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. They can be located in lung (most common), heart, hypothalamus, kidneys, or spleen. The pathogenesis consists primarily of the disorganized replication of normal tissue cells. There are many genetic syndromes that cause multiple hamartomas, such as; 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).
• Hamartomas grow along with, and at the same rate as, the organ from whose tissue they are made.
• These benign tumors result from an abnormal formation of normal tissue, although the underlying reasons for the abnormality are not fully understood.

Lung

• In general, most hamartomas occur in the lungs.
• About 5-8% of all solitary lung tumors and about 75% of all benign lung tumors are hamartomas.
• They 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.
• 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.
• 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, and up to 100% of patients with tuberous sclerosis will have cardiac masses by echocardiography.
• Cardiac hamartoma symptoms depend on the size of the tumor, location relative to the conduction system, and whether it obstructs blood flow.
• Symptoms are usually from congestive heart failure. If patients survive infancy, their tumors may regress spontaneously; resection in symptomatic patients has good results.

Hypothalamus

• A hypothalamic or tuber cinereum hamartoma is benign non neoplasic heterotopia in the brain that typically occurs in the region of the hypothalamus, arising 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, and can cause visual problems, other seizures, rage disorders associated with hypothalamic diseases, and early onset of puberty.
• The symptoms typically begin in early infancy and are progressive, often into general cognitive and/or functional disability.
• 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’s syndrome
  • Bannayan-Riley-Ruvalcaba syndrome

Cowden Syndrome

• Cowden syndrome is a serious genetic disorder characterized by multiple hamartomas.
• Usually patients with Cowden syndrome demonstrate skin hamartomas, and commonly (about 66% of cases) hamartoma of the thyroid gland. Additional growths can form in many parts of the body, especially in mucosa, the GI tract, bones, CNS, the eyes, and the genitourinary tract. The hamartomas themselves may cause symptoms or even death, but morbidity is more often associated with increased occurrence of malignancies, usually in the breast or thyroid.
• For more information on cowden syndrome, See here

Tuberous Sclerosis

• Tuberous sclerosis is a syndrome caused by potentially by more than 900 mutations of the tumor suppressor genes for tuberin (TSC2) and hamartin (TSC1) that cause abnormal cellular signaling through the rapamycin complex 1.
• Tuberous sclerosis is characterized by multiple hamartomas, angiomyolipomas (in 80%), and lymphangioleiomyomatosis.
• Important clinical features include: epilepsy, learning difficulties, and skin tumors.
• For more information on tuberous sclerosis, See here

Peutz-Jeghers Syndrome

• Peutz-Jeghers syndrome is an autosomal dominant disorder characterised by the concurrence of hamartomatous intestinal polyps with mucocutaneous melanotic macules usually on the lips, buccal mucosa, and digits.
• The polyps are usually benign, but there is a 15x increase in the risk of colorectal and other cancers compared to the general population.
• Females are more likely to develop granulosa cell ovarian tumours.
• Cancers of the pancreas, stomach, and even multiple myeloma are associated. It is caused by mutations of the STK11 gene at 19p13.3.
• For more information on Peutz-Jeghers syndrome, See here

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.