Description

• Hamartoma was first described by Albrecht in 1904.
• Defined as nonneoplastic disorganized growths of native cells in native tissues
• Can occur in many different organs, including bile ducts, brain cortex, breast, bladder, cerebellum, skin, heart, muscle, hypothalamus, kidney, liver, pancreas, omentum, spleen, GI tract (including polyps of colon, small intestine, stomach, and esophagus), lung (both parenchyma and endobronchial), tailgut, peripheral nerves, iris, lymph nodes, uterus, and retina
• Hamartomas can be sporadic or associated with inherited syndromes, solitary or multiple, asymptomatic, or profoundly symptomatic. Due to the diversity of their locations and the severity of symptoms, appropriate imaging modalities, treatment, and follow-up will depend on tissue of origin.

Epidemiology

Can be hard to assess because many hamartomas are asymptomatic

Incidence

• Depends on organ system affected
• Breast hamartomas are not common; estimated incidence is 0.1–0.7%.
• Hamartomas of the lung are the most common benign lung tumor, found in 0.025–0.32% of a series of autopsies. 10% of solitary lung nodules are hamartomas. Parenchymal lung lesions are more common in men; central lesions have equal sex incidence.
• Hypothalamic hamartoma (HH) occurs in 1 in 200,000 individuals. Congenital HH are found as part of Pallister-Hall syndrome.
• Uterine fibroids are a common hamartoma.

Prevalence

• Depends on organ and inherited predisposition
• Biliary hamartomas (von Meyenburg complexes) were found in 0.6% of liver biopsies.
• Cowden disease: 85% had colon hamartomas at colonoscopy. However, Cowden disease affects only 1 in 200,000 individuals.
• Breast: 8 cases of hamartoma per 20,000 mammograms
• Kidney: renal hamartoma (angiomyolipoma) found in 40–80% of patients with tuberous sclerosis

Etiology and Pathophysiology

• Functional disorder will depend on tissue of origin. Breast hamartomas may cause a palpable, painless mass. HH can cause gelastic (laughing) seizures (GS) and generalized seizures (see “History”). HH itself generates GS and starts process of secondary epileptogenesis responsible for refractory focal or generalized epilepsy (1).
• In PTEN hamartoma tumor syndrome (PHTS), pathophysiology is related to function of protein product of PTEN gene. Normal function is inhibition of AKT/mTOR and MAPK signaling, leading to regulation of cell growth and promotion of cell death. Loss of function, therefore, causes overproliferation of cells and hamartomatous tumors (2).
• Several theories have been proposed for the development of lung hamartomas, but the cause of these benign neoplastic proliferations is unknown. Multiple cartilaginous lung hamartomas can be seen in Carney syndrome.
• Bile duct hamartomas are more common in polycystic liver and kidney disease.

Genetics

• Tuberous sclerosis complex (TSC): autosomal dominant disorder characterized by hamartomas in different body organs, mainly in the brain, skin, retina, kidney, liver, lung, and heart (rhabdomyoma); generally caused by mutation to TSC1 or TSC2 gene
• Peutz-Jeghers syndrome: autosomal dominant. STK11 gene mutation. 10–20% are de novo mutations. Hamartomatous polyps of the GI tract, majority in the small bowel. There are no distinguishing features of these polyps. Typical pigmentation of lips, oral mucosa, digits, palms, and soles. Increased risk of cancers of the GI tract, pancreas, uterus, ovary, and breast. Breast cancer risk is 50%.
• PHTS comprises Cowden, Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus, and Proteus-like syndromes.
  • Cowden syndrome (multiple hamartoma syndrome): autosomal dominant phakomatosis, variable expression. 80% from mutations of PTEN at locus 10q23.3 (3). Multiple cutaneous trichilemmomas, oral papillomatosis, acral keratoses, macrocephaly/megalencephaly, GI polyps, cerebellar gangliocytomas, mammary hamartomas, thyroid abnormalities, and increased risk of breast, endometrial, thyroid, kidney, and colorectal cancer. Breast cancer cumulative risk as high as 85.2% in affected females, with a 29% risk of a second primary breast cancer within 10 years (4). Skin lesions in 90–100% (punctate palmoplantar keratoses). Revised diagnostic criteria exclude benign breast disease, uterine fibroids, and GU malformations (5).
  • BRRS: also autosomal dominant. Besides hamartomas, they have multiple subcutaneous lipomas, macrocephaly, and penile lentigines; they lack the high penetrance of cancer seen in Cowden syndrome (6).
  • Lhermitte-Duclos disease: part of Cowden syndrome; hamartoma of cerebellum, macrocephaly, progressive cerebellar ataxia, signs of increased ICP
  • Joseph Merrick “The Elephant Man” once thought to have neurofibromatosis-1 (NF1), reclassified as having Proteus syndrome, a much rarer condition
  • PTEN hamartoma of soft tissue is a distinctive lesion in PTEN syndromes: intramuscular mass (usually thigh) manifesting by age 15 years
• Beckwith-Wiedemann syndrome (BWS): associated with hamartoma of the bladder. 15% of cases of BWS are familial, involving abnormalities 11p15.
• NF1: associated with tan pigmented iris hamartomas (Lisch nodules). These are best visualized by direct ophthalmoscopy. Lesions are present in 94% of patients >6 years of age; autosomal dominant transmission, locus 17q11.2
• Birt-Hogg-Dubé syndrome (BHDS): autosomal dominant, mutation in folliculin gene (FLCN) 17p11.2. Characterized by cutaneous hamartomas, pulmonary cysts, spontaneous pneumothorax, and kidney tumors. Renal angiomyolipoma in BHDS has been described, suggesting that FLCN and TSC proteins may function on a common pathway.

Risk Factors

Predisposition due to known inherited disorders; see below.