Hamartoma pathophysiology

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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]

Overview

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. These can be located in the lungs (most common), heart, hypothalamus, kidneys, or spleen. The pathogenesis consists primarily of the disorganized replication of normal tissue cells. Many hereditary syndromes are associated with hamartomatous formation; these include: Peutz-Jeghers syndrome, PTEN hamartoma tumour syndrome, and Cowden's syndrome. Genes involved in the pathogenesis of harmatomatous syndromes include: BMPR1A, SMAD4, PTEN, and STK11.

Pathogenesis

• 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 consists primarily of the disorganized replication of normal tissue cells. The underlying mechanisms for the replication abnormality are not fully understood.
• 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 organ from whose tissue they are made.
• These can be located in lung, heart, hypothalamus, kidneys, or spleen. In general, most hamartomas occur in the lungs.

Lung

• 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 of 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.
• 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.

Heart

• 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 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

Hypothalamus

• 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

Kidneys, spleen, and other vascular organs

• 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.
• 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

Genetics

• Genes involved in the pathogenesis of harmatomatous syndromes include:

• BMPR1A
• SMAD4
• PTEN
• STK11

Associated Conditions

• Many hereditary syndromes are associated with hamartomatous formation, these include:
  • Juvenile polyposis syndrome
  • Peutz-Jeghers syndrome
  • Hereditary mixed polyposis syndrome
  • PTEN hamartoma tumour syndrome
  • Tuberous sclerosis
  • Cowden syndrome
  • Bannayan-Riley-Ruvalcaba syndrome

Gross Pathology

• 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.
• Hamartomas are unencapsulated, lobulated tumors with connective tissue septa.
• Tumoral size ranges between 1 and 3 cm in diameter at the time of diagnosis.

Microscopic Pathology

• 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.
• 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

Gallery

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  Low magnification micrograph of a pulmonary hamartoma. H&E stain.

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  Pulmonary hamartoma: the surrounding lung falls away from the well-circumscribed mass, a typical feature of these lesions. The hamartoma shows a variegated yellow and white appearance, which corresponds respectively to fat and cartilage.

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  Gross pathology of pulmonary hamartoma.

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  Epithelial lined clefts within myxoid fibrous connective tissue.