Hamartoma

BASICS

DESCRIPTION

Hamartoma was first described by Albrecht in 1904.
Defined as a focal tumorlike malformation composed of the tissues normally found in that site of the body but in abnormal proportion or in disarray
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. Because of 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 á
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. 8% 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. True incidence unknown because many are asymptomatic.

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 mass. (HH) can cause gelastic (laughing) seizures (GS) and generalized seizures. See "History."Ł 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): inherited disorder characterized by hamartomas in different body organs, mainly in the brain, skin, retina, kidney, liver, lung, and heart (rhabdomyoma)
Peutz-Jeghers syndrome: autosomal dominant. Variable penetrance. STK11 gene mutation. 50% are de novo mutations. Hamartomatous polyps of jejunoileum, stomach, duodenum, and colon. Typical pigmentation of lips, oral mucosa, digits, palms, and soles. Increased risk of cancers of the GI tract, pancreas, cervix, ovary, and breast. Breast cancer risk is 50%.
PHTS comprises Cowden, Bannayan-Riley-Ruvalcaba (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 lifetime 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"Ł once thought to have 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.
Neurofibromatosis-1: associated with pigmented iris hamartomas (Lisch nodules). Lesions are present in 94% of patients >6 years of age. Autosomal dominant transmission, locus 17q11.2.
Birt-Hogg-Dub ę 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. Has been suggested the syndrome be renamed Horstein-Birt-Hogg-Dub ę.

RISK FACTORS

Predisposition due to known inherited disorders; see below. á

DIAGNOSIS

HISTORY

Lung: Endobronchial lesions frequently cause recurrent pulmonary infections, hemoptysis, and obstructive symptoms (wheezing, stridor, atelectasis). Parenchymal lesions are usually asymptomatic, found on CXR.
Breast: may present as palpable mass or can be found on mammogram.
Brain: hypothalamic neuronal hamartoma. Wide spectrum of symptoms. Mild form: seizures associated with mechanical laughing (GS) and no cognitive impairment. In GS, laughter-like vocalizations are accompanied by facial contractions, flushing, increased HR and respirations. Severe form: Catastrophic encephalopathy, generalized seizures, early onset GS, precocious puberty, behavioral disorders, mental impairment are seen.
Spleen: Splenic hamartoma may be accompanied by thrombocytopenia or other signs of hypersplenism.
Nerve: Fibrolipomatous hamartoma (FLH) may present with symptoms of nerve compression. Median nerve is most commonly affected; can present with symptoms of carpal tunnel syndrome and are easily compressible.
GI tract: Hamartomas may cause bleeding, intussusception, abdominal distention, or obstruction. Neuromuscular and vascular hamartoma of the small bowel is a rare submucosal condition that can cause obstruction. Cecal hamartoma can cause intussusception.
Liver: Mesenchymal hamartoma of the liver is a rare benign lesion, most often seen in infants. Can present in the first 2 years of life with abdominal swelling and palpable abdominal mass; can undergo malignant transformation to undifferentiated sarcoma.
Retina: presents most frequently as painless loss of vision; can also cause metamorphopsia, floaters, or strabismus
Omentum: Omental-mesenteric myxoid hamartoma (OMMH) presents with abdominal distention and vomiting in children.
Cardiac rhabdomyoma: most commonly left ventricle; may be asymptomatic or, depending on location, cause outflow tract obstruction, heart failure, arrhythmias, or death

PHYSICAL EXAM

Breast: Mammary hamartoma may be a palpable mass.
Tailgut cyst: Retrorectal cystic hamartoma presents as mass in presacrococcygeal area. Usually adults, sometimes children. Malignant transformation can occur.
Skin: Exam may reveal typical physical findings of one of the inherited syndromes listed previously (e.g., Cowden syndrome, Birt-Hogg-Dub ę). Sporadic nodules and papules may be present. Hemangiomas are a common hamartoma.
Uterus: Uterine fibroids can cause enlarged uterus.
Shoulder, axilla, and upper arm: Fibrous hamartoma of infancy is seen in the first 2 years of life and presents as a subcutaneous mass. It may be found in other locations such as the thigh. Pathology reveals a mixture of adipose tissue, primitive mesenchymal cells, and fibrous tissue.
Chest wall/rib: Cartilaginous and vascular hamartoma (mesenchymoma) is a lesion of infancy. Most are present as a mass at birth, but can occur in the first year. Predominantly cartilage; large, expansile tumor.
Nose: Nasal chondromesenchymal hamartoma is the upper respiratory equivalent of the chest wall lesion and presents as an intranasal or paranasal polypoid mass in infants.
Face: striated muscle hamartoma (rhabdomyosarcomatous mesenchymal hamartoma). In infants, mass is usually located centrally on the chin or near nasal alae.
Inguinal lymph nodes: enlarged and palpable due to angiomyolipomatous hamartoma (variant of angiomatous hamartoma); rare nodal smooth muscle proliferation.

DIFFERENTIAL DIAGNOSIS

Related to tissue affected
Breast: fibroadenoma, fibrocystic change, carcinoma, pseudoangiomatous stromal hyperplasia (PASH)
Lung: malignancy, other solitary lung nodules
Kidney: renal malignancy, other renal masses
GI tract: other polypoid lesions, adenomas, carcinoma

DIAGNOSTIC TESTS & INTERPRETATION

Lung: Peripheral lung hamartomas are usually an incidental finding on CXR. Endobronchial lesions, often polypoid, can be seen in an air-displacing mass within the bronchi on CXR. Parenchymal masses have been described as sharply defined, lobulated, usually <3 cm in size, "coin lesion."Ł Popcorn calcifications are seen in 1/3. CT may help distinguish parenchymal lung hamartomas from malignancy due to the presence of fat in the lesion.
Breast: Hamartoma (fibroadenolipoma or adenolipoma) can vary in appearance on mammogram based on the proportion of fat and fibrous tissue in the lesion. Typically well circumscribed, with a lucent halo. Classic appearance is "a breast within a breast"Ł because it is made up of the normal breast components.
Hypothalamus: MRI, generally 1 to 2 cm lesion bulging into the suprasellar cistern. Attached to tuber cinereum or mammillary body. Hamartomas of the brain are isointense on T1- and hyperintense on T2-weighted images on MRI.
Kidney: Cystic hamartoma of the kidney is a lesion of the renal pelvis, an intrarenal multicystic mass, seen on CT.
Uterus: Transvaginal US or CT can show presence of fibroids.
Peripheral nerve hamartomas (FLH) have characteristic appearance on MRI, such as coaxial cable-like appearance on axial planes and spaghetti-like appearance on coronal planes.

Diagnostic Procedures/Other

Biopsy when indicated. Method of biopsy and whether to biopsy depend on tissue affected and associated conditions. Core needle biopsy versus excisional biopsy. Classic MRI findings of FLH mean no biopsy is needed.
Bile duct hamartoma (von Meyenburg or Moschowitz complex) presents as multiple small, white nodules throughout the liver, and can be mistaken for metastases at laparotomy or laparoscopy.

Test Interpretation

Depends on tissue of origin. Will conform to definition in "Description"Ł given earlier
Cartilage is present in 96% of parenchymal lung hamartomas and 82% of endobronchial lesions. Peripheral lesions in the lung are an admixture of fibrous tissue, cartilage, and fat. Bile duct hamartomas appear as a focally disorderly collection of bile ducts surrounded by fibrous stroma.
Cystic hamartoma of the renal pelvis comprises a mixture of benign mesenchymal and epithelial components.
HH: large mature neurons embedded in myelinated and nonmyelinated axons. Can elaborate gonadotrophin-releasing hormones and growth hormone-releasing factor
Breast hamartomas contain varying amounts of fibrous tissue, glandular structures, and fat. May be "myxoid,"Ł containing smooth muscle

TREATMENT

MEDICATION

Antiseizure medication if epilepsy is present. Poor success rate for HH. mTOR inhibitors show promise in TSC and other epileptogenic mTORopathies (7). á

ISSUES FOR REFERRAL

Management of HH is best done in specialized comprehensive epilepsy centers. á

ADDITIONAL THERAPIES

Many are part of syndromes and require management by multiple disciplines. á

SURGERY/OTHER PROCEDURES

Endobronchial resection or sleeve resection required for central lung lesion causing symptoms. Surgical wedge resection or enucleation may be required for peripheral enlarging lesions.
Breast: Fine needle aspiration and core needle biopsy (CNB) are not sufficient to establish the diagnosis. As coexisting malignancy can occur, excision is recommended (8).
Thoracolumbar hamartomas can involve the spinal canal and surgical correction, division of immobilized filum; can improve neurologic symptoms.
Core biopsy or excisional biopsy may be needed for symptomatic breast masses or those lacking classic mammogram findings.
Skin hamartomas may require shave biopsy or laser resurfacing.
HH are best treated by excision/disconnection from hypothalamus. Advances in anterior transcallosal interforniceal approach, endoscopic approach, and extended skull-base surgery have resulted in seizure control in 52-66%. Gamma knife radiosurgery and image-guided robotic radiosurgery are safe approaches for small HH.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Continued surveillance for patients at higher risk of malignancy (e.g., Peutz-Jeghers, Cowden syndromes). Annual follow-up postresection of HH to assess seizure control. á

PATIENT EDUCATION

The Tuberous Sclerosis Alliance, 801 Roeder Rd, Suite 750, Silver Springs, MD 20910 (www.tsalliance.org).
National Association for Rare Disorders, 55 Kenosia Avenue, Danbury, CT 06813.
Peutz-Jeghers Syndrome Support Group: http://www.mdjunction.com/peutz-jeghers-syndrome
Hypothalamic hamartoma support: hopeforhh.org.

PROGNOSIS

Depends on organ affected and whether sporadic or inherited. á

COMPLICATIONS

Tissue dependent á

REFERENCES

11 Striano áS, Santulli áL, Ianniciello áM, et al. The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives. Epilepsy Behav. 2012;24(1):7-13.22 Mester áJ, Eng áC. When overgrowth bumps into cancer: the PTEN-opathies. Am J Med Genet Semin Med Genet. 2013;163(2):114-121.33 Orloff áMS, He áX, Peterson áC, et al. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am J Hum Genet. 2013;92(1):76-80.44 Ngeow áJ, Stanuch áK, Mester áJL, et al. Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations. J Clin Oncol. 2014;32(17):1818-1824.55 Pilarski áR, Burt áR, Kohlman áW, et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013;105(21):1607-1616.66 Hendriks áYM, Verhallen áJT, van der Smagt áJJ, et al. Bannayan-Riley-Ruvalcaba syndrome: further delineation of the phenotype and management of PTEN mutation-positive cases. Fam Cancer. 2003;2(2):79-85.77 Curatolo áP, Moavero áR. mTOR inhibitors as a new therapeutic option for epilepsy. Expert Rev Neurother. 2013;13(6):627-638.88 Guray áM, Sahin áAA. Benign breast diseases: classification, diagnosis, and management. Oncologist. 2006;11(5):435-449.

ADDITIONAL READING

OMIM: http://www.ncbi.nlm.nih.gov/omim
Rosenfeld áJV. The evolution of treatment for hypothalamic hamartoma: a personal odyssey. Neurosurg Focus. 2011;30(2):E1.

CODES

ICD10

Q85.9 Phakomatosis, unspecified á

ICD9

759.6 Other hamartoses, not elsewhere classified á

SNOMED

hamartoma (disorder)
hamartoma of lung (disorder)
Hamartoma of brain
vascular hamartomas (disorder)
Liver hamartoma
Hamartoma of skin
Hamartoma of muscle
Splenic hamartoma
Hamartoma of intestine

CLINICAL PEARLS

Hamartomas are disorganized growths of native cells in native tissues. Symptoms vary with tissue of origin; many are found incidentally.
The majority are benign; malignant transformation is more common in certain conditions (e.g., Cowden syndrome).
GS is a feature of HH.
Lung hamartomas can cause popcorn calcifications on CXR.
Breast hamartomas can have well-circumscribed appearance on mammogram of "a breast within a breast."Ł

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