Simmons, Patricia S. MD; Jayasinghe, Yasmin L. MB, BS; Wold, Lester E. MD; Melton, L. Joseph III MD
A young woman presenting with a breast mass raises anxiety in both patient and family regarding the possibility of breast cancer.1 The majority of breast masses occurring in young women and children are benign. A review of published series of breast masses in adolescence demonstrates that fibroadenomas are the most common, constituting 44–94% of breast masses in surgical series,2 whereas malignancy was rare (constituting 0–9.5%) and more often caused by metastases or stromal malignancy such as malignant phyllodes tumor. Breast carcinoma accounted for only 0.02% of breast masses surgically removed in girls and young women.2 The distinct clinical features, management, and prognosis of both phyllodes tumors and metastases have been previously discussed.2,3 For example, malignant phyllodes tumors may experience rapid enlargement causing distortion of breast architecture and overlying skin stretching. They may have a distinct fluid-filled appearance on ultrasound scan, and are treated by wide local excision. Local recurrences may occur whether benign, borderline, or malignant. However, prognosis is excellent, with 5-year survival approaching 100%.2–4 Metastatic disease may present with a recent history of primary carcinoma, multiple lumps in the breast, constitutional symptoms, and masses elsewhere.5 In such circumstances core needle biopsy plays an important role, as systemic rather than operative intervention may be the treatment of choice.
There is a paucity of published research on primary breast carcinoma in young women, and the number of young women in cancer registries and population studies has been too small to allow for calculation of reliable incidence rates.6 Wu et al examined 22 population-based central cancer registries covering 47% of the population of the United States and found the age-standardized incidence rate of breast carcinoma per 100,000 women per year to be 0 in 15- to 19-year-olds and 2.1 in African American women aged 20–24.7 In contrast, breast cancer is the most common cancer and the leading cause of cancer death in women worldwide.8 The age-standardized incidence of breast cancer for women in the United States is 124.0 per 100,000 women per year, with a median age at diagnosis of 61 years.9 Early presentation of breast carcinoma in a young woman may be very similar to that of fibroadenoma.10 As a consequence, however, the rare cases of breast carcinoma in adolescents and young women are commonly associated with delayed diagnosis, due to a low index of suspicion on the part of physicians, delayed presentation by the patient, or both physician suspicion and delayed presentation.10–12 Invasive breast carcinoma occurring at a young age has more aggressive biological behavior and is associated with a worse prognosis.10,13 This study represents one of the largest series of breast carcinoma in young women, and it uses the resources of the Rochester Epidemiology Project14 to assess incidence rates in young women.
The objectives of the study were to estimate the age-specific and overall age-adjusted incidence of primary breast carcinoma in girls and women younger than 25 years of age living in Olmsted County, Minnesota, during the period 1935–2005; to estimate survival among these patients; and to describe the presenting signs and symptoms, modes of diagnosis and treatment, tumor histology, receptor status, stage of disease at diagnosis, and identifiable risk factors for breast cancer found in these young women.
MATERIALS AND METHODS
This study is a retrospective, population-based descriptive study. The study was approved by the Institutional Review Boards of the Mayo Clinic and Olmsted Medical Center, and only patients who had provided authorization to use their medical records as research were included.15 Girls and women under 25 years of age with a diagnosis of primary breast carcinoma between 1935 and 2005 who resided in Olmsted County were identified using the data resources of the Rochester Epidemiology Project,14 and additional patients who were not Olmsted County residents were identified through the Mayo Clinic medical record, as well as review of information in tissue registry and oncology databases. Incidence rates and survival estimates were calculated for the Olmsted County residents. Because of the small number of patients with breast cancer, information regarding clinical presentation of breast cancer in women younger than 25 years was gathered from nonresidents as well.
Olmsted County is 90 miles southeast of Minneapolis and St. Paul, Minnesota. Seventy percent of the population resides within the city limits of Rochester, and it is primarily white middle class, similar to the U.S. white population. The Rochester Epidemiology Project is a comprehensive medical records linkage system encompassing the care delivered to residents of Rochester and Olmsted County.14 Medical records, surgical and medical indexing systems, and tumor registry data from the Mayo Clinic and the Olmsted Medical Center and their affiliated hospitals, along with private practitioners in Olmsted County, contribute to the database. It is an excellent source of incidence data spanning many decades for diseases diagnosed in Olmsted County.14 The medical facilities within Olmsted County include a major tertiary referral center, and the likelihood of residents being referred outside the county for medical care is low. Only individuals with breast carcinoma confirmed by histopathologic examination by a board-certified pathologist were included in this study. Malignancies metastatic to the breast and primary stromal malignancies of the breast (phyllodes tumor, sarcoma) were not included.
Incidence rates for breast cancer were calculated using the number of cases of breast cancer in Olmsted County residents younger than 25 years of age as the numerator. We presumed that all girls and women less than 25 years of age residing in Olmsted County were at risk and determined the denominator using Olmsted County age- and sex-specific census data from 1930 to 2000, with linear extrapolation from 2001 to 2005, presuming a population growth rate of 1.9%. Age-specific risk was calculated according to 5-year time intervals for four age-groups: younger than 10 years, 10–14 years, 15–19 years, and 20–24 years. Rates were age- and sex-adjusted to the total U.S. white population in 2000. The 95% confidence interval (CI) for total age-adjusted breast cancer incidence in women younger than 25 years of age was calculated by assuming that the observed number of cancers followed a Poisson distribution.
The medical records of individuals were reviewed for clinical presentation, risk factors (family history, prior malignancy, prior radiation treatment, gynecologic age at diagnosis, oral estrogen intake, body mass index), tumor histology, estrogen and progesterone receptor status, stage at time of diagnosis, and treatment. Date of diagnosis was defined as the date of biopsy-proven disease. Race was classified according to the medical record, and was included so that results may be comparable with registry data.
Patients were followed passively through their medical records for date of last contact or death, and the cause of death was established. Five-year survival was also estimated.
During the study period, 1935–2005, four incident breast carcinomas were diagnosed over 1,201,539 person-years of observation. The pathology reports for all individuals confirmed a diagnosis of carcinoma, and the slides of three of the four individuals were available for review. The age-adjusted incidence of primary epithelial breast cancer under 25 years of age was 3.2 cases per million person-years (95% CI, 0.1–6.2). All cancers were diagnosed in the 20- to 24-year age group (two patients were 22 years old, and two were 24 years). There were 954,083 person-years observation among girls and women younger than 20 years, but no breast carcinomas were observed in this group (Table 1). The four breast cancers were diagnosed in 1974, 1975, 1980, and 1995.
Overall 5-year survival was 50% (95% CI, 12–88%). One patient with stage IV disease died from disease 1 month after diagnosis; one stage IIIa patient died from disease within 2.5 years of diagnosis; one stage I patient (with bilateral breast cancer) died from stage IV ovarian carcinoma 25 years after diagnosis; and the other stage I patient is alive with no evidence of disease 30 years after diagnosis.
Eight additional cases of newly diagnosed breast cancer were identified in women under 25 years of age who presented to a medical facility in Olmsted County during the study period. Combined with the four incident cases, the slides of 11 of the 12 were available for histologic re-examination by a board-certified pathologist, and all were confirmed as primary breast carcinoma. Demographic features, histopathology, staging, and receptor status of the tumors are demonstrated in Table 2. The youngest patient was diagnosed at 18 years of age, and the median age at presentation was 23 years. Eleven patients were white and one was Hispanic. No patient was diagnosed with secretory carcinoma.
The presenting complaint was a self-detected breast mass in eight patients, four of whom also complained of mastalgia; a single patient complained of bloody nipple discharge associated with constitutional symptoms; and another had constitutional symptoms (anemia, fever, fatigue, and severe weight loss) associated with disseminated carcinoma. One patient was asymptomatic and found to have a mass on examination by her physician. Complete details of the clinical presentation and examination are unknown for one patient.
Findings on clinical examination are summarized in Table 3. Most patients were found to have a palpable mass, located in the left breast in six individuals, right breast in four, and bilateral in one. Median greatest diameter was 4 cm (range 0.7–10 cm). Characteristics of the masses are summarized in Table 4.
Of 11 patients with documentation, all were postmenarcheal and thin. Median body mass index (calculated as weight (kg)/[height (m)]2) was 22 (range 19–30). Gynecologic age (years since menarche) was known for six patients, and ranged from 8 to 11 years (median 11 years). No features of anovulation were found (as defined by cycle length 35 days or more, hyperandrogenism, diagnosis of polycystic ovary syndrome or hyperinsulinemia). Three patients had never taken oral contraceptive pills (OCP), six were taking the OCP at diagnosis, and one had taken it in the previous year before diagnosis. No patient had taken hormone replacement therapy. Duration of OCP use ranged from 12 to 36 months (median 19 months). Age of first use was known in only three patients, and the median age was 20 years (range 18–22 years). Eight patients did not smoke tobacco. The three who did had a history of smoking one pack per day for 3–5 years.
Six patients were parous, four of whom had been diagnosed with breast carcinoma during or soon after pregnancy. One patient with stage I disease was diagnosed with breast carcinoma during her third pregnancy at 12 weeks of gestation, and another with stage IV disease was diagnosed 2 months after giving birth to her first child. At 28 weeks of gestation, she was diagnosed with hemolysis, elevated liver enzymes, low platelets syndrome and renal obstruction. Postpartum she was found to have rectosigmoid obstruction and biopsy of a pelvic mass 2 months postpartum was compatible with a breast carcinoma primary. She did not have a palpable breast mass. One patient with stage IIIa disease was diagnosed 7 months after her second delivery. She presented 2 months postpartum with breast pain and a breast mass and was initially diagnosed with mastitis. The fourth patient, who had stage IIIb disease, was diagnosed 8 months postpartum after noticing a 7-cm lump while breastfeeding, associated with asymmetry and a bloody discharge. Median age of first delivery for the six patients was 22.5 years (range 17–29 years).
Of these 11 patients, two had a strong family history of breast cancer (defined as at least one first-degree relative with breast cancer before the age of 50 years or two or more relatives with breast cancer, at least one a first-degree relative). Six patients had a weak family history of breast cancer (defined as any lesser degree of family history of breast cancer). Three had no family history of breast cancer. Nine patients had a positive family history for any malignancy. No patients were tested for genetic mutation. One patient had a prior diagnosis of malignancy (Hodgkin lymphoma, diagnosed and treated with mantle and abdominal radiotherapy 5 years before presentation with breast carcinoma). No other patients received prior radiotherapy or chemotherapy. Two patients had a history of fibrocystic change before diagnosis, but the rest did not have any previous known breast disease.
The time from onset of symptoms to presentation was 0.8 months (or 26 days; range 0.1 to 3 months). Time between presentation and biopsy diagnosis was 1.1 months (range 0–16 months). Time between onset of symptoms and biopsy diagnosis was 3 months (range 0.2–19 months). Reasons for delayed biopsy beyond 1 month after presentation are summarized in Table 5.
Only 2 of the 11 young women had a suspected diagnosis of breast carcinoma after the initial clinical history and examination. Of the two, one patient had a history of Hodgkin lymphoma. The other patient was 24 years of age with a weak family history but had a visible 4-cm hard breast mass with an irregular edge.
Biopsy diagnosis was most commonly performed by wide local excision or lumpectomy. A positive diagnosis for malignancy was made in three of five patients who had a breast ultrasonography performed (sensitivity, 60%), four of six patients who had mammography performed (sensitivity, 66%), one patient who had a computerized tomographic scan of the breast, one of two patients who had fine needle aspiration cytology performed (50% sensitivity), and in both of the two patients who had core needle biopsy performed (sensitivity, 100%). One patient with bloody nipple discharge had a ductogram, which was negative.
We evaluated known factors that may lend support to management with surgical excisional biopsy in young women who present with a breast mass (Table 6). All 11 patients with known clinical presentation had at least one suspicious feature identified on initial clinical history, examination, or imaging. Two patients had one suspicious feature, four had two suspicious features, two had three, one had four, and two had six.
Patients were treated with a combination of surgery, chemotherapy, and radiotherapy. Eight were treated by mastectomy, one had lumpectomy followed by wide local excision, and one had lumpectomy and axillary node dissection. The patient with widely metastatic disease had palliative care only. Of the 10 patients who had surgery, all had adjuvant chemotherapy except one patient with stage 1a disease; four had adjuvant radiation. Three patients (one with stage I disease and a history of Hodgkin lymphoma, and others with stage IIIa and IIIb disease) had both regional and local recurrences 11–25 months after original diagnosis (median 19 months) that were managed with local surgery, chemotherapy, and radiotherapy. Two patients had other malignancies diagnosed after original diagnosis. One patient had a contralateral breast cancer diagnosed 11 years after original diagnosis, and stage III ovarian carcinoma diagnosed 19 years after original diagnosis. Another patient had a contralateral breast carcinoma diagnosed 2 years after original diagnosis. Median duration of clinical follow-up from biopsy diagnosis was 25.5 months (range 0–371 months). Median duration of follow-up by any means was 44.5 months (range 0–371 months). At time of last follow-up, four patients had died from disease, one had died from disseminated ovarian carcinoma, five were alive with no evidence of disease, and two were alive with disease. Eight patients had duration of follow-up for at least 5 years. All of those with stage I (2/2) and II disease (2/2) were alive at 5 years, whereas no patients with stage III (0/3) or IV disease (0/1) were alive at 5 years. Overall 5-year survival was 50%.
Breast masses are common in young women and mostly benign.5,16–18 In one clinical study, 3.2% of young women presenting for any reason were found on physical examination to have a breast mass.16 In a retrospective review of 185 surgically treated breast masses occurring in adolescent patients at the Mayo Clinic, 2.6% (4 cases) were malignant: a primary rhabdomyosarcoma, a metastatic rhabdomyosarcoma, a metastatic neuroblastoma, and one case of non-Hodgkin lymphoma.5 Similarly, in another study of 178 breast masses in patients aged 20 years or younger, no carcinomas were found.19 Dehner et al17 found one case of breast cancer in a review of 374 breast masses in patients younger than 20 years of age, and Corpron et al12 reported 10 cases of infiltrating carcinoma (nine ductal, one lobular) in 16 patients 13–19 years of age referred to M. D. Anderson Cancer Center with malignant breast masses.
This 70-year population-based study confirms that breast carcinoma in young women is rare. Similarly, between 1992 to 2002, data from the Surveillance, Epidemiology and End Results (SEER) database demonstrated the age-adjusted incidence rate of breast cancer in white girls and women under the age of 25 years to be 1.7 per million person-years in 15- to 19-year-olds and 12.0 per million for 20- to 24-year-olds. Corresponding figures for African American young women are 3.4 and 24.8 per million.20
The overall 5-year relative survival for 2001–2007 from 17 SEER geographic areas for women of all ages with breast cancer was 89%, with survival being 99% for localized disease, 84% for disease with regional spread, and 23% for metastatic disease.9 In contrast, survival for younger women with breast cancer is less favorable.21 Poorer survival, in young patients, could be related to reduced screening, more aggressive disease, and delayed diagnosis. Seventy percent of women older than 40 years participate in screening mammography,22 resulting in earlier disease detection. Consequently, the proportion of breast cancer patients who present with a palpable mass has declined from 70% in 1983 to 44%.23,24 In the year 2000 at our institution, 57% of breast cancers treated with surgery were screen-detected. Median age of patients was 60 years, median tumor size was 1.5 cm; invasive ductal carcinoma was present in 60%; and stage I, II, and III cancers were detected in 46%, 33%, and 4%, respectively.24
A study of more than 1 million women with breast cancer recorded in the American College of Surgeons Cancer Database between 1998 and 2005 demonstrated that women younger than 40 years of age were more likely to present with more advanced (stage III or IV) disease (20% compared with 13.5%), and they were more likely to have infiltrating ductal carcinoma (76.9 compared with 67.9), as did the patients in this study.25 Furthermore, younger women still have significantly poorer survival even after adjusting for stage, histology, and grade.26
We found that delayed diagnosis in young women results from delayed presentation and biopsy, similar to other reports.12 Pregnancy may have been a contributing factor as also described in previous reports,27 although in one patient diagnosed at 12 weeks of gestation the antenatal visit may have afforded an opportunity for a breast examination not otherwise scheduled. Sensitivity of mammograms and ultrasound examinations has been reported as 55% and 58%, respectively, attributed to the nodularity of breast tissue.10 Most patients in this study did not undergo imaging or core biopsy, as these diagnostic techniques were not commonly used during the entire period of observation of the study. Of the 11 patients in whom clinical presentation was known, all had at least one concerning feature on original clinical history that required consideration of immediate biopsy.
The triple test (palpation, ultrasound examination by an experienced breast imager, and core needle biopsy) is currently considered the gold standard for evaluation of breast masses in women younger than 30 years.10 Excisional biopsy is now reserved for the patient in whom the core needle is nondiagnostic; when there is discordance among the pathology, physical examination, and radiologic appearance; or for patients who will not tolerate a core needle biopsy, such as younger patients under age 18 years. There is growing evidence that core needle biopsy is not routinely required in evaluation of breast masses in young women, except where metastatic disease is suspected.5 In a review of 357 patients aged 25 years or younger with a breast mass consistent with a fibroadenoma on ultrasound scan, 0.8% were found to have a benign phyllodes tumor, 0.3% had a breast carcinoma, and the rest had benign disease.28 Furthermore, phyllodes tumors may display heterogeneity on histologic assessment, and needle biopsy alone may be indeterminate.29 Our report did not identify any patients younger than 18 years with breast cancer. It has been the authors' practice and recommendation that small, discrete, mobile breast masses in teenagers undergo clinical with or without ultrasound surveillance, unless there are concerning clinical features or features on imaging that would warrant surgical excision regardless.2,3 In Box 1, we propose criteria for either surgical excisional biopsy or interim core needle biopsy, which may be a useful tool in the evaluation of a young woman with a breast mass. Around 10% of patients under 40 years with breast cancer harbor a BRCA1 or BRCA2 mutation,30 and those older than 18 years would also be offered genetic testing; the benefits of testing in adolescent women are not as clearly established.31
The limitations of this study include the fact that it does not evaluate the incidence of all breast masses in the study population and so we cannot comment on the relative frequency of metastases or stromal tumors in the breast. Because only evaluation data on patients with breast cancer are reported, no comment can be made about the specificity of clinical findings and diagnostic imaging modalities for breast masses in young women. The findings may not be generalizable to all young women, because the Olmsted County study population was 98% white and mainly of non-Hispanic ethnicity, and the observations span several decades.
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© 2011 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.