare occurrence) which is likely due to six month of tamoxifen therapy is a puzzling question. Women diagnosed and treated for breast cancer need to be followed up for development of other metachronous gynecological cancers.