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NEOPLASTIC SMALL INTESTINE & COLON - Coggle Diagram

- - - - when FOB+, colonoscopy
        
        every salience or endoluminal vegetation (polyps) is searched
  - - - morphology
        
        pedunculated: inflammatory benign, hamartomas, classic adenomas
        
        sessile: hamartomas, hyperplastic / serrated or classic adenomas
        
        flat: hyperplastic or serrated adenomas
      - neoplastic
        potential
        
        non-neoplastic
        
        neoplastic
        
        serrated sessile lesions
        +/- dysplasia
        
        hyperplastic and neoplastic polyps derive from the irregular migration of cells from the proliferation area towards the lumen with hyperplastic "tuft" aspects and saw tooth configuration
    - - inflammatory
        
        pseudopolyps
        
        pedunculated lesions induced by IBD, mainly ulcerative colitis
        
        similar to polyps
        
        formed by residual erythematous mucosa surrounded by ulceration
        
        during endoscopy, the diagnosis is oriented to IBD, but a biopsy is still performed
      - hamartomas
        
        benign growth
        
        abnormal mixture of cells and tissues
        
        pedunculated or sessile and sporadic or hereditary
        
        types
        
        single hamartomatous polyp
        
        sporadic
        
        <2% of children <10 y
        
        not associated with an increased risk of transformation in cancer
        
        multiple polyp
        
        juvenile polyposis syndrome
        
        colorectum (>90%), stomach (15%), duodenum (7%), jejunum and ileum (7%)
        
        germline mutations in the SMAD4 and BMPR1A, related to the TGF beta
        
        more problematic than sporadic form
        
        cystic alteration of the gland: cystic spaces are formed by dilated glands containing aboundant mycin and inflammatory debris
        
        Peutz Jeghers syndrome
        
        hereditary syndrome
        
        germline mutation of the STK11
        
        involvement of the whole GI
        
        non-neoplastic epithelium + smooth muscle components
        
        clinical signs: cafè au lait spots, pigmentation/maculae
        
        Cowden syndrome
        
        autosomal germline mutation of PTEN
        
        frequently associated with other conditions: hamartomas, intestinal lipomas, ganglionuromas, increased lifetime risk of breast (multiple fibroadenomas), thyroid, uterine cancers and other signs (facial trichilemmomas)
      - hyperplastic polyps
        
        asymptomatic, no malignant potential
        
        most common colonic polyp
        
        1-5 mm
        
        most common in the left colon, often multiple
        
        usually found during endoscopy in pts >50y
        
        kudo II pattern (stellate lumen)
      - serrated sessile lesions
        
        bridge between non-neoplastic and neoplastic polyps
        
        large sessile lesions (>5 mm) flat, quite extended with a serrated appearance (sawtooth or stellate)
        
        an immediate mucosectomy is required
        
        without dysplasia
        
        J or L form (not stellate, not straight)
        
        not dysplastic, cells are normal
        
        predilection for the right colon
        
        with dysplasia
        
        cells are darker and more crowded
        
        make sure the lesion is not ivasive
        
        MICROSATELLITE INSTABILITY
        (complete loss of MLH1 expression)
  - - - BRAF
        
        normal mucosa undergoes methylation
        
        microvesicular hyperplastic polyp
        
        crypts are straight and narrow and they are lined by serrated epithelium; a mixture of goblet cells and cells with microvesicular mucin droplets are present
      - KRAS
        
        normal mucosa undergoes modification and becomes goblet cell hyperplastic polyps
        
        many goblet cells
        
        the lumen of the gland is not straight like in microvesicular hyperplastic polyp, but stellate
    - - SSL can evolve in traditional serrated adenoma
      - characterized by
        
        slit-like serration
        
        ectopic crypt formations (epithelial buds)
        
        tall columnar cells with intensely eosinophilic cytoplasm and pencillate nuclei
        
        large protuberant polyps are predominant in the distal colorectum or in the lefto colon (flat lesions)
        
        evaluate the frade of dysplasia
        
        make sure they are not invasive
        (check the lamina propria)
      - microvesicular hyperplastic polyps, sessile serrated polyps +/- dysplasia are more related to BRAF, while goblet cell polyps are more related to KRAS; the traditional serrated adenoma can be due to both
    - - much more frequent than serrated lesions
        
        sporadic or hereditary
        
        growth alterations and monoclonal differentiation that increase the risk of developing an adenocarcinoma
        
        biopsy should be performed carefully
        
        mainly in the left colon
        
        configurations
        
        villous
        (25%)
        
        higher risk, but rare; greater possibility of transformation (40%) into cancer
        
        tubular
        (75%)
        
        only 5% of possibility to transform into cancer
        
        tubulo-villous
        (20%)
        
        minimum cut-off of villous component
      - sequence of degeneration:
        dysplasia -> in situ carcinoma -> invasive carcinoma
        
        adenoma-to-carcinoma sequence
        
        6x risk higher adenoma frequency in colon resected for carcinoma
        
        metachronous carcinoma is 2x more frequent in pts with previous adnoma
        
        75% of pts with carcinoma have other adenomas
        
        inspect the rest of the colon for sentinel adenomas
        
        carcinoma foci are found in adenomas
        
        adenomas are more numerous and larger in populations at higher risk of cancer
        
        molecular dysplasia sequwnce up to invasive carcinoma
        
        alteration of proliferation of cells is believed to take 10–15 ys
      - adenomas are non-invasive neoplastic lesions dysplastic by definition
        
        histological criteria of dysplasia
        
        glandular architecture
        
        abnormal (not the same colour,
        glands abnormally distributed)
        
        muciparous goblet cells reduction
        
        clonal proliferation of cells
        not able to differentiate
        
        crowded nuclei in different layers
        
        not in line
        
        mitosis
        
        in a different location than expected rather than at the base of the crypts towards the surface
        
        dysplasia should be graded
        
        low-grade
        
        even if the lesion is not totally removed, follow up is sufficient
        
        high-grade
        
        it needs to be totally removed (sometimes with surgery and not only with endoscopy)
        
        one or two glands must show this presentation
        
        architectural
        
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        cytological
        
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        high-grade neoplasia is present in only 1% of adenomas smaller than 10 mm
        
        parameters for the diagnosis of the advanced adenoma
        
        dimension: >1 cm
        
        dysplasia: high-grade
        
        villous at histology: >20% of the adenoma
        
        number of adenomas: >3
        
        criteria for referral to surgical resection of cancerous adenoma
        
        depth of lesion
        
        if the lesion is pedunculated, it is more difficult for it to reach deeper layers where lymphatic vessels are present
        
        sessile or flat lesions can invade the submucosa more easily and quickly
        
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        lymphatic vessel invasion is related to lymph node metastases
        
        other parameters
        
        grade of differentiation
        
        neoplastic embolization
        
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        presence of tumoral budding
        
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        state of endoscopic resection margins
        
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    - - familial adenomatous
        polyposis (FAP)
        
        inherited autosomal dominant mutation of Ch5q21 gene, also called Adenomatous Polyposis Coli gene (APC)
        
        most mutations are nonsense
        
        APC gene is a tumor suppressor gene that in this condition is suppressed, leading to the excessive proliferation of cells in each gland of the tissue
        
        without surgical intervention, patients have nearly a 100% risk of developing colorectal cancer
        
        untreated, the mean age of colon cancer diagnosis is 39 years old
        
        A-FAP
        
        attenuated form, with fewer colorectal adenomatous polyps, later age of adenoma appearance and lower cancer risk
        
        extraintestinal manifestations
        
        osteomas
        
        dental abnormalities
        
        congenital hypertrophy of the retinal pigment epithelium
        
        desmoid tumors
        
        extracolonic cancers (thyroid, liver, bile ducts, CNS)
        
        Gardner syndrome
        
        specific variant associated with skull and mandible osteomas, dental abnormalities and fibromas on the scalp, sshoulders, arms and back
        
        Turcot syndrome
        
        it presents medulloblastoma
      - MYTYH-associated
        polyposis (MAP)
        
        autosomal recessive polyposis syndrome caused by biallelic pathogenic germline variants in the MUTYH gene
        
        MUTYH is a gene responsible for DNA repair
        
        1-2% of the general population carry a single (monoallelic) germline MUTYH pathogenic variant, with two (biallelic) pathogenic variants identified in <1% of individuals diagnosed with colorectal cancer
        
        multiple big adenomatous colon polyps during life, but less than FAP
    - - risk factors
        
        defined by genetic predisposition and environmental factors, with age being the most important risk factor
        
        90% of sporadic colon cancer occurs in individuals >50y
        
        others
        
        family history of CRC, a diet low in fibers and folate and high in fat and red meat, alcohol, cigarette smoking, sedentary occupation, obesity and diabetes
      - gross appearance
        
        ulcerate
        
        vegetant (right colon)
        
        stenosing/infiltrating (left colon)
        
        gelatinous (right colon)
      - histologic analysis
        
        histologic subtype (mucinous, classic, etc.)
        
        differentiation grade (low, high)
        
        invasion depth according to TNM
        
        presence of lympho-vascular invasion (intramural vascular, extramural vascular, lymphatic)
        
        perineural growth (present/absent)
        
        resection margin status (proximal, distal, circumferential; positive/negative; distance in cm)
        
        diameter of the tumor
        
        site/localization of the tumor
        
        number of investigated lymph nodes and number (the sample needs to have more than 12 lymph nodes)
        
        positive lymph nodes
        presence of adjuvant treatment response (yes/no)
        
        tumor budding status (single cells moving)
        
        immune response (good response to immunotheraoy when lymphatic vessels are involved)
        
        presence or absence of relevant mutations
        
        microsatellite status/presence of DNA mismatch repair proteins
      - staging of colon cancer
        
        it is much more important
        than grading for prognosis
        
        it follows the Duke criteria, which are based on the depth of the tumor
    - - most common locations
        
        lymph nodes, peritoneum, liver and lungs
      - if the patient is oligometastatic (only 1-2 metastases), the intestine and the metastases are operated together
        
        in other cases, with neoadjuvant treatment the metastases totally disappear
      - markers of distal metastases
        
        CK20 and CDX2
        
        they are positive in the colon
        and negative in the lung
    - - distiinguished into sporadic and hereditary
      - three distinct molecular pathways leading to genomic instability may be causes of sporadic CC
        
        CIN - chromosomal instability
        
        changes in chromosomal numbers and structure
        
        gain/loss of segments
        
        rearrangements
        
        loss of heterozygosity
        
        generally, they affect the expression of KRAS and/or genes that regulate cell proliferation and cell cycle checkpoints (loss-of-function mutations of TP53), causing CC initiation and progression
        
        60–80% of patients with CRC overexpress EGFR, associated with the progression of the malignancy and with poor prognosis
        
        therapy consists of the administrations of humanized monoclonal antibodies against extracellular domain of EGFR (cetuximab and panitumumab)
        
        resistance is caused by point mutations in KRAS,
        e.g. BRAF V600E mutation
        
        MIS - microsatellite instability
        
        microsatellites are repeated sequences of DNA that found in 10-15% of sporadic cancers
        
        MSI is the condition of genetic hypermutability (predisposition to mutation) that results from impaired DNA mismatch repair
        
        the genetic basis for instability in MSI tumors is an inherited germline alteration in any one of the five human MMR genes: MSH2, MLH1, MSH6, PMS2 and PMS1
        
        Lynch syndrome
        
        aka hereditary non-polyposis colorectal cancer
        
        germline mutation of MSH2 and MSH1
        
        it mainly affects the right colon
        
        divided into
        
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        histological diagnosis
        
        mainly in the right colon
        
        highly mucinogen
        
        poorly differentiated
        
        rich in tumor-infiltrating lymphocytes
        
        presence of a Crohn-like host response
        
        CIMP - CpG Island Methylator Phenotype
        
        hypermethylation represses transcription of the promoter regions of tumor suppressor genes, leading to gene silencing
        
        most CIMP-positive CRCs exhibit also an MSI phenotype or a BRAF V600E mutation
        
        they occur in later age, mainly in females and in the proximal colon, characterized by poor tumor differentiation