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GIT Pathology (Small and Large Intestines (Colorectal Cancer (Molecular…

- - - - Chromosomal Instability Pathway (85% of colorectal cancers)
        
        Loss of function of tumour suppressor genes:
        
        APC, K-RAS, SMAD2, SMAD4, p53, telomerase
        
        Associated familial syndrome:
        
        Familial polyposis coli
        
        Precursor lesion:
        
        Tubular/villous adenoma
        
        Colorectal cancer type:
        
        Typical adenocarcinoma
        
        Amount of DNA:
        
        Aneuploid or polyploid
        
        Typical location:
        
        L-sided (descending colon)
        
        Degree of differentiation:
        
        Highly differentiated
        
        Little presence of lymphocytic infiltration
        
        Rarely mucinous
        
        Worse prognosis
      - Microsatellite Instability Pathway (15% of colorectal cancers)
        
        Loss of function of DNA mismatch repair genes:
        
        MSH2, MSH6, MLH1, TGF-beta-RII, BAX, BRAF
        
        Associated familial syndrome:
        
        Hereditary non-polyposis colorectal cancer
        
        Precursor lesion:
        
        Sessile serrated adenoma
        
        Colorectal cancer type:
        
        Mucinous adenocarcinoma (may have signet-ring cells)
        
        Amount of DNA:
        
        Diploid
        
        Typical location:
        
        R-sided (ascending colon)
        
        Degree of differentiation:
        
        Poorly differentiated
        
        Marked presence of lymphocytic infiltration
        
        Often mucinous
        
        Better prognosis
    - - Familial Adenomatous Polyposis (FAP)
        
        Hereditary AD disorder (APC gene mutation)
        
        Development of numerous colorectal adenomas as
        teenagers, with 100% of untreated cases developing
        colorectal adenocarcinoma often before 30 years old
        
        Standard treatment: Prophylactic colectomy
        
        Associations:
        
        Adenomas of GIT:
        
        Stomach, adjacent to ampulla of Vater
        
        Extra intestinal manifestations:
        
        Congenital hypertrophy of retinal pigment epithelium
        
        Neoplastic syndromes:
        
        Garder syndrome (intestinal adenomas + osteomas + thyroid tumours etc)
        
        Turcot syndrome (intestinal adenomas + CNS tumours)
      - Hereditary Non-polyposis Colorectal Cancer (HNPCC)
        
        Hereditary AD disorder (MSH2, MSH6, MLH gene mutations)
        
        Predominantly R colonic involvement, with the development of sessile serrated adenomas
        
        Amsterdam criteria: 3 family members with cancer, 2 generations apart, 1 with early onset cancer (before age of 50)
    - - Right-sided (ascending colon) colorectal cancers
        
        Polypoid, exophytic masses
        
        Obstruction is uncommon
        
        Often called to clinical attention due to iron deficiency anaemia
      - Left-sided (descending colon) colorectal cancers
        
        Annular, encircling lesions that produce napkin-ring constrictions of the bowel
        
        Can produce obstruction
        
        Often presents as
        
        Occult bleeding
        
        Changes in bowel habits
        
        Cramping, left lower quadrant pain
- - - - Histology:
        
        Active inflammation
        
        Intraepithelial neutrophils which may accumulate in gastric pits to form crypt abscesses
        
        Subepithelial macrophages, plasma cells & lymphocytes which in severe cases may form lymphoid follicles with germinal centres
        
        Regenerative changes
        
        Mitoses in epithelium, loss of mucous vacuoles
        
        Intestinal metaplasia
        
        Appearance of goblet cells
        
        Mucosal atrophy
        
        Loss of glandular structures and specialised cells
        
        Potentially:
        
        Hyperplasia --> Dysplasia --> Carcinoma in situ --> Carcinoma
        
        Endoscopically:
        
        Erythematous antral mucosa with coarse/nodular appearance
      - Pathological Effects and Complications:
        
        Mostly asymptomatic
        
        PUD
        
        Chronic atrophic gastritis
        
        Malignancies (gastric carcinoma, gastric lymphoma)
  - - - Etiology and Associations:
        
        H. pylori chronic gastritis (intestinal metaplasia as a precursor lesion)
        
        Diet (nitrites, smoked food, lack of vegetables)
        
        Cigarette smoking
        
        Partial gastrectomy (allows reflux of bile, induces chronic gastritis)
        
        Barrett oesophagus (increased risk of GE junction tumours
      - Gastric Cancer Classification - Lauren System
        
        1. Intestinal type (majority)
        
        Asc with env risk factors
        
        Asc with gastric atrophy, intestinal metaplasia
        
        Men > Women
        
        Increasing incidence with age
        
        Microscopy:
        
        Gland formation (well formed, lined by cuboidal to columnar epithelium cells)
        
        Pattern of genetic alterations resemble colonic carcinoma
        
        Papillary, mucinous, tubular
        
        Haematogenous spread
        
        Microsatellite instability
        
        APC gene mutations
        
        p53, p16 inactivation
        
        2. Diffuse type
        
        Asc with familial risk factors: Blood type A
        
        Women > Men
        
        Younger age group
        
        Poorer prognosis
        
        Microscopic:
        
        Poorly differentiated signet ring cells - large cytoplasmic mucin vacuoles and peripherally displaced crescent-shaped nuclei
        
        Transmural/lymphatic spread
        
        Decreased E-cadherin (CDH1 mutation)
        
        APC gene mutations
        
        p53, p16 inactivation
      - 3 macroscopic growth patterns:
        
        Exophytic growth (typical of intestinal types)
        
        Excavated growth (typical of intestinal types)
        
        Flat growth (typical of diffuse types)
        
        Extensive infiltration of a broad region of the stomach in advanced flat growth patterns creates a rigid, thickened leather bottle appearance of the stomach termed linitis plastica (metastatic lung & breast cancers to the stomach can also give a similar appearance)
      - Clinical Features:
        
        Insidious clinical course
        
        Remains asymptomatic until late in its course
        
        Non-specific symptoms:
        
        Weight loss, abdominal pain, anorexia, vomiting, altered bowel habits, dysphagia, anaemia, hematemesis
        
        Prognostic factors:
        
        Depth of invasion (most impt)
        
        Nodal and distant metastasis
        
        Metastases to supraclavicular nodes (Virchow’s node, Trousseau’s sign) may be first clinical manifestation
        
        Death due to widespread seeding of peritoneum and lung/liver metastases; also distant metastases to adrenal gland, peritoneum, ovary, spleen
        
        HER-2 (allows Tx with Trastuzumab)
        
        Treatment:
        
        Surgical resection with or without adjuvant chemotherapy and radiotherapy
        
        Prognosis:
        
        5-year survival rate for surgically treated early gastric cancer = 90-95%; that for advanced
        gastric cancer < 15%
    - - Etiology and Associations:
        
        Setting of chronic atrophic gastritis with secondary hypergastrinemia
        
        Multiple endocrine neoplasia type I
        
        Zollinger-Ellison syndrome
        
        Note: all of them results in a hypergastrinemic state which causes ECL cell hyperplasia, a presumed precursor lesion
      - Morphology:
        
        Gross:
        
        Intramural or submucosal masses that create small polypoid lesions
        
        May ulcerate through epithelial or serial surfaces
        
        Histology:
        
        Islands or uniform cells with scant, pink granular cytoplasm and a round stippled nucleus
        
        Positive immunohistochemical staining for endocrine granule markers (chromogranin A, synaptophysin)
      - Clinical Features:
        
        Carcinoid syndrome
        
        Due to release of vasoactive substances into systemic circulation
        
        Characterised by cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, diarrhoea, R-sided cardiac valvular fibrosis
        
        Note: carcinoids confined to the GIT typically do not cause carcinoid syndrome as vasoactive substances produce undergo ‘first-pass’ effect in liver, hence carcinoid syndrome is strongly associated with metastatic disease
        
        Prognostic Factors - Location:
        
        Gastric carcinoids: good prognosis
        
        Midgut carcinoids: very aggressive
- - - - Pleomorphic Adenoma (50%)
        
        Beingn epithelial (mixed) neoplasm
        
        Associations:
        
        Most common tumour of the salivary glands (90%)
        
        10x more common in the parotid gland
        
        40 years old
        
        Gross:
        
        Lobulated, unencapsulated knobbly mass
        
        Solid and firm
        
        Whitish translucent
        
        Histology:
        
        Epithelial components (ducts, squamous metaplasia)
        
        Myoepithelial component
        
        Chondromyxoid component
        
        Clinical Features:
        
        Painless, slow-growing mass
        
        Prone to recurrence due to lack of a true capsule
        
        Malignant transformation is rare - if happens, will become adenocarcinoma or undifferentiated carcinoma
      - Warthin Tumour (5-10%)
        
        Benign neoplasm
        
        Associations:
        
        2nd most common tumour of the salivary glands in SG
        
        Occurs almost exclusively in the superficial lobe of the parotid gland
        
        Male, 50-70 years
        
        Gross:
        
        Bilateral (10%), multifocal (10%)
        
        Oval or round encapsulated mass
        
        Soft, pale, grey
        
        Contains cystic spaces filled with milky secretions
        
        Histology:
        
        Cystic spaces lined by double layer of epithelial cells
        
        Dense lymphoid stroma with germinal centres