Hamartoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

A hamartoma (from Greek hamartion “bodily defect”) is a focal malformation that resembles a neoplasm in the tissue of its origin. Hamartoma is a non-malignant tumor, and it grows at the same rate as the surrounding tissues. It is composed of an overgrowth of mature cells and tissues that normally occur in the affected area.^[1] They emerge in many different parts of the body and are most often asymptomatic and undetected unless seen on an image taken for another reason (incidentaloma). The most common hamartomas occur in the lungs. About 5–8% of all solitary lung nodules, and about 75% of all benign lung tumors, are hamartomas. Hamartomas mostly arise from connective tissue and are generally formed of cartilage, fat, and connective tissue cells, although they may include many other types of cells.^[2] Hamartomas must be differentiated from other diseases that cause abnormal tissue growth and calcification, such as calcified metastases and lipomas.^[3] Surgery is the mainstay of treatment for hamartomas.^[4]

Hamartomas were first described by Eugen Albrecht, a German pathologist, in 1904.^[5]

Hamartomas may be classified into different types based on their location, such as: lung (most common), heart, hypothalamus, kidneys, or spleen. Other classifications can consider lesion class, dividing hamartomas into 4 different categories, such as bone-forming, cartilage-forming, fiber-forming and benign non–matrix-forming.^[6]

Hamartomas arise from connective tissue and are generally formed of cartilage, fat, and connective tissue cells, although they may include many other types of cells. They can be located in lung (most common), heart, hypothalamus, kidneys, or spleen. The pathogenesis consists primarily of disorganized replication of normal tissue cells. There are many genetic syndromes that cause multiple hamartomas, such as Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome, and Cowden’s syndrome. Genes involved in the pathogenesis of harmatomatous syndromes include: BMPR1A, SMAD4, PTEN, and STK11.^[7][6]

The causes of hamartomas have not been identified.^[4][8]

The incidence of pulmonary hamartoma is approximately 0.25% in general population.^[9] The incidence of other hamartomas remains unknown.^[10][11] Pulmonary hamartomas are estimated to be 8% of all lung neoplasms. Most lesions are diagnosed incidentally.^[12][13] Hamartomatous syndromes are usually first diagnosed among adolescents and adult patients.^[10] In general, most hamartomas affect males more commonly than females.^[10]

The most potent risk factors in the development of hamartomas are familial hamartomatous syndromes, such as: Cowden’s syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, PTEN hamartoma tumor syndrome, hereditary mixed polyposis syndrome, tuberous sclerosis, and Bannayan-Riley-Ruvalcaba syndrome.^[3]

Screening for sporadic hamartoma is not recommended. However, according to the American College of Gastroenterology (ACG), screening for multiple hamartomas by genetic evaluation is recommended among patients with hamartomatous polyposis syndromes, such as juvenile polyposis syndrome, Peutz-Jeghers syndrome, and Cowden’s syndrome.^[3]

Hamartomas must be differentiated from other diseases that cause abnormal tissue growth and calcifications, such as calcified metastases, and lipomas.^[3]

If left untreated, hamartomas normally grow slowly and may progress to develop a considerable size, however pulmonary hamartomas have low or no malignant potential. Nevertheless, it is essential to rule out the presence of cancer. Common complications of hamartomas will depend on the location and size. Prognosis is generally regraded as excellent.^[14]

There is no established system for the staging of hamartomas.

Hamartomas are usually asymptomatic. However, in some cases such as, hypothalamic hamartomas and pulmonary hamartomas, symptoms may be more noticeable. In hypothalamic hamartomas, gelastic seizures, visual problems, early onset of puberty, and behavioral problems are the most reported.^[13] On the other hand, symptoms of pulmonary hamartoma may result as a respiratory obstruction and include chronic cough, hemoptysis, or fever.^[13] It is important to obtain the history about familial inheritance, as it provides insight into the associated conditions.

Patients with hamartoma usually have a normal appearance. Physical examination shows no remarkable findings.^[13]

There are no diagnostic laboratory findings associated with hamartoma. However, in some cases complete blood count, serum electrolytes, urea, and alkaline phosphatase levels may be indicated if the tumor becomes symptomatic.^[15]

On chest radiography, lung hamartomas are characterized by showing a sharply demarcated pulmonary nodule and popcorn calcifications (feature of chondroid calcification in hamartomas).^[10]

CT scan is the imaging modality of choice for the diagnosis of pulmonary hamartoma. On CT scan, hamartoma is characterized by focal collections of fat, a lesion with a smooth edge, and collections of fat alternating with foci of calcification.^[16][17]

MRI is the modality of choice for assessment of hypothalamic, spleen, kidney, and other abdominal hamartomas. On MRI, hamartoma is characterized by a heterogeneous signal in T1 and high signal due to fat and cartilaginous components in T2.^[13]

On ultrasound, splenic hamartomas are hyperechoic solid masses, with or without cystic changes, and are hypervascular in Doppler ultrasound.^[18]

Bronchoscopy may be useful to obtain biopsy and evaluate symptomatic bronchial hamartomas.^[16]

There is no medical therapy for hamartomas; the mainstay of therapy is surgical treatment.^[19][4]

Surgery is the mainstay therapy for hamartomas.^[4]

There is no established method for prevention of hamartomas.

Secondary prevention strategy for multiple hamartoma syndromes includes periodical imaging surveillance with CT scan.^[20]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Vamsikrishna Gunnam M.B.B.S [3]

Hamartoma name is derived from a greek word meaning fault or defect. Hamartomas were first described by Eugen Albrecht, a German pathologist, in 1904.

• Hamartoma was first described by the German pathologist Eugen Albrecht (1872-1908) in 1904.^{[1] [2]}
• He was the first person to describe the difference between hamartoma and choristoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Vamsikrishna Gunnam M.B.B.S [3]

Hamartomas may be classified into different types based on their location, such as lung (most common), heart, hypothalamus, kidneys, or spleen. Other classification method considers lesion class, dividing hamartomas into 4 different categories, such as bone-forming, cartilage-forming, fiber-forming, and benign non–matrix-forming.

Based on the location, hamartomas can be classified into the following types:^[1][2]

Based on the lesion class, hamartomas may be classified into the following types:^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Vamsikrishna Gunnam M.B.B.S [3]

Hamartomas usually arise from connective tissue and are generally composed of cartilage, fat, and connective tissue cells. Hamartomas can be found in the lungs (most common), heart, hypothalamus, kidneys, or spleen. The pathogenesis primarily consist of disorganized replication of normal tissue cells. Many hereditary syndromes are associated with hamartomatous formation. These include Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome, and Cowden’s syndrome. Genes that are involved in the pathogenesis of hamartomatous syndromes include BMPR1A, SMAD4, PTEN, and STK11.

• Hamartomas occur in the same location as the normal tissue (in the tissue of its origin) as opposed to choristomas, which grow in other tissues (different from its origin).
• The pathogenesis primarily consists of disorganized replication of normal tissue cells. The underlying mechanisms for the replication abnormality are not fully understood.^[1]
• Hamartomas arise from connective tissue and are generally formed of cartilage, fat, and connective tissue cells, although they may include many other types of cells.
• Hamartomas grow at the same rate as the normal cells of the organ.^[2]
• These can be located in the lungs (most common), heart, hypothalamus, kidneys, or spleen.^[1]

• Bone-forming tumors (bone islands) are most commonly located in the intramedullary bones of:^[3][4][5]
  • Pelvis
  • Femur
  • Humerus
  • Ribs
• Bone-forming tumors are masses that are small, white-yellow and round.
• Tumors greater than 2 cm in size are known as giant bone islands.

• It is understood that cartilage-forming tumors like osteochondroma is produced from abnormal cartilaginous epiphyseal growth plate tissue and abnormal regulation of cartilage proliferation.^[6][7][8]

• Cartilage-forming tumors are termed as congenital error of epiphyseal development.

• It is understood that fiber-forming tumors is produced from continued growth of fibrous cortical defects that extrude into the medullary cavity.
• The most commonly involved bone are tibia and the femur.

• Lung hamartomas mostly arise from connective tissue and are generally formed of cartilage, fat, and connective tissue cells, although they may include many other types of cells.
• About 5-8% of all solitary lung tumors and about 75% of all benign lung tumors are hamartomas.
• The majority of pulmonary hamartomas form from connective tissue on the outside of the lungs, although about 10% form in the linings of the bronchi.
• In the majority of patients, it can be difficult to distinguish hamartoma from malignancies.^[2]
• Pulmonary hamartomas can be divided into two subtypes endobronchial and parenchymal.
• An endobronchial location is described in 3%–20% of all pulmonary hamartomas. This subtype is mainly composed of cartilage and fibrous tissue.
• Endobronchial hamartomas typically contain more fat tissue than parenchymal hamartomas.

• Cardiac rhabdomyomas are hamartomas comprised of altered cardiac myocytes that contain large vacuoles and glycogen.
• Cardiac hamartomas arises from the striated muscle cells (cardiac myocytes), which are normally involved in the coordinated contractions of cardiac muscle cells.
• Development of cardiac hamartomas is the result of multiple genetic mutations.
• Mutations in the TSC1 or TSC2 genes are related with tuberous sclerosis.
• There is a strong association between cardiac rhabdomyomas and tuberous sclerosis (characterized by hamartomas of the central nervous system, kidneys and skin, as well as pancreatic cysts; 25-50% of patients with cardiac rhabdomyomas will have tuberous sclerosis.
• Cardiac hamartoma symptoms will depend on the size of the tumor and location relative to the conduction system.
• For more information on heart hamartoma, See here.

• Hypothalamic hamartoma is a benign tumor composed of disorganized collections of neurons and glia.
• Hypothalamic hamartoma is a non-neoplasic heterotopia that typically occurs in the region of the hypothalamus. This tumor arises from the tuber cinereum, a part of the hypothalamus located between the mamillary bodies and the optic chiasm.
• Unlike other hamartomas, hypothalamic hamartoma is symptomatic; it most often causes gelastic seizures, visual problems, and rage disorders associated with hypothalamic diseases.
• For more information on hypothalamic hamartoma, See here

• Spleen and kidney hamartomas may impinge on blood vessels, resulting in a risk of serious bleeding.
• Because hamartoma typically lacks elastic tissue, it may lead to the formation of aneurysms and thus possible hemorrhage. When a hamartoma impinges into a major blood vessel, such as the renal artery, hemorrhage may be life-threatening.^[1]
• Hamartoma of the kidney is also called angiomyolipoma and can be associated with tuberous sclerosis.
• Spleen hamartomas are often associated with hematologic abnormalities and spontaneous rupture.
• For more information on angiomyolipoma, See here.

• Genes involved in the pathogenesis of harmatomatous syndromes include:^[9]

• BMPR1A
• SMAD4
• PTEN
• STK11

• Hereditary syndromes associated with hamartomatous formation include:^[10]
  • Juvenile polyposis syndrome
  • Peutz-Jeghers syndrome
  • Hereditary mixed polyposis syndrome
  • PTEN hamartoma tumor syndrome
  • Tuberous sclerosis
  • Cowden syndrome
  • Bannayan-Riley-Ruvalcaba syndrome

• On gross pathology, a hallmark feature of hamartoma is a well-circumscribed mass that may show a variegated yellow and white appearance, which corresponds to fat and cartilage, respectively.^[11]
• Hamartomas are unencapsulated, lobulated tumors with connective tissue septa.
• Tumor size ranges between 1 and 3 cm in diameter at the time of diagnosis.

• On microscopic pathology, hamartomas have benign tumors features such as disorganized (non-neoplastic) growth, tissue of the region within it is found, and no invasion to surrounding tissue or structures.^[11]
• Common findings include:

• Cartilage single cells in lacunae surrounded by abundant matrix and paucicellular vis-a-vis malignant lesions
• Fat (adipocytes)
• Respiratory epithelium (columnar epithelium with cilia), only present in lung hamartoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Vamsikrishna Gunnam M.B.B.S [3]

The cause of hamartomas has not been identified.

The cause of hamartomas has not been identified.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Syed Hassan A. Kazmi BSc, MD [3]

Hamartomas must be differentiated from other diseases that cause abnormal tissue growth and calcifications, such as calcified metastases and lipomas.^[1]

Hypothalamic Hamartomas

• The differential diagnosis is broadly that of suprasellar and hypothalamic lesions, although the imaging characteristics of hypothalamic hamartomas significantly reduces the differential.
• Hypothalamic-chiasmatic glioma is the main differential.
• Other lesions encountered in the region either have markedly different signal intensity or demonstrate enhancement on MRI.^[2]
• The table below summarizes the findings that differentiate hypothalamic hamartoma from other conditions that are also suprasellar and hypothalamic lesions.^[3]

Pulmonary Hamartomas

• The differential diagnosis of pulmonary hamartoma is dependent on CT scan imaging features.
• The differential is dependent on whether fat or calcification is identifiable within the lesion. If fat is visualized then the differential is narrow, with almost all cases representing pulmonary hamartoma.
• If neither fat nor calcification is present, then the differential is that of a solitary pulmonary nodule and is significantly broader.
• The table below summarizes the findings that differentiate pulmonary hamartoma from other conditions that cause a fat containing solitary pulmonary nodule.

Heart Hamartomas

• The table below summarizes the findings that differentiate cardiac hamartoma from other conditions that cause a fat containing lesion within the striated muscle of the heart.

Spleen, Kidney and Vascular Organs

• The table below summarizes the findings that differentiate spleen, kidneys, and vascular organs from other conditions that cause incidental findings similar to hamartoma.

Cardiac fibroma or fibrous hamartoma should be differentiated from other cardiac tumors that present as a cardiac mass. The following are the differentials:^{[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Vamsikrishna Gunnam M.B.B.S [3]

The incidence of pulmonary hamartoma is approximately 0.25% in general population. The incidence of other hamartomas remains unknown. Pulmonary hamartomas are estimated to be 8% of all lung neoplasms. Most lesions are diagnosed incidentally. Hamartomatous syndromes are usually first diagnosed among adolescents and adult patients. In general, most hamartomas affect males more commonly than females.

• The incidence of pulmonary hamartoma is approximately 0.25% in general population.^[1][2][3]
• The incidence of bone-forming tumors is approximately 1% in general population.
• Pulmonary hamartomas are estimated to be 8% of all lung neoplasms. The majority of pulmonary hamartomas are diagnosed incidentally.^[4][5]
• The incidence of other hamartomas remains unknown.

• Pulmonary hamartomas are usually first diagnosed among patients in the 4th and 7th decades of life.^[2]
• Bone islands often occur in children than adults.
• Pulmonary hamartomas are very uncommon in children.^[2]
• Hypothalamic hamartomas are usually first diagnosed during puberty.^[6]
• Cardiac hamartomas are usually first diagnosed among adolescents and young adults.^[7]
• Kidney hamartomas are usually first diagnosed among middle age adults.^[8]

• Males are more commonly affected with pulmonary hamartomas than females. The male to female ratio is approximately 3 to 1.^[2]
• Males are slightly more affected with hypothalamic hamartomas than females. The male to female ratio is approximately 1.3 to 1.
• Females are more commonly affected with kidney hamartomas than males. The female to male ratio is approximately 4 to 1.
• Cardiac hamartoma affects males and females equally.
• Osteosarcomas most commonly affect males than females.

• There is no racial predilection to hypothalamic hamartoma.^[9]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Vamsikrishna Gunnam M.B.B.S [3]

The incidence of pulmonary hamartoma is approximately 0.25% in general population. The incidence of other hamartomas remains unknown. Pulmonary hamartomas are estimated to be 8% of all lung neoplasms. Most lesions are diagnosed incidentally. Hamartomatous syndromes are usually first diagnosed among adolescents and adult patients. In general, most hamartomas affect males more commonly than females.

• The incidence of pulmonary hamartoma is approximately 0.25% in general population.^[1][2][3]
• The incidence of bone-forming tumors is approximately 1% in general population.
• Pulmonary hamartomas are estimated to be 8% of all lung neoplasms. The majority of pulmonary hamartomas are diagnosed incidentally.^[4][5]
• The incidence of other hamartomas remains unknown.

• Pulmonary hamartomas are usually first diagnosed among patients in the 4th and 7th decades of life.^[2]
• Bone islands often occur in children than adults.
• Pulmonary hamartomas are very uncommon in children.^[2]
• Hypothalamic hamartomas are usually first diagnosed during puberty.^[6]
• Cardiac hamartomas are usually first diagnosed among adolescents and young adults.^[7]
• Kidney hamartomas are usually first diagnosed among middle age adults.^[8]

• Males are more commonly affected with pulmonary hamartomas than females. The male to female ratio is approximately 3 to 1.^[2]
• Males are slightly more affected with hypothalamic hamartomas than females. The male to female ratio is approximately 1.3 to 1.
• Females are more commonly affected with kidney hamartomas than males. The female to male ratio is approximately 4 to 1.
• Cardiac hamartoma affects males and females equally.
• Osteosarcomas most commonly affect males than females.

• There is no racial predilection to hypothalamic hamartoma.^[9]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Vamsikrishna Gunnam M.B.B.S [3]

Screening for sporadic hamartoma is not recommended. However, according to the American College of Gastroenterology (ACG), screening for multiple hamartomas by genetic evaluation is recommended among patients with hamartomatous polyposis syndromes such as juvenile polyposis syndrome, Peutz-Jeghers syndrome, and Cowden syndrome.

According to the American College of Gastroenterology, screening for multiple hamartomas is recommended among patients with :^[1][2][3][4]

• Genetic evaluation
• Annual thyroid ultrasound
• Skin check with physical examination
• Monthly breast self-examination, annual breast and endometrial screening (mammogram, transvaginal ultrasound, biopsy, and MRI may also be incorporated)^[1]
• Colonoscopy
• Renal imaging

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Vamsikrishna Gunnam M.B.B.S [3]

If left untreated, hamartomas normally grow slowly and may progress to develop a considerable size, however pulmonary hamartomas have low or no malignant potential. Nevertheless, it is essential to rule out the presence of cancer. Common complications of hamartomas will depend on the location and size.Prognosis is generally regarded as excellent.

• If left untreated, hamartomas normally grow slowly and may progress to develop a considerable size, however hamartomas no malignant potential. Nevertheless, it is essential to rule out the presence of cancer.^[1]

• Common complications of hamartomas will depend on the location and size of the tumor.^[2]
• Large hamartomas are associated with more complications.
• Hamartomas are more likely to cause major complications when located in the hypothalamus, spleen, or kidneys.

• Prognosis is generally regarded as excellent because most osteochondromas cease to grow when skeletal maturity is achieved^[1]
• The prognosis of patients with enchondromatosis is difficult to assess.
• The prognosis also varies with the size and location of tumor, small hamartomas have the most favorable prognosis.

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