What syndrome is associated with breast carcinoma and gallbladder carcinoma?

Peutz-Jeghers Syndrome

The syndrome associated with both breast carcinoma and gallbladder carcinoma is Peutz-Jeghers syndrome (PJS), caused by germline pathogenic variants in the STK11 (LKB1) gene. 1

Defining Features of Peutz-Jeghers Syndrome

PJS is a multi-system autosomal dominant disorder characterized by:

• Gastrointestinal hamartomatous polyposis 1
• Mucocutaneous hyperpigmented macules (melanotic pigmentation) 1
• Dramatically elevated cancer risks across multiple organ systems 1, 2

Cancer Risk Profile

The cancer burden in PJS is exceptionally high:

• Overall lifetime cancer risk: 93% (relative risk 15.2 compared to general population) 2
• Breast cancer risk: 32-54% by age 60-80, comparable to BRCA1/2 mutation carriers 1, 2
• Gastrointestinal cancers including colorectal (39%), gastric (29%), small intestine (13%), and pancreatic (36%) 1, 2
• Biliary tract tumors including gallbladder carcinoma 1

Gallbladder Carcinoma Association

Gallbladder involvement in PJS occurs through two mechanisms:

• Primary gallbladder carcinoma has been documented in PJS patients, representing the first reported case of this association in 1987 3
• Hamartomatous polyps can develop in the gallbladder itself, consisting of normal lining epithelium and pseudopyloric gland-type metaplastic cells without cellular atypia 3
• The carcinoma typically arises in areas separate from the hamartomatous polyps 3

Clinical Distinction from Other Syndromes

It is critical to distinguish PJS from other hereditary cancer syndromes:

• BRCA1/2 mutations (Hereditary Breast/Ovarian Cancer syndrome) increase risk of breast, ovarian, pancreatic, and prostate cancers but are NOT associated with gallbladder carcinoma or gastrointestinal polyposis 1, 4
• Li-Fraumeni syndrome (TP53) causes early-onset breast cancer, sarcomas, brain tumors, and adrenocortical carcinoma—not gallbladder cancer 1, 5
• Cowden syndrome (PTEN) confers 67-85% breast cancer risk with thyroid and endometrial cancers—not gallbladder involvement 1, 5
• Hereditary Diffuse Gastric Cancer (CDH1) causes lobular breast cancer and diffuse gastric cancer—not gallbladder carcinoma 1, 5

Surveillance Requirements

Patients with confirmed or suspected PJS require intensive multi-organ surveillance:

• Breast surveillance starting at age 25: Annual mammography (or MRI if mammography limited) and semiannual clinical breast examination 2
• Gastrointestinal surveillance starting at age 8-18: Upper endoscopy, colonoscopy, and small bowel series every 2-3 years with removal of all polyps >1 cm 2
• Pancreatic surveillance starting at age 25: Endoscopic ultrasound (EUS) every 1-2 years, as EUS is superior to CT/MRI for early lesion detection 2
• Gynecologic surveillance starting at age 21-25: Annual pelvic examination with Pap smear, transvaginal ultrasound, and CA-125 for ovarian (21% risk) and uterine (9% risk) cancers 2

Critical Clinical Pitfalls

Avoid these common errors in PJS management:

• Do not falsely reassure patients with negative STK11 testing if characteristic melanotic pigmentation is present—full surveillance protocols should still be followed 2
• Do not overlook symptoms of cholecystitis in PJS patients with breast cancer history, as this may indicate either primary gallbladder carcinoma or metastatic disease (particularly from lobular breast cancer) 3, 6, 7
• Do not miss adenoma malignum (aggressive cervical adenocarcinoma) on Pap smears, which is overrepresented in PJS with mean diagnosis age 34 years and poor prognosis 2
• Recognize that intussusception occurs in 47% of PJS patients (95% in small intestine), making aggressive endoscopic polyp management essential to prevent life-threatening complications 2

Breast Cancer Characteristics in PJS

When breast cancer develops in PJS patients:

• Median age at diagnosis is 45 years (range 26-67) 8
• Most are ductal carcinomas (invasive or DCIS) with favorable characteristics 8
• Typically estrogen receptor positive (14/15 cases), with no triple-negative breast cancers reported 8
• Five-year survival is 73%, suggesting relatively favorable prognosis 8
• Bilateral synchronous or metachronous tumors can occur 9, 8