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Journal of Clinical Oncology, Vol 24, No 3 (January 20), 2006: pp. 525-527 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.0447
CASE 4. Fibrocystic Breast Disease in a 16-Year-Old Female With PTEN Hamartoma Tumor Syndrome
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX CASE 4. Fibrocystic Breast Disease in a 16-Year-Old Female With PTEN Hamartoma Tumor Syndrome A 16-year-old African American female presented to the breast clinic seeking evaluation. Specialists from an outside medical facility had previously recommended bilateral prophylactic mastectomy due to the presence of a strikingly large number of breast masses and the resultant inability to screen breast tissue effectively. Breast examination revealed subtle visual protrusions from underlying masses. Palpation confirmed the presence of almost confluent masses, leading to the impression that the breast tissue was virtually totally replaced with nodules. As mammography and sonography were thought to be inadequate for effective screening, magnetic resonance imaging (MRI) was requested. The MRI findings included more than 100 breast masses replacing approximately 70% of breast area. Figure 1 demonstrates sagittal T1 (Fig 1A), 3-D 2-mm T1 (Fig 1B), and postcontrast 3-D 2-mm fat-suppressed T1 (Fig 1C) MRI images of the right breast. As demonstrated by small arrows in Figure 1, the individual spherical lesions were of varied sizes, ranging from a barely perceptible 1 to 2 mm to approximately 2.5 cm, with predominantly homogenous early prominent contrast enhancement. Because of the morphology and number of discrete lesions, combined with the clinical presentation, malignancy as a cause of the lesions was considered very unlikely. The innumerable masses, however, create significant difficulty in using MRI to exclude early malignancy in the future. A large lipoma, 17 cm in length, was also found (large arrow in Fig 1). This large lesion paralleled the chest wall deep to the pectoralis muscles and also consisted of a 4-cm component extending into the breast itself. The patient's medical history included macrocephaly diagnosed shortly after birth, multiple lipomas in the abdomen and left groin regiondiagnosed at age 4 years, and a history of thyroid disease, with adenomatous hyperplasia diagnosed and managed with partial thyroidectomies at ages 5 and 15 years. She developed her first breast lump at age 13 years, roughly coincident with the onset of puberty, and had several subsequent breast biopsies revealing fibroadenoma with features of tubular adenoma. Her family history was also significant for breast and uterine cancers, including one maternal cousin reportedly diagnosed with breast cancer at age 19 years. These combined histories strongly suggested a clinical diagnosis of either Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS), two proliferative disorders included in the PTEN hamartoma tumor syndrome (PHTS). The patient was referred for genetic evaluation, and subsequent testing revealed a four base pair deletion (955del4) in exon 8 of the PTEN gene. This confirmed both the suspected diagnosis of PHTS and her significantly increased risk for developing breast cancer.
PHTS is a proliferative disorder caused by germline mutation of the PTEN gene. It is comprised of four clinical entities including CS, BRRS, Proteus syndrome (PS), and Proteus-like syndrome.1-4 Although the clinical presentation of these four disorders differs significantly, all have increased likelihood of benign tumor growth. A diagnosis of PHTS is reserved for patients with a confirmed PTEN mutation, as it is yet unknown whether mutation of other genes may be responsible for a subset of patients meeting clinical criteria for these disorders. Research indicates that roughly 85% of individuals meeting clinical criteria for CS and 65% of individuals meeting criteria for BRRS have an identifiable PTEN mutation.2,5-7 A diagnosis of PHTS carries with it significant risk for malignancy. Breast cancer is of particular concern in CS patients, as lifetime risk is estimated at 25% to 50%.8-10 Furthermore, a review of breast cancer histology in patients clinically diagnosed with CS revealed a high frequency of ductal carcinoma in situ, sclerosis, adenosis, and fibrocystic change.10 Although it remains unclear whether BRRS and PS patients have comparable risk, conservative treatment is suggested for those with a confirmed PTEN mutation.2,4 The average age of breast cancer diagnosis in CS patients is between 38 and 46 years, with the youngest reported case occurring at age 14 years.8,9 Additional cancer risks include thyroid, uterine, and possibly other cancers.4,9,11 Of the four entities listed above, CS and BRRS display the highest degree of clinical overlap and are the two most likely to present with fibrocystic breast disease and macrocephaly. Other characteristic findings of BRRS include thyroid disease, lipomas, hemangiomas, hamartomatous polyps of the small and large intestine, freckling of the penis, and mental retardation/developmental delay.12 Characteristic findings of CS include fibrocystic breast disease, thyroid abnormalities, gastrointestinal hamartomas, uterine fibroids, and macrocephaly.9,13 Mucocutaneous lesions such as trichilemmomas, papillomatous papules, and acral keratoses are pathognomonic for CS and are found in virtually 100% of CS patients by age 30 years.9,14 Although uncommon, severe fibrocystic breast disease may present during early adolescence and may indicate an underlying genetic syndrome. This is especially true when seen in combination with other features such as thyroid disease, macrocephaly, and mucocutaneous lesions of the face and oral mucosa. Distinguishing between the syndromic patient and the patient with isolated findings can be critically important, given the significantly increased risk for breast and other cancers and the possibility of risk reduction through early detection of malignancy. Diagnostic criteria for PHTS, along with current guidelines for screening can be found at http://www.genetests.org.15 Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
ACKNOWLEDGMENTS This work was supported by the Doris Duke Distinguished Clinical Scientist Award (CE) and the Children's Cancer Fund Distinguished Professorship in Pediatric Oncology Research (GT). We thank Rob Pilarski, genetic counselor and research coordinator of the Cowden-PTEN study. REFERENCES 1. Nelen MR, Padberg GW, Peeters EAJ, et al: Localization of the gene for Cowden disease to 10q22-23. Nat Genet 13:114, 1996[CrossRef][Medline] 2. Marsh DJ, Kum JB, Lunetta KL, et al: PTEN mutation spectrum and genotype phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 8:1461-1472, 1999 3. Zhou XP, Hampel H, Thiele H, et al: Association of germline mutation in the PTEN tumor suppressor gene and Proteus and Proteus-like syndromes. Lancet 358:210-211, 2001[CrossRef][Medline] 4. Pilarski R, Eng C: Will the real Cowden syndrome please stand up (again)? Expanding the mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 41:323-326, 2004 5. Liaw D, Marsh DJ, Li J, et al: Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16:64-67, 1997[CrossRef][Medline] 6. Marsh DJ, Coulon V, Lunetta KL, et al: Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 7:507-515, 1998 7. Zhou XP, Waite KA, Pilarski R, et al: Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet 73:404-411, 2003[CrossRef][Medline] 8. Brownstein MH, Wolf M, Bikowski JB: Cowden's disease: A cutaneous marker of breast cancer. Cancer 41:2393-2398, 1978[CrossRef][Medline] 9. Starink TM, van der Veen JP, Arwert F, et al: The Cowden syndrome: A clinical and genetic study in 21 patients. Clin Genet 29:222-233, 1986[Medline] 10. Schrager CA, Schneider D, Gruener AC, et al: Clinical and pathological features of breast disease in Cowden's syndrome: An underrecognized syndrome with an increased risk of breast cancer. Hum Pathol 29:47-53, 1998[CrossRef][Medline] 11. Eng C. Will the real Cowden syndrome please stand up: Revised diagnostic criteria. J Med Genet 37:828-830, 2000 12. Gorlin RJ, Cohen MM Jr., Condon LM, Burke BA: Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet 44:307-314, 1992[CrossRef][Medline] 13. Lloyd KM, Dennis M: Cowden's disease: A possible new symptom complex with multiple system involvement. Ann Intern Med 58:136-142, 1963 14. Brownstein MH, Mehregan AH, Bikowski JV: Trichilemmomas in Cowden's syndrome. JAMA 238:26, 1977 15. Pilarski R, Hampel H, Eng C: PTEN Hamartoma tumor syndrome (PHTS): Gene Reviews. Available at http://www.genetests.org. Accessed December 16, 2006
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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