57.A.

Basic classification of tumors /cancer , ethiopathogenesis of tumors/cancer

57.B.Crohn diease-Surgical treatment
57.C.Tumors of the adrenals
57.D.X-ray, Vesicourethral refuels -voiding cystourethrography
57.A.Basic classification of tumors /cancer , ethiopathogenesis of tumors/cancer
Nomenclature:
- Neoplasia — abnormal growth of cells. Can be either malignant or benign.
- Benign tumor — well-differentiated (low-grade), slow growth with low rate of cell division. Well-demarcated from surrounding tissue. No
metastases. Most common problem are «mass effect» with compression of non-tumor tissue. Microscopically, almost no irregularities of cellular
structures.
- Malignant tumor — poorly-differentiated (high-grade). Rapid growth with high rate of cell division. Locally destructive and invasive. Usually
no tumor capsule, infiltrative to surrounding tissue. Metastases and relapses are common. Invasive and infiltrative growth causes malignant cells
to enter blood and lymphatic vessels, which serve as pathways for metastasis. Commonly present with cellular atypia (enlargement,
polymorphism, enlarged nucleoli, polychromasia, mitotic figures).
- Carcinoma — malignant cells arise from epithelium (e.g. squamous cell carcinoma, basal cell carcinoma)
- Sarcoma — malignant cells arise from mesenchyma (e.g. sarcoma botryoides, liposarcoma, leiomyosarcoma)
- Teratoma — mix of all tissue types
- Carcinoma in situ — irreversible dysplasia, involves the entire thickness of the epithelium, but no invasion of the basement membrane
- Invasive carcinoma — invasion of basement membranes
- Metastasis — spread of malignant cells to distant organs, tissues (e.g. colorectal cancer spreading to the liver) — lymphatic spread, hematogenous
spread or direct spread
Tumor origin:
- Epithelial tumors:
- Squamous epithelium — papilloma, squamous cell carcinoma
- Glandular/mucosal epithelium — adenoma, adenocarcinoma
- Cuboidal epithelium — papillary thyroid carcinoma
- Mesenchymal tumors:
- Fibrocytes — fibroma, fibrosarcoma
- Adipocytes — lipoma, liposarcoma
- Chondrocytes — chondroma, chondrosarcoma
- Osteoblasts — osteoblastoma, osteosarcoma
- Blood vessels — hemangiomas, hemangiosarcoma
- Hematopoietic cells (e.g. B-cells, T-cells): Leukemia, Myeloma, Lymphoma
- Neuroectodermal cells:
- Glial cells — glioma, astrocytoma, glioblastoma
- Melanocytes — nevus, malignant melanoma
Carcinogenesis:
- A multistep process by which normal cells develop and accumulate genetic mutations (inherited or acquired), resulting in a monoclonal expansion
of mutated cells that can progress to the development of neoplasia
- Process:
1. Initiation — DNA damage — The body's repair mechanisms usually remove any damage. If the damage can no longer be confined, it is passed on to
daughter cells.
2. Promotion — DNA damage is passed on — Results in functional disorders of (proto-)oncogenes, DNA repair genes, tumor suppressor genes,
and apoptosis-regulating genes
3. Latency — time between promotion and progression
4. Progression — the neoplastic cell line proliferates with the acquired DNA damage, leading to malignant transformation
DNA damage:
- Mutations — duplications, insertion, deletion, point mutations
- Chromosomal translocations (e.g. translocation in CML t(9;22) Philadelphia chromosome)
- Amplification — increased gene expression (e.g. overexpression of HER2/neu in breast ca)
Carcinogens:
- Chemical carcinogens:
- Benzene, Benzol — related to Leukemia, Lymphomas
- Alkylating agnets — related to leukemia, lymphoma
- Cigarette smoke — carcinoma of bladder, SCC cervic, mouth, esophagus, larynx, SC lung cancer, pancreatic adenocarcinoma
- Vinyl chloride — Lung cancer, hepatocellular carcinoma
- Nitrosamines — gastric cancer
- Asbestos — lung cancer, mesothelioma
- Aromatic amines — bladder cancer
- Ethanol — Squamous cell carcinoma of esophagus
- Radon, Aflatoxin,Arsenic
- Radiation:
- Nonionizing — skin cancers
- Ionizing — leukemias, thyroid cancer, osteosarcoma,
- Oncogenic infections:
- EBV — Lymphomas
- HBV — hepatocellular carcinoma
- HPV 16, 18 — SCC vulva, cervix, anus, oropharynx, larynx
- Schistosoma haematobium — SCC of bladder
- Clonorchis sinensis — cholangiocarcinoma
- H.pylori — gastric adenocarcinoma
Key genes involved in carcinogenesis:
- Proto-oncogenes:
- Gain of function mutations of proto-oncogenes —> formation of oncogenes (leads to uncontrolled cell proliferation and tumor growth (SPEED
UP)
- Example: BRAF, N-myc, KRAS, BCR-ABL, ALK, HER2, JAK2,
- Tumor suppressor genes:
- Inhibits uncontrolled proliferation —> Loss of function mutation leads to uncontrolled cell growth
- Example: RB gene, TP53, APC gene, BRCA1/2, NF1/2, VHL gene
- Apoptosis regulatory genes
 - Loss of regulatory genes leads to cell immortality and increased proliferation
Factors that affect key genes involved in carcinogenes:
- Exposure to risk factors — Exposure to risk factors (such as smoking) increases the risk of DNA mutation and tumor formation.
- Diet — A diet high in nitrosamines (e.g., cured meat, fish, bacon) increases the risk of gastric cancer.
57.B.Crohn diease-Surgical treatment
CD is an inflammatory bowel disease, the pathogenesis of which is not full understood.
Etiology:
- Cause: Unknown factors lead to an imbalance between pro-inflammatory and anti-inflammatory mediators.
- Risk factors:
- Nicotine abuse — Nicotine consumption is the only (known) controllable risk factor for CD. Therefore, quitting smoking is especially
important for CD patients!
- Familial predisposition (e.g. mutation of the NOD2 gene, HLA-B27 association)
Pathophysiology:
- Unknown mechanisms lead to the activation of lymphatic cells (Th1) in the intestinal walls —> Inflammation is triggered —> Local tissue damage
(edema, erosions/ulcers, necrosis) —> Obstruction, fibrotic scarring, stricture, and strangulation of the bowel
- Abscess and fistula formation — intestinal aphthous ulcers —> transmural fissures and inflammation of the intestinal walls —> adherence to other
organs or the skin —> penetration of these structures —> microperforation and abscess formation —> macroperforation into these structures —>
fistula formation
- Main locations: Terminal ileum and colon, but it can be located anywhere between mouth and the anus — the rectum is spared!
Clinical features:
- Typically, CD occurs episodically and there is a 30% risk of recurring inflammation over the span of one year. If symptoms persist for six months,
the disease is considered chronic.
- Intestinal symptoms:
- Typically non-bloody, chronic diarrhea — microscopic bleeding may still be present
- Abdominal pain, typically in RLQ
- Signs of malabsorption:
- Weight loss
- Failure to thrive and growth failure in children
- Anemia (iron def, vit b12 def)
- Complications of disturbed reabsorption of bile acids
- Bile acid diarrhea
- Bile acid malabsorption: Steatorrhea, deficiencies in fat-soluble vitamins, gallstones, kidney stones
- Abdominal mass - due to adhesions within the intestine that are caused by inflammation — the solid mass is often palpable in RLQ, as CD
most commonly manifest itself in the terminal ileum
- Clinical features of abscesses (50% of cases) and fistulas (30% of cases): Typically involve the terminal ileum and/or perianal region
- Stenosis/strictures
- If perforation —> signs of peritonitis
- Extraintestinal symptoms:
- Joints: enteropathic arthritis (e.g. sacroilitis)
- Eyes: iritis, episcleritis, uveitis
- Liver/bile ducts: Primary sclerosing cholangitis (less common than in UC)
- Dermatological:
- Erythema nodosum
- Acrodermatitis enteropathica - bullous skin abrasions, especially in genital areas, hands and feet
- Pyoderma gangrenosum:
- Associated with various conditions, including CD, UC, RA and trauma
- Most common site: extensor side of the lower limbs
- Clinical features: Very painful, rapidly-progressive, red spots that can change into purulent pustules or deep ulcerated lesions
with central necrosis
- Pyostomatitis vegetans (oral aphthae)
Diagnosis:
- Approach:
- Initially: if a patient has clinical features indicating CD, conduct blood and stool tests
- Confirm with endoscopy and/or radiographic imaging and/or biopsy
- Perform contrast radiological studies and/or ultrasound to assess extent, severity and complications (i.e. abscesses, fistulas, stenoses)
- Laboratory tests:
- Blood:
- Increased inflammatory markers (increased CRP, ESR, thrombocytes)
- Anemia (of chronic disease, vitamin B12 deficiency, blood loss (iron))
- Increased ASCA (Anti-Saccharomyces cerevisiae antibodies)
- Stool:
- Stool analysis to rule out gastroenteritis caused by bacteria (e.g. C.difficile)
- Possible detection of fecal calprotectin and/or lactoferrin:
- Imaging:
- Plain abdominal x-rays - bowel distention, pneumoperitoneum
- Plain radiography with barium swallow (enteroclysis)
- Indication - to detect fistulas or stenoses
- Findings: String sign, Creeping fat — proliferated mesenteric fat between the intestinal loops is pathognomic for CD
- Ultrasound findings:
- GI wall thickening caused by inflammation and edema, Possible detection of abscesses/fistulas
- MR enterography with contrast medium (MRI enteroclysis)
- Indicated in identification of the extent and pattern of intestinal inflammation, detection of perianal and pelvic disease and prediction
of activity
- Endoscopy:
- Confirms the diagnosis, assesses the extent of disease, differentiate CD from other diseases (e.g. UC, peptic ulcers, etc), and may also be
used as a therapeutic tool (e.g. dilatation of ducts, intestinal loops):
- Ileocolonoscopy:
- Typical findings:
- Pattern of involvement: Segmental/discontinuous
- Macroscopic findings include linear ulcers, pinpoint lesions, cobblestone sign, fissures and fistulas, erythema and
transmural inflammation
 - Esophagogastroduodenoscopy:
- Used to evaluate the possible involvement of esophagus, stomach and duodenum
- Findings include aphthae on mucosa
Treatment:
- Pharmacotherapy:
- Treatment of CD can be approached in two different ways: Step-up therapy and top-down therapy.
- Symptomatic:
- Anti-diarrheal agents (e.g. loperamide, bile acid binders)
- Topical corticosteroids (for pain relief in oral lesions) (e.g. triamcinolone)
- Topical 5-AminoSalycilicAcids (for inflammation of distal colon) (e.g suppository, enema)
- Acute episodes:
- Mild to moderate disease:
- Topical corticosteroids (e.g. oral budesonide)
- 5-ASA (e.g. Mesalamine (rectal, systemic)
- Antibiotics (e.g. Metronidazole, Ciprofloxacin)
- Moderate to severe disease:
- First-line treatment: Systemic corticosteroids (e.g. prednisone)
- Steroid-refractory disease, escalation therapy:
- Immunosuppressants:
- First-line: TNF-alpha antibodies (e.g. infliximab, adalimumab)
- If necessary in combination with Azathioprine. Alternatives include methotrexate and alpha-4 integrin inhibitors
(natalizumab)
- Maintenance therapy:
- First-line treatment: 5-ASAs
- Alternatives: Azathioprine, 6-mercaptopurine , Methotrexate, TNF-alpha inhibitors
- Surgical intervention:
- Goal: Resect affected and non-functional intestinal loop(s) while preserving intestinal length and function. Minimally-invasive surgery if
possible.
- Indicated if medical therapy fails or in severe complications (e.g. abscesses, perforation, toxic megacolon, obstruction, stricture,
hemorrhage etc.)
- Methods:
- Resection of affected bowel (e.g. ileostomy, ileocolostomy, colectomy, proctocolectomy)
- Intestinal stenosis (e.g. balloon dilatation or tissue-sparing end-to-end anastomosis)
- Fistulas, abscesses (e.g. percutaneous drainage, surgical drainage)
Complications: Intestinal: Carcinoma, Short bowel syndrome (after surgery), Fistula and abscesses
57.C.Tumors of the adrenals
Important tumors associated with adrenal cortex: Adrenal adenoma, Adrenal adenocarcinoma
Important tumors associated with adrenal medulla: Pheochromocytoma, Neuroblastoma
Adrenal adenoma:
- A benign tumor of the adrenal gland that, in the vast majority of cases, does not lead to excess hormone production (nonfunctioning adenoma)
and therefore does not cause symptoms. In rare cases, the adenoma does lead to increased hormone levels (functioning adenoma), which results in
conditions such as Cushing syndrome (Primary hypercortisolism) or Conn syndrome (Hyperaldosteronism).
- Diagnosis:
- Serum ACTH levels — low levels indicate primary hypercortisolism (adrenal adenoma, carcinoma)
- No effect of dexamethasone suppression tests
- CT and/or MRI of abdomen for adrenal tumors
- Treatment:
- Operable disease:
- Surgical therapy — Laparoscopic or open adrenalectomy (surgical procedure to remove one or both adrenal glands)
- Nelson syndrome (post-adrenalectomy syndrome) — can occur after bilateral adrenalectomy in patients with a previously
undiscovered pituitary adenoma
Pheochromocytoma:
Definition: is a catecholamine-secreting tumor that typically develops in the adrenal medulla. They are usually benign (about 90% of cases) but may
also be malignant.
Etiopathogenesis:
- Tumor arise from chromaffin cells, which are derived from the neural crest
- Localization: About 90% adrenal medulla (physiologically activated by acetylcholine)
- 25% of pheochromocytomas are hereditary. Associations include:
- Multiple Endocrine neoplasia type 2 (MEN 2A, 2B)
- Neurofibromatosis type 1 (NF1)
- Von Hippel-Lindau (VHL) disease
Clinical features:
- Clinical presentation is related to fluctuating levels of excess epinephrine, norepinephrine and dopamine.
- Episodic hypertension (or persistent hypertension in some cases) - PCC is an important cause of secondary hypertension
- Paroxysmal:
- Throbbing headache
- Diaphoresis
- Heart palpitations and tachycardia
- Pallor - catecholamines cause vasoconstriction, which decreases blood supply to skin, hence causing pallor
- Abdominal pain and nausea
- Anxiety
- Weight loss - due to increased basal metabolism
- Hyperglycemia
- If EPO secretion, signs of polycythemia
Diagnosis:
- Laboratory tests:
- Best initial test - metanephrines (metabolites of catecholamines) in plasma (high sensitivity)
- Confirmatory test - metanephrines and catecholamines in 24-hour urine (high specificity)
- Genetic testing: If MEN2A, MEN2B, NF1, or VHL is suspected
- Other diagnostic tests:
 - 24-hour ambulatory blood pressure monitoring - evaluation of night time BP drop
- Adrenal/abdominal CT or MRI - after positive biochemistry tests to localize tumor
- Scintigraphy (MIBG) - I-123 labeled metaiodobenzylguanidine (MIBG) scan to identify extra-adrenal pheochromocytomas. This
test is useful when biochemistry is positive, but no tumor can be found on imaging.
Differential diagnosis:
- Pheochromocytoma is often referred to as the great mimic because signs and symptoms are similar to those produced by many other clinical
conditions. Examples include:
- Endocrine - hyperthyroidism, carcinoid syndrome, hypoglycemia, medullary thyroid carcinoma, menopause, mastocytosis
- CVS - heart failure, arrhythmias, ischemic heart disease
- Neurological - migraine, stroke, meningioma
- Miscellaneous - panic disorder, anxiety disorder, drug-induced sympathomimetic syndrome, recreational (e.g. cocaine)
Treatment:
- Management consist of preoperative blood pressure management and surgery (if possible):
- Operable disease:
- Preoperative BP management:
- First, a non-selective alpha blocker is given: Phenoxybenzamine - blocks alpha-1 and alpha-2 receptors equally and
irreversibly.
- After sufficient alpha blockade, a beta blocker may be started for additional blood pressure control and control of
tachyarrhythmias
- Treatment of choice:
- Laparoscopic tumor resection (adrenalectomy) — «No touch-technique!»
- Inoperable disease - in the case of extensive metastatic disease or unresectable primary tumors:
- Benign pheochromocytoma - primary therapy with phenoxybenzamine
- Malignant pheochromocytoma - MIBG therapy, palliative treatment (chemotherapy, tumor embolization)
57.D.X-ray, Vesicourethral reflux -voiding cystourethrography