A Man With Breast Cancer After Mantle Radiation

Introduction. Men with breast cancer tend to have a worse prognosis than women, as they commonly have more advanced disease at diagnosis. While many practitioners utilize mammography screening for women, there is less awareness of recommendations regarding screening for men. The diagnosis of breast cancer can be delayed in men due to misdiagnosis as gynecomastia, and men may not come forward with symptoms of breast cancer due to a lack of knowledge or stigma.

We present a case of a 50-year-old man diagnosed with estrogen receptor/progesterone receptor (ER/PR) positive, human epidermal growth factor receptor-2 (HER-2) negative, T1cN1aM0 invasive ductal carcinoma. His medical history was significant for stage IIA nodular sclerosing Hodgkin lymphoma in childhood, for which he underwent total mantle/lymphoid radiation and chemotherapy. Among the treatments for this patient’s lymphoma, it is most likely the mantle radiation that placed him at highest risk of a future cancer. This case demonstrates that practitioners should maintain a high level of suspicion in men with prior history of risk factors who present with changes in breast size or a palpable breast lump.

Case description. A 50-year-old man presented to his primary care provider with a palpable right breast mass which he had first noted approximately 3 months prior. It had not increased in size but had become increasingly tender. He had no other palpable masses, areas of pain, or other breast or systemic symptoms. His medical history was notable for stage IIA nodular sclerosing Hodgkin lymphoma at the age of 12 years, for which he underwent a splenectomy followed by total mantle/lymphoid radiation for a total dose of 40 Gy. He experienced a recurrence in the auricular region 18 months after index treatment and was managed with right axillary excisional biopsy, local auricular radiation therapy, and chemotherapy with nitrogen mustard, vinblastine, vincristine, and procarbazine. The dose of the auricular radiation was unknown. There have been no other recurrences of lymphoma or other significant health concerns in the 38 years following the childhood Hodgkin lymphoma, except for right upper extremity lymphedema related to his Hodgkin axillary surgery and radiation. This was stage I-II and relatively asymptomatic.

Physical examination at time of presentation demonstrated a palpable right retroareolar mass with adherence to the skin.  He underwent a bilateral mammogram and axillary ultrasound, which confirmed the presence of a suspicious mass in the retroareolar region. Axillary lymph nodes were within normal limits and given no other systemic symptoms, no metastatic work-up was performed.

The differential diagnosis for a man with a breast mass includes a cyst, fibroadenoma, gynecomastia, lipoma, fat necrosis, lymphoma, and breast cancer. The most common of these is gynecomastia. Imaging characteristics can further narrow the differential diagnosis. Definitive diagnosis is typically obtained by core-needle biopsy, which in this case was positive for cancer.

Ultrasound-guided core-needle biopsy of the mass demonstrated invasive ductal carcinoma, Nottingham histologic grade 2, estrogen receptor and progesterone receptor positive, HER2/neu negative. He was staged as clinical stage T1cN0.

He was treated with right simple mastectomy with sentinel lymph node biopsy. A single focus of invasive carcinoma was found within the breast measuring 19 x 18 x 17 mm and two out of three sentinel lymph nodes were positive for macrometastases, with the largest deposit being 2.5 mm with extranodal extension--pathologic stage T1cN1aM0 (American Joint Committee on Cancer stage IA).

Due to the patient's prior mantle radiation therapy and axillary surgery with resulting grade 2 lymphedema of the right upper extremity, axillary dissection was not recommended by the institutional multidisciplinary tumor board. He received chest wall and regional nodal irradiation therapy with 25 fractions of 180 cGy (total 4500 cGy) to the right supraclavicular and level 3 lymph nodes, as well as 28 fractions of 180 cGy (total 5040 cGy) to the chest wall and internal mammary lymph nodes. He was then started on adjuvant endocrine therapy with tamoxifen 20mg daily. The patient's 47-gene panel test was negative and his 21-gene expression assay (Oncotype Dx) score was 5 (low risk <16, intermediate risk 16-25, high risk >25), so adjuvant chemotherapy was not recommended.

The patient was changed to a reduced dose of tamoxifen 10 mg daily after 16 months of therapy due to hot flashes, depression, and decreased libido. He tolerated this for an additional year but continued to have these adverse effects, so he was then changed to anastrozole 1 mg daily 2.5 years after surgery. His symptoms improved significantly and he is tolerating therapy quite well. Given his longstanding gynecomastia and history of mantle radiation, he underwent a screening mammogram for his contralateral breast which was without abnormality. Now 3 years after his diagnosis, he remains without evidence of disease.

Discussion. Breast cancer in men is an understudied disease and the literature on the topic is scarce, as most clinical trials and prospective studies regarding breast cancer exclude men.¹ About 1% of all breast cancer cases occur in men and the lifetime risk for breast cancer in men is approximately 1 in 1000 compared with 1 in 8 for women.¹ Risk factors for breast cancer in men include genetic mutations, radiation exposure, liver disease, long-standing gynecomastia, and elevated levels of estrogen.¹ Elevated estrogen levels are known to occur due to endocrine abnormalities, increased adipose stores, and genetic syndromes.²

Men with breast cancer can have a worse prognosis and lower survival rate compared with women, in large part because men tend to have a more advanced disease stage and are older when they are diagnosed.¹ Diagnosis may be delayed because breast enlargements in men can be misdiagnosed as gynecomastia.³ Additionally, some men may dismiss a painless mass or may not notice an abnormality until it is much more advanced, since self-examination is not encouraged in men the same way as it is in women.⁴ While survival rates for breast cancer have improved over the decades, the improvement has not been as substantial in men as in women.^1,5 Specifically, a study of more than 5000 men and 800,000 women found that the hazard ratio for breast cancer death fell by 28% for men in 1996-2005 compared with 1976-1985; however, the hazard ratio fell by 42% over the same interval for women.⁵ This could stem from a delay in diagnosis due to the general lack of knowledge of breast cancer in men as well as the social stigma men face regarding breast cancer.⁴

The risk of prior radiation is a key aspect of this case presentation. Although more research needs to be done on the effect of radiation and the risk of breast cancer in men, data from the Childhood Cancer Survivor Study showed that women who underwent chest radiation for childhood cancers had an elevated risk of breast cancer on par with those who have BRCA mutations.⁶

The effect radiation has on the future risk of breast cancer is well known. A case-control study of 6647 women who were survivors of childhood cancer found that women who received radiation with 40 Gy had an 11 times increased risk for developing breast cancer compared with nonirradiated patients.⁷ While this study found a linear correlation between radiation dose and breast cancer risk, a 2014 study found a high risk of breast cancer even following radiation with a lower median dose of 14 Gy.⁶ There are a few studies concerning the role of radiation in breast cancer among men. One study of 45,880 Japanese men who were atomic bomb survivors showed a statistically significant dose-response relation between external radiation and breast cancer in men.⁸ Another study of 227 men with breast cancer found that ionizing radiation was a risk factor and that the likelihood increased with a higher frequency of chest X-rays.⁹

Data on the Lake Effects Study Group cohort of children diagnosed with Hodgkin disease showed that the cumulative incidence of any second malignancy was 10.6% at 20 years and 26.3% at 30 years, and the majority of whom received radiation therapy.¹⁰ Research from a Dutch study of 3905 survivors of Hodgkin lymphoma showed a cumulative incidence of a second cancer was 33.2% at 30 years after treatment and 48.5% at 40 years, compared with the expected incidence of cancer in the general population of 9.6% and 19.0%, respectively.¹¹ Based on these findings, it would be reasonable to consider that any survivor of Hodgkin lymphoma, especially in childhood, would benefit from high-risk conversations and screening.

Women who are at high risk for breast cancer due to prior mantle radiation before the age of 30 years are recommended to start receiving mammography screening 8 years after radiation therapy but not before the age of 25 years.¹² For men with BRCA mutations, it is recommended to start breast self-examination training and annual clinical breast examinations at age 35 years. Annual mammography should also be considered in men with gynecomastia at age 50 years or 10 years before the earliest known case of breast cancer in the family.¹³ Regular mammography screening for high-risk men could help detect breast cancer earlier and decrease the morbidity and mortality of breast cancer in men.¹⁴

Conclusion. The patient in this case presented with breast cancer 38 years after he underwent mantle/lymphoid radiation. His case is a good example of the need to maintain a higher level of suspicion for breast cancer because of his history of mantle radiation. His cancer could have easily been overlooked as a case of gynecomastia. Finally, this case demonstrates the need for further research into breast cancer among men as a whole and its relationship to mantle radiation, in particular.