With to availability of effective cancer therapy and improvement in survival, the incidence of double malignancy has risen [1]. Double malignancy now comprises of the sixth most common cancers and it makes 16% of all incident cancers [2]. Renal cancer is known to be associated with multiple tumors involving bladder, prostate, rectum, lung, non-Hodgkin's lymphoma, stomach and melanoma etc. [3]. Breast cancer is also associated with increased risk of second tumor involving colon, vulva, lung, larynx, liver, uterus and thyroid [4]. All these associations can be metachronous (develop consequently) or synchronous (tumors coexist at the time of diagnosis). Synchronous breast and renal cell carcinoma (RCC) can occur rarely [3]. We hereby report a case of carcinoma breast with synchronous renal cell carcinoma.

A 38-year-old premenopausal, multipara female with no significant family history presented with a lump in right breast since eight months duration. Sonomammography of ipsilateral breast showed a fibroadenoma of 23x18 mm at 9 o'clock position, surrounding fibroadenosis and reactive axillary lymph nodes. Excision Biopsy was done by a surgeon at a peripheral hospital and it was reported as pT 4.5x3 cm, infiltrating duct carcinoma with predominant ductal carcinoma in situ (cribriform pattern).

The patient was referred to our hospital for further management. Computed tomography scan of abdomen for metastatic workup showed a 45x42 mm mass in mid-lower pole of right kidney with small exophytic component and associated perilesional fat density suspected to be malignant (Figure 1). Bone Scan, CT chest and other routine investigations were within normal limits. Right modified radical mastectomy and right radical nephrectomy were done. Histopathology of breast specimen was reported as lumpectomy cavity of size 6x3.5x3 cm, no residual primary tumor, 4/26 lymph nodes positive for metastatic duct carcinoma (Figure 2), immunohistochemistry profile of axillary lymph node showed positivity for GCDFP and negativity for ER/ PR/ Her 2 neu/ CD 10/ PAX 8 and Vimentin. Gross size of the right kidney specimen was 12.5x7x3 cm with ureter 4 cm in length.

On cutting a well circumscribed tumor identified in middle region of kidney measuring 4.5x3.2x3 cm, with variegated cut surface, and Gerota's fascia adherent to the tumor at one focus measuring 3x1.2 cm. Histopathology of renal mass was reported a well-circumscribed tumor, grade I, clear cell renal cell carcinoma, Gerota's fascia uninvolved, vascular and ureteric cut end unremarkable, renal sinus and perinephric fat free of tumor (Figure 3).

Immunohistochemistry of renal mass was positive for CD 10, PAX8, Vimentin and negative for GCFDP. She was finally diagnosed as a case of synchronous carcinoma right breast (pT2pN2cM0) along with conventional renal cell carcinoma right kidney (pT1bpN0cM0, Grade I). She received adjuvant chemotherapy (FEC x 4 followed by Taxol x 4 cycles). She further received external beam radiotherapy to ipsilateral chest wall and SCF.

Renal cell carcinoma and breast cancer are associated with increased risk of double malignancy [3] [4]. Sato et al. [3] found multiple primary malignant tumors in up to 12% of patients with renal cell cancer. Rabbani et al. [5] also reported 30–40% incidence of other primary malignancies on autopsy series in patients with renal cell carcinoma. Synchronous breast and renal carcinomas are rarely reported [3].

The exact mechanism of double malignancy is not well understood. The predisposing risk factors for dual malignancy include tobacco and alcohol, genetic predisposition (Li Fraumeni and Beckwith–Wiedemann syndrome, Cowden syndrome and BRCA mutations), improved survival, history of prior radiation or chemotherapy, environmental risk factors, old age [1]. PTEN gene is associated with Cowden syndrome which has high risk of developing tumors of the thyroid, breast, kidney, endometrium [6].

Detection bias may be another important factor as metastatic workup or long-term surveillance for first malignancy increases chances of detection of second primary tumor.

Hormone-ER complex may be playing a role in development of RCC. Di Silvero et al. [7] reported a series of 17 cases of renal cell carcinoma associated with primary tumors of steroid hormone target tissue such as breast, ovary and endometrium. Liu et al. [8] in a study of differentially expressed genes (DEGs), reported that ER target genes were closely associated with renal cell carcinoma development. Tanaka et al. [9] investigated that exposing the Syrian hamsters to estrogens results in the development of kidney cancer and aneuploidy in renal cells. Henriksson et al. [10] found no difference in survival for metastatic renal cell carcinoma patients treated with immunotherapy (interleukin 2/interferon alpha) and tamoxifen arm versus tamoxifen alone arm in a multicentric randomized controlled trial. These results suggest that the role of endocrine manipulation for renal cell cancer needs to be investigated more. Epidemiological studies of survivors of atomic bomb irradiation links the radiation as potential carcinogenic but the proportion of second cancers that attributes to radiotherapy is still unknown. Radiotherapy techniques have changed significantly in last two decades. These rapidly evolving techniques (intensity modulated radiotherapy (IMRT), volumetric arc therapy (VMAT) tomotherapy, cyberknife, stereotactic radiotherapy, proton therapy) have different acute and late toxicity profiles compare to conventional radiotherapy. IMRT delivers more conformal radiation doses to the target tumor volume but it involves more number of radiation fields and exposes a larger volume of normal tissue to lower doses. IMRT and its implication as increased second cancer incidence is a matter of debate.

Methodological research is required on association of dual malignancy with late side-effects of chemotherapy/radiotherapy, genetic modifiers, environmental risk factors.

As the survival of cancer patients has improved due to early detection and availability of advance treatment options, the risk of second cancer or double malignancy has also increased significantly. Long-term surveillance and high index of suspicion of double malignancy by treating physician and reviewing pathologist is warranted for early detection of second tumor. Further research is required to quantify the association between second malignancy and genetic, environment al and treatment related factors like IMRT and newer chemotherapy.

1. Travis LB, Rabkin CS, Brown LM, et al. Cancer survivorship–genetic susceptibility and second primary cancers: Research strategies and recommendations. J Natl Cancer Inst 2006 Jan 4;98(1):15–25.   [CrossRef]   [Pubmed]    
2. Ries LAG, Harkins D, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2003, National Cancer Institute. Bethesda, MD. [Available at: http://seer.cancer.gov/csr/1975_2003/]   [CrossRef]   [Pubmed]    
3. Sato S, Shinohara N, Suzuki S, Harabayashi T, Koyanagi T. Multiple primary malignancies in Japanese patients with renal cell carcinoma. Int J Urol 2004 May;11(5):269–75.   [CrossRef]   [Pubmed]    
4. Mellemkjaer L, Friis S, Olsen JH, et al. Risk of second cancer among women with breast cancer. Int J Cancer 2006 May 1;118(9):2285–92.   [CrossRef]   [Pubmed]    
5. Rabbani F, Grimaldi G, Russo P. Multiple primary malignancies in renal cell carcinoma. J Urol 1998 Oct;160(4):1255–9.   [CrossRef]   [Pubmed]    
6. Eng C. Will the real Cowden syndrome please stand up: Revised diagnostic criteria. J Med Genet 2000 Nov;37(11):828–30.   [CrossRef]   [Pubmed]    
7. Di Silverio F, Sciarra A, Flammia GP, Mariani M, De Vico A. Multiple primary tumors: 17 cases of renal–cell carcinoma associated with primary tumors involving different steroid–hormone target tissues. World J Urol 1997;15(3):203–9.   [CrossRef]   [Pubmed]    
8. Liu Z, Lu Y, He Z, Chen L, Lu Y. Expression analysis of the estrogen receptor target genes in renal cell carcinoma. Mol Med Rep 2015 Jan;11(1):75–82.   [CrossRef]   [Pubmed]    
9. Tanaka Y, Sasaki M, Kaneuchi M, Fujimoto S, Dahiya R. Estrogen receptor alpha polymorphisms and renal cell carcinoma–a possible risk. Mol Cell Endocrinol 2003 Apr 28;202(1–2):109–16.   [CrossRef]   [Pubmed]    
10. Henriksson R, Nilsson S, Colleen S, et al, Survival in renal cell carcinoma–a randomized evaluation of tamoxifen vs interleukin 2, alpha–interferon (leucocyte) and tamoxifen. Br J Cancer 1998 Apr;77(8):1311–7.   [CrossRef]   [Pubmed]