Flashcards in 18.06.28 Carcinomas Deck (27):
What is carcinoma?
Cancer that develops from epithelial cells
What are some of the different histological types?
o Adenocarcinoma: Glandular origin
E.g. Invasive Ductal Carcinoma (most common form of breast cancer)
o Hepatocellular Carcinoma. Form of adenocarcinoma. Most common type of liver cancer
o Renal Cell Carcinoma. Form of adenocarcinoma. Multiple subtypes associated with specific hereditary syndromes
o Squamous Cell Carcinoma. Squamous cell origin i.e. in the skin, lining of the digestive tract. E.g. Papillary thyroid carcinoma
What is the meaning of carcinoma in situ?
Carcinoma in situ refers to cells that are significantly abnormal but are not (yet) cancer.
What are some of the features and of renal cell carcinoma including age of onset?
1. Most common adult renal tumour.
2. Arise from the proximal tubular epithelium
3. Rarely present before 40 years of age. 4. Most RCCs are sporadic and commonly associated with deletion of the short arm of chromosome 3.
What is the clinical presentation of renal cell carcinoma including age of onset?
Patients with RCC may present with:
2) loin pain
5) weight loss
7) anaemia (from depression of EPO)
8) hypertension (due to the excess secretion of renin by the tumour).
Approximately 5% of patients will have polycythaemia.
How many RCC patients will have disease associated with a hereditary syndrome?
Give a brief overview of von Hippel-Lindau syndrome including incidence, inheritance pattern and clinical features.
1) Autosomal Dominant
2) Loss of function of the VHL tumour suppressor
3) Mutation spectrum: point mutations, partial and complete deletions
Incidence 1:35,000 (Haas et al 2014)
1. Malignant RCC (clear cell type) in 35-75% of affected individuals
4. Renal cysts
Which hereditary syndromes are associated with renal cell carcinoma?
2. Herediatry papillary RCC
3. Hereditary leiomyomatosis and RCC
4. Birt-Hogg-Dubé syndrome
5. Tuberous sclerosis
6. Hereditary Paraganglioma/phaeochromocytoma
7. BAP1 Tumour Predisposition Syndrome
8. Chromosome 3 Translocations
Give a brief overview of Hereditary papillary RCC syndrome including inheritance pattern and clinical features.
1) Autosomal Dominant
2) Mutation in MET proto-oncogene
3) Mutations in MET (receptor tyrosine kinase) lead to auto-phosphorylation of the receptor and increased downstream signalling.
1. Type 1 papillary RCC
2. Multiple/bilateral tumours
3. Family history of RCC
4. ‘Metastatic potential is low’
Give a brief overview of Hereditary leiomyomatosis and RCC (HLRCC)syndrome including inheritance pattern and clinical features.
1) Autosomal Dominant
2) Fumarate hydratase (FH) – enzyme in the tricarboxylic acid (Krebs) cycle
3) Mutations in FH result in alteration to the metabolism.
4) Penetrance estimates vary (for RCC) from 10-50%
1. Multiple Cutaneous Leiomyomas
2. Single cutaneous leiomyoma (with family history)
3. Uterine leiomyoma
4. Papillary type 2 RCC
5. Prone to early metastases and local invasion
6. Requires aggressive management
Which gene is associated with hereditary papillary RCC?
Which gene is associated with hereditary leiomyomatosis and RCC (HLRCC)
FH - fumarate hydratase
What proportion of tuberous sclerosis patients develop renal tumous?
What is the incidence of tuberous sclerosis? Which genes are associated with this condition?
1 in 58,000
What are the features of BAP1 tumour predisposition syndrome?
Somatic mutations in BAP1 are associated with higher tumour grade and decreased survival.
Mutations in BAP1 have recently been identified as predisposing to RCC amongst other cancers (below)
1. Atypical Spitz tumours (skin lesion)
2. Uveal (eye) melanoma
3. Malignant Mesothelioma
4. Cutaneous Melanoma
5. Clear cell renal carcinoma
6. Basal cell carcinoma)
What is the association between RCC and chromosome 3 translocations?
Inherited susceptibility to renal cancer due to balanced chromosome 3 translocation.
The rearranged chromosome is thought to be lost during mitosis (at formation of the quadrivalent).
Multiple renal cancer genes are on chromosome 3p including VHL, PBRM1, BAP1 and SETD2.
What are adenocarcinomas?
Adenocarcinoma is a type of cancer that forms in mucus-secreting glands throughout the body
Give some examples of cancer types in which adenocarcinoma is prevalent.
1. Lung cancer: Non-small cell lung cancer accounts for 80 percent of lung cancers, and adenocarcinoma is the most common type (30-50%).
2. Prostate cancer: Cancer that forms in the prostate gland is typically an adenocarcinoma, which makes up 99 percent of all prostate cancers. Androgen related genes form fusion partners with ERG. Eg. NDRG1/ERG fusion
3. Pancreatic cancer: Exocrine pancreatic cancer tumors are called adenocarcinomas. They form in the pancreas ducts.
4. Esophageal cancer: Cancer that forms in the glandular cells of the esophagus is known as adenocarcinoma. This is the most common type of esophageal cancer.
5. Colorectal cancer: Cancer that develops in the intestinal gland cells that line the inside of the colon and/or rectum is an adenocarcinoma. It makes up 95 percent of colon and rectal cancers (see 18.06.04)
What are squamous cell carcinomas?
Squamous cell carcinoma is a cancer that arises from squamous cells found in the outer layer of skin and in the mucous membranes, which are the moist tissues that line body cavities such as the airways and intestines.
Approx. 30% of lung carcinomas are squamous cell. Mostly due to smoking.
Which sites in the body can head and neck squamous cell carcinoma develop?
Develops in the mucous membranes of the mouth, nose, and throat. HNSCC is classified by its location: it can occur in the 1. mouth (oral cavity)
2. The middle part of the throat near the mouth (oropharynx)
3. the space behind the nose (nasal cavity and paranasal sinuses)
4. the upper part of the throat near the nasal cavity (nasopharynx),
5. the voicebox (larynx)
6. The lower part of the throat near the larynx (hypopharynx).
What is the presentation of HNSCC?
Depending on the location:
1. abnormal patches or open sores (ulcers) in the mouth and throat
2. unusual bleeding or pain in the mouth
3. sinus congestion that does not clear,
4. sore throat
6. pain or difficulty swallowing
7. a hoarse voice
8. difficulty breathing
9. enlarged lymph nodes.
Which genes have been associated with HNSCC?
CDKN2A, FAT1, HRAS, NOTCH1, PIK3CA, PTEN, TP53.
Give an overview of heaptocellular carcinoma
1. Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm.
2. It is the fifth most common cancer and the third most common cause of death from cancer worldwide.
3. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes.
4. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age.
5. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes.
Which genes have been associated with hepatocellular carcinomas?
Somatic mutations in a number of different genes have been identified in hepatocellular carcinoma (HCC) and hepatoblastoma. These include TP53, MET , CTNNB1 , PIK3CA , AXIN1 , and APC .
Which is the main oncogenic pathway activated in HCC?
Activation of the Wnt/β-catenin pathway is the main oncogenic pathway in HCC with recurrent mutations identified in CTNNB1, AXN1, TP53 and CDKN2A. NGS studies have identified new recurrent activating mutations of TP53 and ATM and also in genes coding for proteins involved in chromatin structure and maintenance (ARID1A & ARID2) in 10% of HCC
Another signalling pathway identified by NGS is the NRF2/KEAP1 pathway. NGS has identified mutations in many more putative driver genes.
Which chromsome alterations are frequently observed in HCC?
A number of chromosome alterations are frequently observed in HCC tumours (see Liu et al for review and table). Gains of 1q are most frequent with 1q21 the minimal region containing CHDL1. See in >50% of HCC patients. 8q amplification (8q24 c-Myc and PTK2)