PATHOLOGY - tumors

Benign epithelial tumors

Benign epithelial tumors are tumors of the superficial or glandular epithelium. -These tumors assume the form of either papillomas or adenomas -depending on if the tumor epithelium develops branching or tubular forms

Childhood tumors

Benign tumors are more common than cancers. Most cancers occur spontaneously by nature, but a genetic predisposition increase the likelihood. Downs syndrome -> Leukemia Li Fraumeni -> Various cancers Noonan syndrome -> Rhabdomyosarcoma Beckwith-Wiederman syndrome -> Wilms Tumor Hippel - Lindau syndrome -> Hemangioma Benign tumors -Tumor like lesions: Choristoma, Hamartoma ★Hemangioma -blood vessel tumor, most common in infants, most on skin/scalp -port wine stains, many spontaneosly regress. -capillary hemangioma "strawberry nevus" usually found on eyes,regress -cavernous hemangioma in CNS, liver, eye - may cause hemmorrhage ★Lymphangiomas -fluid filled cystic spaces lined by endothelial cells surrounded by lymphoid aggregates. may occur in skin, deep region of axilla, neck, mediatinum, retroperitoneum. may compress nerves. ★Sacrococcygeal teratoma -most common germinoma of childhood. most benign, 12 % malignant Malignant tumors ★Neuroblastoma -tumors of sympathetic ganglia and adrenal medulla -occur mostly sporadically (1-2% familial ALK gene mutation) -40% arise adrenal medulla, rest in sympathetic chains -Homer Wright pseudo-rosettes -prognosis depending on age, and n-myc oncogene amplification -younger better prognosis -screening: catecholamines, homovanilic or vanillylmandelic acid ★Retinoblastoma -common primary intraocular malignancy in children -40% Rb1 gene mutation - multiple, bilateral tumors with higher risk of osteosarcoma and other soft tissue tumors -60% somatic Rb1 gene sporadic mutation - unilateral, unifocal -tend to be nodular masses in posterior retina -Flexner Wintersteiner rosettes (with lumen in center) -may disseminate beyond the eye via optic nerve or subarachnoid space. Metastasis to skull, CNS, distal bones, LN ★Wilms Tumor / Nephroblastoma -most common kidney tumor in children (2-5y) -Three types of congenital malformations increase risk: 1. WAGR syndrome (Wilms tumor, Aniridia, Genital abnorm. Retardation) -1/3 with WAGR will get Wilms tumor (deletions of WT1 gene) 2. Denys-Drash syndrome (gonodal dysgenesis, renal abnormalities) -90% with DD gets Wilms tumor (mutation in WT1 gene) 3. Beckwith-Wiedeman syndrome (enlarged tonge, kidney or liver) -or enlargement of entire body segment. -WT2 gene, imprinting abnormalities with insulin like GF 2 leading to overexpression og IGF2, causing organ enlargement, tumorigenesis -large, well circumscirbed mass. can contain hemmorrhage, cystic degeneration, necrosis. -small round blue cells and epithelial and stromal elements

Differences between benign and malignant epithelial tumors

Benign: -grow locally (pushing borders) -often encapsulated -resembles cell of origin (well differentiated) -few mitosis -normal or slight increase in NC ratio -cells are uniform throughout the tumor Malignant -invasive growth (may metastasize) -not encapsulated -may show failure of differentiation -many mitosis, some of which are abnormal forms -high NC ratio -cells vary in shape and size (cellular pleomorphism/anisocytosis) and/or nuclei (nuclear pleomorphism/anisokaryosis)

Carcinogenesis

Cancer formation is initiated by damage of DNA of stem cells. The damage overcomes DNA repair mechanism and is not lethal. ★Hallmarks of cancer ★Carcinogens ★Disrupted systems of proto-oncogenes, TSG, apoptosis regulators. ★Telomerase, angiogenesis, avoiding immune surveillance ★Stages

Carcinogens

Carcinogens are agents that damage DNA, increasing the risk of cancer. Important carcinogens include chemical, oncogenic viruses and radiation ★Radiation -Ionizing (AML, CML, papillary carcinoma of thyroid) -Non ionizing (Basal cell carcinoma, Squamous cell carcinoma, melanoma) ★Oncogenic virus -EBV (Nasopharyngeal carcinoma, Burkitt lymph., CNS lymphoma in AIDS) -HHV-8 (Kaposi saarcoma) -HBV, HCV (Hepatocellular carcinoma) -HPV (16,18,31,33) (SCC of vulva, vagina, anus, cervix, Adenocarc. of cervix) ★Chemical -Alcohol (SCC of oropharynx, upper esophagus, Pancreatic carcinoma, Hepatocellular carcinoma) -Aflatoxin (Hepatocellular carcinoma) -Alkylating agents (Leukemia, Lymphoma - side effect of chemotherapy) -Arsenic (SSC of skin, lung cancer, angiosarcoma of liver) -Asbestos (Lung carcinoma, mesothelioma) -Smoking (Carcinoma of oropharynx, esophagus, lung, kidney, bladder)

Non seminoma: Choriocarcinoma

Choriocarcinoma -malignant tumor composed of cytotrophoblast and syncytiotrophoblasts -mimics placenta, however the villi are absent -small irregular mass with hemorrhage and necrosis -no stromal support to supply tumor, gets directly from blood vessels -with early hematogenous spread to lungs -occurs mainly in placenta during pregnancy 1. hydatidiform mole (the cause of 50% of choriocarcinoma) 2. spontaneous abortion 3. ectopic pregnancy 4. normal term pregnancy 5. hyperemesis gravidarum (severe nausea causing ketosis, weight loss) -in testis: most aggressive germ cell tumor -occur in age 20-30 years -all patient have elavated hCG due to syncytiotrophoblasts

Choristoma

Choristoma is a rare benign tumor consisting of normal tissue derived from germ cell layers foreign to that body site. -classified according to their type of tissue -can occur in skin, oral cavity, intestinal organs -developmental abnormality (dermoid cyst arise from epithelium trapped along lines of embryonic fusion), presented in later life -benign lesions with little risk of malignant transformation and recurrence after excision are low. (usually excised when found) Examples -Pancreatic heterotopia (pancreatic tissue outside of its boundaries of pancreas and without anatomic or vascular connections to the pancreas) -Osseous choristoma (present as hard tumor-like masses in tongue)

Dysplasia and metaplasia

Dysplasia (intra-epithelial neoplasm) -important term when studying precancerous lesions. -refers to epithelial anomaly of growth and differentiation, with structural and cytological irregularities that can induce carcinogenesis. -can be low grade or high grade (carcinoma in situ) ★CIN: cervical intraepithelial neoplasia ★VIN: vaginal intraepithelial neoplasia ★Histopathology of dysplasia in tissues -Loss of uniformity - Loss of architecture orientation -Pleomorphism -Basophilic nucleus, changed NC ratio -more abundant mitosis Carcinoma in situ: dysplasia in the entire thickness of epithelium. eg- carcinoma in situ of skin: Bowen´s disease Metaplasia -important term when studying precancerous conditions. -defined a replacement of one differentiated tissue with another -fex. Barret´s esophagus and squamous metaplasia of respiratory epithelium -where certain stressors induce metastatic changes in order for the cells to better withstand the adverse environment. -if stressor that triggers metaplasia persists, it may predispose malignant transformation.

Non-seminoma: Embryonal carcinoma

Embryonal carcinoma -in ovaries and testes -composed of immature, primitive cells that may produce glands -aggressive with early hematogenous spread -in most cases mixed with cells characteristic for other germ cell tumors -occur in age 20-30 years

Epithelial tumors

Epithelial tumors -group of tumors that arise from epithelial cells -which line cavities and surfaces throughout the body,also form glands -epithelial cells arise from endoderm or ectoderm germ layer during embryogenesis -epithelial tumor is composed of neoplastic parenchymal cells and surrounding stroma (non-neoplastic) -epithelial tumors express cytokeratin (proteins of keratin-containing intermediate filaments providing mechanical support and other functions to epithelial cells) Superficial tumors: Papilloma (benign), Carcinoma (malignant) Glandular tumors: Adenoma (benign), Adenocarcinoma (malignant) Organ specific: Hepatocellular adenoma (B), Hepatocellular carcinoma (M)

Germinal tumors

Germ cell tumors are malignant and benign tumors that are derived from germ cells. -Germ cells are the cells giving rise to gametes and become cells that make up the reproductive system. -Germ cell tumors are the most common type of testicular tumor, and second most common type of ovarian tumor. -Can also occur extragonadal: pineal region, retroperitoneal, mediastinal, sacrococcygeal and cervical region. Germ cell tumors division into: ★Seminoma -originate from undifferentiated cells -called dysgerminoma in women ★Non-seminoma -originate from totipotent cells -less common and tend to grow and spread more quickly -include: 1.Embryonal carcinoma 2.Yolk sac tumor 3.Choriocarcinoma 4.Teratoma *Crytochidisim - absence of one or both testes in scrotum due to failure of descending. it may be a result of premature birth or narrowing of inguinal canal. it can descend within the 1st year, be atrophic or develop into a tumor. if ectopic testes persist, the risk of cancer increase by 3-5 fold*

Hamartoma

Hamartoma is a benign, focal malformation resembling neoplasm in tissue of its origin. -grows at the same rate as surrounding tissues. -composed of tissue element normally found at that site, but grows in disorganized manner. -commonly found in people with some genetic syndromes. -often accidentally found on images taken for another reason. -can be harmless or dangerous, depending on location -it may obstruct organs such as eye, lungs or colon. -they can cause hemorrhage and anemia. Examples: -pulmonary hamartoma (most common) -hemangioma, bone hemangioma -hamartoma of hypothalamus -chondrohamartoma -polypoid hamartoma -Cowden´s disease (multiple hamartoma in skin, mucous membranes, thyoroid, breast - increased risk of breast cancer and thyroid cancer)

Hyperplasia, Hypertrophy

Hyperplasia: - increase number of normal cells in tissue or organ without tumor formation. - eg. benign prostatic hyperplasia, hyperplasia of adrenals Hypertophy -increased size of cells that cause non-tumorous enlargement of organ or tissue. -eg. skeletal muscle

Inflammatory pseudotumor

Inflammatory pseudotumors are a heterogenous group of benign lesions that may occur e.g in lung with variable mix of inflammatory cells and fibroblasts. -Any circumscribed or irregular inflammatory nodule, mass or consolidation. -Enlargement from swelling in acute inflammation or enlargement from proliferation (fibrous tissue) in chronic inflammation. Examples: ★Nasap polyps in chronic inflammation ★Inflammatory polyps in GIT

Tumors of parenchymatous organs - Liver

Liver tumors Benign: Adenoma, Hemangioma ★Hepatocellular adenoma -rare, women in reproductive age using contraceptives, sex hormone therapy, pregnancy -solitary, partly/completely capsulated, ligher color or bile stain -can be up 30 cm in diameter,cut:varying infarction, hemorrhage -sheets, cords of hepatocytes well.diff or variation of size/shape -lack portal tracts, bile ducts . thrombosis may occur ★Hemangioma -most common benign tumor of liver (most asymptomatic) -rarely hemangioma rupture into peritoneal cavity -solitary or multiple, circumscribed, red-purple lesions, commonly subcapsular. cavernous type give spongy appearance. -characteristic large, cavernous, blood filled spaces, led by a single layer of endothelium and separated by CT. -some may undergo progressive fibrosis and calcify. Malignant: Hepatocellular carcinoma, Hepatoblastoma, Cholangiocarcinoma ★Hepatocellular carcinoma -accounts for approx. 85% of all primary malignancies of liver -infection of HBV, HCV, alcohol -single yellow-brown large mass, most often in right lobe with central necrosis, hemorrhage, occasional bile-staining, may be encapsulated. less often multiple. -most common: trabecular or sinusoidal pattern -cells resembling hepatocytes, increasingly basophilic with malignancy - pleomorphism, bizarre giant cells, spindle shaped cells, tumor cells with clear cytoplasm -★Fibrolamellar carcinoma -variant of HCC found in young people of both sexes -tumor forms a single large mass which may be encapsulated and occurs in absence of cirrhosis. -oncocytes forms cords and nests separated by bands of fibrous stroma -often hepatomegaly, right upper quadrant pain -less often: jaundice, fever, hemorrhage, ascites -rarely: endocrine manifestions due to paraneoplastic syndrome (hypercalcemia, hypoglycemia, gynecomastia) ★Cholangiocarcinoma -arise from bile duct epithelium within liver (peripheral type) -firm to hard and whitish tumor. -tumor cells resemble biliary epithellium without bile secretion = no bile formation -extrahepatic duct carcinoma: Klatskin tumor

MEN

Multiple endocrine neoplasia type 1 syndrome -include adenomas of parathyroid, pancreatic islets, pituitary -AD trait 1) Parathyroid -hyperplasia or adenoma -frequently with Zollinger-Ellison syndrome/Gastrinoma 2) Pancreatic islet cells - hyperplasia or adenoma -manifest as acromegaly or pheochromocytoma 3) Pituitary - hyperplasia or adenoma -manifest as acromegaly or pheochromocytoma Adrenals and Thyroid may be involved.

Myeloid neoplasms

Myeloid neoplasms -Myeloid cells: monocytes, macrophages, dendritic cells, granulocytes, erythrocytes, megakaryocytes and thrombocytes. -almost always primarly involve BM, secondary hematopoietic organs (spleen, liver, LN) -can be divided into: ★Acute myeloid leukemia (accumulation of immature myeloid in BM cells) ★ Myelodysplastic syndrome (ineffective hematopoiesis and associated cytopenias) ★Chronic myeloproliferative disorders (increased production of terminally differentiated myeloid cells)

Myeloproliferative neoplasms

Myeloproliferative neoplasms -hyperproliferation of myeloid progenitors -> increased erythrocytes, granulocytes or platelets in blood -caused by mutation in activated tyrosine kinase causing GF independent proliferation - the neoplastic progenitors tend to seed secondary hematopoietic organs (liver, spleen, lymph nodes) causing extramedullary hematopoiesis -> hepatosplenomegaly Different conditions ★Chronic myeloid leukemia ★Polycythemia vera ★Primary myelofibrosis ★Systemic mastocytosis

Breast cancer grading

Nottingham grading system for breast cancer Grading of breast tumors based on: -Tubule formation (how much normal breast duct structures in tumor) -Nuclear grade (evaluation of size and shape of nucleus in tumor cells) -Mitotic rate (how many dividing cells present, indicating how fast the tumor cells grow and divide) Each category gets a score from 1-3 , where 1: cells and tumor tissue look the most normal and 3: most abnormal. Added scores = 3 to 9 ★Total score 3-5: Grade 1 (Low grade or well differentiated) ★Total score 6-7: Grade 2(Intermediate grade/ moderately differentiated) ★Total score 8-9: Grade 3 (High grade or poorly differentiated)

Tumors of GIT

Oral cavity: Fibroma, Leukoplakia, SCC Salivary glands: Pleomorphic ademona, Warthin tumor, Mucoepidermoid carcinoma Odontogenic: Ameloblastoma, Odontoma Esophagus: Adenocarcinoma, SCC Stomach: Gastric adenoma, adenocarcinoma, GIST Colon: Colonic polyps, FAP, Lynch syndrome, Colorectal carcinoma

Papillomas

Papillomas -broad based superficial tumor of branching villous stroma covered by neoplastic epithelium. -exophytic papillomas most common - grows above epithelial surface -endophytic papillomas are rare - grows beneath epithelial surface, exhibit smooth surface and can mimic invasive malignancy. tend to recur! ★Basal cell papilloma -occur in trunk, arms and face in older patients -cap-like epidermal projection of villous layer of acanthocytes growing into the deep plane and exhibit scaly keratinized epithelium extending into the projecting papillae. domelike keratinized projections. ★Mucosal papilloma -occur in oral cavity, nose (sometimes inverted form), nasopharynx, larynx -branching growth of columnar or squamous epithelium. ★Papilloma of glandular excretory ducts -occur in exocrine glands and breast -resemble mucosal papillomas. immunohistochem test for actin to demonstrate the myoepithelium. ★Urothelial papilloma -occur as multiple lesions in the urinary tract and are potential precancerous lesions. the tumor tissue is easily injured because of exposure to urine, leading to microhematuria. -branching villous proliferation of urothelium about 7 cell layers thick with highly vascular stroma. ALL GLANDULAR AND MUCOSAL PAPILLOMAS ARE POTENTIALLY PRECANCEROUS LESIONS.

Paraneoplastic syndrome

Paraneoplasia. Tissue changes (lesions) or syndromes, developing in patients suffering from malignant tumor which are not directly related to local growth of the tumor or to its generalization. • Ectopic production of hormones or substances similar to hormones. • Production of other biologically active substances (growth factors) IL1, TGF alpha, TNF alpha. • Genetic dearrangements. • Endocrinopathias. o Cushingsyndrome. o Hypercalcemia. o Hypoglycemia. o Carcinoidsyndrome. o Polycythemia. • Neuropathies and myopathies. o Myasthenia. oCentralandperipheralneuropathy. • Skin changes.

PNS tumors

Peripheral nerve sheath tumors -group of neurogenic tumors that arise from nerve sheath outside of CNS. -majority is benign, malignant transformation seen particularly in large tumors and those associated with NF1. -these tumors manifest as soft tissue masses or with pain/loss of sensation due to impingement on nerves. -in most peripheral nerve tumors, neoplastic cells show evidence of Schwann cell differentiation. -these tumors usually occur in adults. -an important feature is their frequent association with NF1&2 ★Schwannoma/Neurinoma ★Neurofibroma ★Malignant PNS tumors

Salivary glands tumors

Salivary glands tumors -relative uncommon, 80% in parotid. -the bigger, the more likely to be benign -sublingual 70-80% malignant ★Pleomorphic adenoma -most common, composed of stromal myoepithelium and epithelial ductal tissue. can also find cartilage, myxoid, bone. -movable and capsulated, usually in parotid -high rate of recurrence after incomplete resection -rarely transform to carcinoma -facial nerve for diagnosis ★Warthin tumor -benign cystic tumor with abundance of lymphocytes and germinal centers -2nd most comon tumor. almost always in parotid. ★Mucoepidermoid carcinoma -most common malignant -consist of mucinous and squamous cells lining cords, cysts or sheets. -arise usually in parotid and involve factial nerve -well circumscribed, but lack capsule - infiltrative growth -low to high grade Odontogenic tumors ★Ameloblastomas -> from odontogenic epithelium, dont demonstrate chondroid or osseous differentiation. typically slow growing locally aggressive cystic lesions. ★Odontoma - most common, arise from epithelium. show extensive deposition of enamel and dentin

Seminoma and Dysgerminoma

Seminoma -most common malignant germ cell tumor -tumor derived from immature germ cells -composed of large cells with clear cytoplasm and central nuclei (resemble oocyte or spermatogonia). -cells are glycogenrich - PAS positive - and lymphocte infiltrate in stroma -metastasise late, have good prognosis, respond good to radiotherapy -occur in the age 40-50 -placental alkaline phosphatase is a marker for the cancer ★Testicular seminoma -arise from germinal epithelium of seminiferous tubules -comprise half of germ cell tumors of the testes -spread intratestricular or via epididymis or through layers of testes. -in 15% of cases - syncytiotrophoblasts are present (elevated hCG) ★Spermatocytic seminoma -distinct clinical and histological entity, not to be confused with classic -uncommon tumor occuring in much older patients -does not mix with other germ cell tumors and doesnt metastasise. SEMINOMAS/DYSGERMINOMAS=ALWAYS MALIGNANT

Pseudocysts

Similar to cysts, but lack epithelial lining. -often occur following necrosis, inflammation and degeneration Examples: ★Pancreatic pseudocyst -following chronic pancreatitis, the enzymes digest the pancreas and liquefy it, pseudocyst consist of pancreatic fluid within fibrous tissue wall or granulation tissue. ★Postencephalomalacic pseudocyst -following liquefactive necrosis of brain tissue due to inflammation and hemorrhage. the brain does not have CT.

Staging - TNM system, AJC system

T: primary tumor N: regional lymph node involvement M: metastases In TNM system: ★T - describe increasing size of primary lesion -TX: main tumor cannot be measured -T0: main tumor cannot be found -T1,T2,T3,T4: refers to size of tumor ★N - indicate progressively advancing node involvement -NX: cancer in nearby lymph node cannot be measured -N0: there is no cancer in nearby lymph node -N1,N2,N3: refers to number and location of lymph node affected ★M - reflect absence and presence of distant metastases. -MX: metastasis cannot be measured -M0: cancer has not spread to other parts of body. -M1: cancer has spread to other parts of the body AJC (American Joint Committee) -cancers are divided into stages 0 to IV, incorporating size of primary lesion and presence of nodal spread and distant metastases. *Examples of cancers with different staging system include brain and spinal cord tumors and blood cancers.

Tumor suppressor genes

TSG regulates cell growth, decrease risk of tumor formation. ★P53 gene - regulates progression of cell cycle from G1 to S phase -in response to DNA damage, p53 slows cell cycle and upregulate DNA repair enzymes. -if repair is not possible, p53 induces apoptosis. (cytochrome c leak) -both copies of p53 gene must be hit for tumor formation -mutation seen in over 50% of cancers -Germline mutation in Li Fraumeni (+ somatic hit) can develop multiple types of carcinomas and sarcomas. ★Rb gene - regulates progression from G1 to S phase -holds E2F transcription factor(necessary for transition to S phase) -E2F is released when Rb is phosphorylated by cyclinD/CDK4 complex -Rb mutation -> free E2F -> cell cycle progression, uncontrolled growth -both copies must be hit for tumor formation -Sporadic mutation (both somatic) - unilateral retinoblastoma -Germline mutation in familial Rb (+ somatic hit) - bilateral retinoblastoma and osteosarcoma ★WT gene - Wilms tumor ★NF1 gene - Neurofibroma ★APC gene - Adenomatous polyposis of colon

Non seminoma: Teratoma

Teratoma -tumor composed of mature and immature embryonic tissue derived from two or three embryonic layers ( skin, hair, bone, cartilage, gut, thyroid) -teratomas may result from germ cells (totipotent) or from embryonal cells. -> Teratomas of germ cells occur in testes and ovaries -> Teratomas of embryonic cells most often found as congenital defects at birth, in young children and occur in the midline path (brain, skull--coccyx) -in women: usually differentiated and mature tumor resulting in a benign tumor, often referred to as dermoid cyst ★Cystic teratoma -most common germ cell tumor in female -in 10% of cases is bilateral -can occur at any age -in men: typically solid, immature and undifferentiated, resulting in a malignant tumor. (in prepupertal boys -benign) ★Struma ovarii -rare form of teratoma containing mostly thyroid tissue, causing hyperthyroidism -not restricted to the ovary Pure forms of teratoma are fairly common in infants and children, but rare in adults. In adults: most commonly mixed with embryonal carcinoma.

Tumors of ANS

Tumors of ANS -tumors derived from ganglion cells ★Neuroblastoma ★Ganglioneuroblastoma ★Ganglioneuroma ★Paraganglioma

Mesenchymal tumors of connective tissue and cartilage

Tumors of connective tissue ★Fibroblastic tumors -Fibroma -Fibrosarcoma ★Fibrohistiocytic tumors (neoplastic cells - fibroblast, myofibroblast and lipid-laden macrophages) -Dermatofibroma -Dermatofibrosarcoma protuberans Tumors of cartilage ★Chondroma ★Chondroblastoma ★Chondrosarcoma ★Osteochondroma

Mesenchymal tumors of muscle and adipose tissue

Tumors of muscle tissue - Leiomyoma - Leiomyosarcoma - Rhabdomyoma - Rhabdomyosarcoma Tumors of adipose tissue - Lipoma - Liposarcoma - Hibernoma

Urothelial carcinoma

Urothelial carcinoma -collective term for malignant carcinoma of urinary tract. ★Papillary urothelial carcinomas -anaplastic or invasive carcinomas with urothelial thickness of at least 7 cell layers. these carcinomas form a macroscopic border. ★Solid urothelial carcinomas -solid, often ulcerated carcinomas that project mushroom-like into the lumen. anaplastic and invasive tumors.

Tumors of stratified epithelium

Vagina ★ Squamous Cell Carcinoma -VIN precursor lesion associated with HPV infection usually -most often due to extension of SCC of cervix -vagina infrequently the primary site ★Clear cell adenocarcinoma -rare malignant tumor, daughters of women received DES during pregnancy. -vaginal adenosis precursor of CCA. Penis ★Carcinoma in situ -Bowen disease - erythematous plaque on shaft or scrotum (erytroplasia of Queyrat) 10% progress to SCC -Bowen papulosis - multiple reddish brown papules on glans, progression only in immunocompromised. ★Squamous Cell Carcinoma -appear gray, crusted, papular lesion on glans or prepuce -carcinoma can infiltrate underlying CT to produce indurated, ulcerated lesion with irregular margins. -regional to inguinal LN in 25%, distant uncommon Cervix ★Dysplasia and carcinoma in situ -squamocolumnar junction involved -major ass. with HPV (16,18,31,33) -dysplasia progress through mild, moderate and severe forms to carcinoma in situ (CIN1-2-3) -CIN 3 = carcinoma in situ (atypical changes extending through entire thickness of epithelium) ★Invasive carcinoma -most often SCC, 5% Adenocarcinoma -most frequently arise from CIN at squamoucolumnar junction -dysplastic cells demonstrate koilocytosis (enlarged nuclei, hyperchomasia) Skin ★Squamous cell carcinoma -most often locally invasive, less than 5% metastasise -ass. with excessive sunlight exposure,involve lower part of face -UV light cause unrepaired DNA damge -frequently originate from actinic keratosis -immunocompromised, xeroderma pigmentosum increased risk -present as scaling, indurated, ulcerated nodule -invasion of dermis with keratin pearls typical ★Basal cell carcinoma -most common of all malignant skin tumors -tend to involve sun exposed areas,most frequently in head and neck -clusters of dark stained basaloid cells with palisade arrangement of nuclei of the cells at the periphery of tumor cell clusters. -often prominent, dilated subepidermal blood vessels (telangiectasia) -almost never metastasize -associated with dysregulation of sonic hedgehog or PTCH pathway. inherited defects in PTCH gene can cause familial basal cell carcinoma syndrome = Grolin syndrome.

Non seminoma: Yolk sac tumour

Yolk sac tumour -also called endodermal sinus tumour -malignant tumour that mimics yolk sac -most common germ cell tumor in children (testis) -alpha fetoprotein is elevated in 90% of the patients -schiller duval bodies (glomerulus-like structures) seen histological

Tumors of parenchymatous organs - Gall bladder

★ Adenocarcinoma of Gallbladder -more prevalent than other cancers of extrahepatic biliary tract -more frequent in women than in men with peak at 70 -cholelitiasis and cholecystitis more common in females -two types: infiltrating type (may have deep ulcerations causing direct invasion of GB wall and liver bed) and fungating type (papillary growth into lumen and into wall of GB)

Tumors of parenchymatous organs - Cervix, Vulva

★ Mucinous carcinoma ★ Squamous cell carcinoma ★ CIN Vulva ★ Vulvar carcinoma ★ Vulvular Squamous cell carcinoma -invasion through basement membrane ★ VIN

Esophageal tumors

★Adenocarcinoma -typically in background of Barretts and GERD -also linked to tobacco, obesity, alcohol, radiation therapy -lower third - exophytic patches and diffuse infiltrate growth or ulcerate and go deep. -form glands and produce mucin -manifest as difficulty swallowing, weight loss, vomiting, chest pain. more common in men -present late so usually prognosis. -normal esophagus color is grey white, adenocarcinoma: pink ★Squamous cell carcinoma -more common than adenocarcinoma -men above 45. alcohol, tobacco, hot drinks, achalasia, injury and plummer vinson syndrome, - in middle of esophagus begins squamous dysplasia. -signs: hoarseness, cough, -LN involvement -upper cervical, middle mediastinal, lower gastric and celiac LN. -complications: bleedings and sepsis, infiltrative growth into surrounding structures, fistula formation like respiratory tree (pneumonia), aorta, mediastinum, and pericardium.

Tumors of Colon

★Colonic polyps -polyps (mucosal protrusions) is most common in colon -if they have stalk: pedunculated, if more flat: sessile ★Adenomatous polyp -benign neoplastic proliferation of glands giving rise to most adenocarcinomas (although most adenomas dont progress) -epithelial dysplasia (hyperchromasia, elongation, stratification) -present in nealy 50% of adults above 50years in western -the bigger the worse. pedunculated tubular is more frequent and better. sessile villous less frequent and worse. ★Familial adenomatous polyposis -AD, chromosome 5 APC gene gene mutation -100-1000 adenomatous polyps in colon, need to be removed -Gardner syndrome (FAP + fibromatosis and osteoma) -Turcot syndrome (FAP + CNS tumors) ★Hereditary nonpolyposis colorectal cancer -aka Lynch syndrome - inherited mutation of DNA mismatch repair enzyme (AD) -increased risk for colorectal, ovarian and endometrial cancer -arise de novo at relatively early age, usually right sided ★Colorectal carcinoma -third most common cancer in world, common cause of death -males 60-70 y, higher in developed countries. -risk factors: high fat and carb diet, low fiber. (aspirin protective) -most commonly arise from adenoma-carcinoma sequence, another is microsatelite instability (repeated sequences of non-coding DNA) -carcinoma can develop anywhere along length of colon, usually left sided grow as "napkin ring" lesion (decreased stool caliber, left lower quadrant pain, blood streaked stool) -right sided: raised lesion (iron deficiency - occult bleeding, vague pain) -colonic carcinoma ass. with increased risk of Strep bovis endocarditis. -most common metastasis - liver, regional LN, lungs, bones *CEA = tumor marker

Stomach tumors

★Gastric adenoma -represent 10% of all gastric polyps -males 50-60 years more affected -similar to other forms og gastric dysplasia, usually from chronic gastritis with atrophy and intestinal metaplasia. -risk for development into adenocarcinoma increase with size -usually in antrum, composed of columnar epithelium -all have dysplastic epithelium in low or high grade. ★Gastric adenocarcinoma -carcinoma of glandular epithelial of stomach -most common gastric malignancy (Japan, Eastern Europe) -most important prognostic marker: depth of invasion and nodal and distal metastasis. -penetration of tunica muscularis: progressed tumor -symptoms present late. problems with ingestion, nausea, swallowing problems. -can spread to virchows lymph node (left supraclavicular) -diffuse type: distant metastasis to liver, somtimes bilateral ovaries (krukenberg tumor) *Intestinal type -more common, represent large irregular ulcers -risk factors: intestinal metaplasia(H.pylori), nitrosamines in smoked food -APC gene mutation also increase risk -grow as a bulk of glandular like structures -can be exophytic, tubular or ulcerated tumor *Diffuse type -not associated H.pylori, intestinal metaplasia, smoked food -display infiltrative growth of cells with accumulation of mucin in cytoplasm pushing the nucleus to the periphery forming signet ring cells. they either grow in nests or alone. -often cause gastric wall to stiffen - linitis plastica appearance -associated with EBV. Loss of E-cadherin (adhesion protein) GIST - Gastrointestinal stromal tumor -most common mesenchymal tumor of adbdomen -half of them occur in stomach -occur in men 60 years. mutation in tyrosine kinase genes. -arise from common stem cell with interstitial cells of Cajal (pacemaker of peristalsis). -usually solitary, well circumscribed and composed of spindly cells or sometimes epitheliod cells. can spread to liver.

Adenocarcinoma

Adenocarcinoma -collective term for carcinomas of the mucosa or exocrine or endocrine glandular epithelium with formation of lumina within tumor cell complex or lumina within tumor cells themselves in the form of inner surfaces. ★Highly differentiated forms -Acinic carcinoma: epithelium of carcinoma exhibit histologic pattern resembling glandular acinus. -Tubular carcinoma: carcinoma mimics glandular tubules. these tubules lie back-to-back due to slight stromal reaction. ★Moderately differentiated forms - Cribriform carcinoma: epithelium exhibit a gland in a gland pattern resembling a sieve. Ex. prostate carcinoma, adenoid cystic carcinoma -Papillary carcinoma: epithelium folds to form a tumor papilla. Ex. bronchial, thyroid and ovarian carcinomas. ★Mucigenous carcinomas -several types of mucin-producing carcinomas are differentiated according to the quantity of mucin produced and where it is deposited. -Cystadenocarcinoma -secrete massive amount of mucin, creating a cavity in the tumor tissue. -Tubular carcinoma -excrete mucin into tumor tubules. -Mucinous carcinomas - produce massive amounts of mucin in the glandular acini of the tumor. this causes the acini to burst, creating extracellular deposits of mucin and giving the cut section of the tumor a glassy, transparent appearance. -Signet-ring cell carcinoma - undifferentiated carcinoma characterized by loss of intercellular cohesion with massive vacoular accumulation of mucin in all cells of the tumor. this produces a typical "signet-ring" cellular deformation with peripheral displacement of nucleus. -Solid carcinomas - mucinous single cells, are undifferentiated carcinomas characterized by intercellular cohesion. these tumors exhibit small amounts of intracellular mucin in isolated tumor cells without significant cellular deformation.

Adenomas

Adenomas -tumors arising from glandular, parenchymal or mucosal epithelium and consist of proliferative epithelial folds or tubules in or on a stroma. ★Solid adenoma -occur in glandular organs -nodular tumor with proliferation of glandular epithelium in a stroma. -sharply demarcated from surrounding tissue of origin and exhibit smooth surface with a fibrous tumor capsule. ★Tubular adenoma -occur primarily in intestinal tract -lesion is generally pediculate, superficially smooth tumor nodule of proliferating epithelial tubules (mucosal polyp) in the lumen of hollow organ. example: appendiceal adenoma. ★Villous adenoma -occur primarily in intestinal tract -lesion is generally broad-based tumor of epithelial villi on a highly vascularized stroma that projects into the lumen of a hollow organ. Its villous surface is easily injured, resulting in bleeding. ★Cystadenoma -occur primarily in ovaries and salivary glands -ballooning tumor consist of epithelium that forms a hollow cavity due to stasis of secretion, with smooth surface. ★Fibroadenoma -occur primarily in breast -smooth nodular tumor of epithelial tubules that become compressed and folded as the stroma proliferates.

Tumors of CNS

Characters of CNS tumors -difficult to define borders of malignancy -anatomical site of neoplasm can have lethal consequences, a benign tumor can compress surrounding structures - damage -resection of tumor may limited because of location -primary malignant CNS tumors rarely metastasize (the other way around is more common (25-50% of CNS tumors are secondary) -in children - majority of intracranial tumors are infratentorial -in adults - majority of intracranial tumors are supratentorial -CNS tumors are the 2nd most common malignancy in children (leukemia #1) -seizures is often the fist symptom. CNS tumors can be classified into: 1. Gliomas (Astrocytoma, Oligodendroglioma, Ependymoma) 2. Neuronal tumors (Central neurocytoma, Ganglioglioma, Dysembryoplastic neuroepithelial tumor, Neuroblastoma) 3. Poorly differentiated tumors (Medulloblastoma) 4. Meningiomas

Soft tissue tumors

Soft tissue = any non-epithelial tissue other than bone, cartilage, CNS, lymphoid tissue. Soft tissue include: -Fibrous connective tissue -Adipose tissue -Skeletal muscle -Blood/lymph vessels -Peripheral nervous system Most soft tissue tumors originate from pluripotent stem cells. -but in peripheral nerve sheath tumors: neoplastic cells show evidence of schwann cell differentiation. -many soft tumors develop of unknown cause -some caused by toxin, radiation, burn, viral infection (HHV-8->KS) -small part associated with genetic syndromes -most soft tissue tumors are either benign or malignant, but many are intermediate (locally aggressive behvaior with low-moderate likely to metastase)

Cysts

Cyst is a closed sac with a distinct membrane that is enclosed by nearby tissue. The cells forming the membrane is distinctly abnormal in appearance & behavior compared to all surrounding cells at that location. -may contain air, fluid or semi-solid material -once its formed, it may resolve on its own. if it fails to resolve, it may be removed by surgery depending on type and location. -most cysts are harmless, but should be removed when possible because they occasionally mach change into malignant growths, become infected or obstruct a gland. -developmental or acquired ★developmental in kidney, liver (adult PKD, infantine PKD) ★acquired cysts in ductal, glandular, adnexal (skin), follicular or inclusion. -often after blockage of duct(mucocele in GB,fibrocystic change in breast) Types of cysts ★Retention cyst -resulting from obstruction to the excretory duct of a gland (mucocele) ★Exudation cyst -formed by slow outflow of exudate into a closed cavity ★Embryonic cyst -developing from bits of embryonic tissue that have been overgrown by other tissues, or from developing organs that normally disappear before birth (branchial cyst) ★Parasitic cyst -from larval parasites: tapeworms, amebas, thichinae (hydatid cyst) ★Nabothian cyst -occuring when mucus producing glands in columnar epithelium of uterine cervix become covered by squamous epithelium, resulting from metaplasia - usually found in transformation zone of cervix. ★Renal retention cyst -resulting from scarring or obstruction of tubules in chronic renal disease- ★Dermoid cyst -teratoma of cystic nature that contains mature, solid tissue (skin, hair, nails, fat, bone etc) which can occur anywhere and is nearly always benign. ★Keratocyst -keratocystic odontogenic tumor is rare and benign and usually occur in posterior mandible.

Familial tumor syndromes

Familial tumor syndromes -several inherited syndromes are associated with an increased risk of particular tumors, most syndromes linked to a loss of TSG ★Neurofibromatosis type 1 (1/3000, AD) -NF1 gene (TSG) - neurofibromin -characterized by neurofibromas (plexiform and solitary), gliomas of optical nerve, lisch nodules (pigmented nodules of iris) and skin cafe au lait spots. -especially plexiform neurofibroma can undergo malignant transformation -the course of disease is highly variable: asymptomatic to spinal deformities. ★Neurofibromatosis type 2 (1/40 000, AD) -NF2 gene (TSG) - merlin -patients develop range of tumors: bilateral vestibular, multiple meningiomas, gliomas, ependymomas of spinal cord ★Tuberous sclerosis (1/30 000, AD) - uncertain genes (TSC1 gene - hamartin, TSC2 gene - tuberin) -characterized by cortical hamartomas, subendymal giant cell astrocytomas -> seizures -extracerebral lesions: angiolipoma of kidney, rhabdomyoma of heart, retinal hamartomas, lymph angioleiomyomatosis of lung -cyst formation in liver, kidney, pancreas ★ Von Hippel - Lindau disease (1/40 000, AD) -VHL gene - pVHL -associated with inactivation of VHL gene -> increased hemangioblastoma of cerebellum, retina, medulla and SC and renal cell carcinoma -cyst in pancreas, liver and kidneys

Mixed germ cell tumor

Germ cell tumors are usually mixed with two or more germ cell tumors. -most common mix: teratocarcinoma (teratoma + embryonal carcinoma) -metastasis via lymph nodes (to seminoma) or via blood (to lungs, liver, brain, bones) -bad prognosis

Prostate cancer grading

Gleason scoring system grade prostate cancer. ★Primary pattern represent most common pattern ★Secondary pattern represent the next most common pattern Each pattern is given a grade from 1-5, 1: most normal looking prostate The two grades are then added to a gleason score ★Gleason X: gleason score cant be determined ★Gleason 2-6: tumor tissue well differentiated ★Gleason 7: tumor tissue moderately differentiated ★Gleason 8-10: tumor tissue poorly differentiated or undifferentiated Difficulties in establishing clear-cut criteria have led in some instances to descriptive characterizations ("well. diff adenocarcinoma with no evidence of vascular or lymphatic invasion" or "highly anaplastic sarcoma with extensive vascular invasio")

Gliomas

Gliomas are the tumors of the CNS that histologically resemble different types of glial cells; astrocytes, oligodendrocytes and ependymal cells. ★Astrocytoma 1. Fibrillary astrocytoma -80% of adult primary brain tumors -usually found in cerebral hemispheres -based on degree of differentiation, divided into three: 1) astrocytoma 2) anaplastic astrocytoma 3) Glioblastoma multiforme -most frequent astrocytoma, one of the most aggressive tumors in the body. -develops in adulthood (60+) -typically localized in white matter of hemispheres and can infiltrate contralateral hemisphere -uncircumscribes, infiltratively growing -can develop de novo or through malignancy of astrocytoma -big, unclearly circumscribed, necrotic and hemmorrhagic 2. Pilocytic astrocytoma -relatively benign tumor that occur in children, young adults -often cystic, and usually located in cerebellum -rarely occur in the wall of 3rd ventricle and in optic nerves ★Oligodendroglioma -10 % of gliomas -mostly located in cerebral white matter -relatively good prognosis -well circumscibed, grey and cystic ★Ependymoma -most often arise in ventricular system, including central canal -in adults - spinal cord is the most common location -CSF dissemination is a common occurence, may cause hydrocephalus due to obstruction of CSF flow -tumor cells may form rosettes and perivascular pseudorosettes

Grading of cancer

Grading and staging: Methods to measure the clinical aggressiveness of a given neoplasm and its apparent extent and spread in individual for accurate prognosis and treatment. Grading -establish some estimate of aggressiveness or level of malignancy based on cytologic differentiation of tumor cells and number of mitosis found. -indicator of how quickly a tumor is likely to grow and spread. ★Well differentiated tumors, if cells and organization of tumor´s tissue are clos to normal cells and tissue - tend to grow and spread slow ★Undifferentiated or poorly differentiated - abnormal looking cells and may lack normal tissue structures Examination of biopsied tissue determines tumor grade. -The cancer may be classified as grade 1-4 with increasing anaplasia. ★Grade X: undetermined grade (cant be assessed) ★Grade 1: well differentiated (low grade) ★Grade 2: moderately differentiated (intermediate grade) ★Grade 3: poorly differentiated (high grade) ★Grade 4: undifferentiated (high grade)

Squamous cell carcinoma

Squamous cell carcinoma -collective term for carcinomas that mimic squamous epithelium, exhibiting filamentous eosinophilic cytoplasm, sharply demarcated cell borders and often keratinization. Tissue patterns in SCC range between two extremes according to the degree of differentiation of the tumor. ★Highly differentiated forms -exhibit layers of cells that tend to keratinize and form cornified clumps that are layered like an onion. ★Undifferentiated forms -polymorphic carcinomas with high mitosis count, usually dont keratinize. Spindle cell carcinoma -special histologic form. -undifferentiated SCC exhibiting pronounced stroma and spindle-shaped deformation of the tumor cells. -this produces a pattern of growth resembling sarcoma. -Poor prognosis.

Hodgkin lymphoma

Hodgkin lymphoma -group pf neoplasms that arise almost exclusively in a single LN or chain of LNs and spread stepwise to other nearby. -this spreading mechanism is characteristic for HL. -characterized by presence of Reed-Sternberg cells, clinical picture and pattern of spread. -tumor arising from germinal center B cells. -50% associated with EBV infection (mixed-cellularity HL) -present as painless lymphadenopathy, advanced: fever, weight loss, night-sweats and anemia. -good prognosis with chemo, radiotherapy Types ★Nodular sclerosis HL ★Mixed cellularity HL ★Lymphocyte rich HL ★Lymphocyte depletion HL ★Lymphocyte predominance HL Reed Sternberg cells: -owl eye appearance - two nuclei with large nucleoli -subtypes: ★Hodgkin´s cell: mono-nucleated ★Lacunar cell: large cell with a single nucleus with multiple small nucleoli, eosinophilic cytoplasm which is retracted around the nucleus, creating empty space. ★Pleomorphic RS cell: multiple irregular nuclei ★Lymphohistiocyte RS cell: popcorn cell - small cell with very lobulated nucleus, small nucleoli ★Mummy RS cell: compact nucleus, no nucleolus and basophilic cytoplasm RS cells and its variants are the ONLY neoplastic cells. They account for only 0.5-2% of the cells. The more RS cells, the worse

Neuronal tumors

Neuronal tumors are rare tumors that can arise anywhere at any age. They are frequently mixed with glial components. ★Central neurocytoma - low grade tumor found within ventricular system -majority grow inwards into the ventricular system, forming interventricular neurocytomas. -> leading to 2 primary symptoms: blurred vision, increased intracranial pressure ★Gangliogliomas -tumors with mixture of glial cells and ganglion cells -most of these tumors are slow growing -most commonly located in temporal lobes ★Dysembryoplastic neuroepithelial tumor -low grade tumor of childhood -slow growth and relatively good prognosis after resection -typically located in temporal lobe -consist of glial cells and neurons ★Neuroblastoma -aggressive tumor arising from neuroblasts -usually affects children under 5 -mostly starts from one of the adrenals -most common cancer in babies and the 3. most common cancer in children after leukemia and brain cancer

NEUROENDOCRINE TUMORS

Islet cell tumors ★Insulinoma -most common islet cell tumor -neoplastic beta cells secrete insulin -> hypoglycemia -solitary, encapsulated, varies in size -cords and sheets of well difff. B cells -difficult to distinguish ★Gastrinoma -most often occur in duodenum -may be benign or malignant, ass with peptic ulcers -hypergastrinemia -> gastric acid hypersecretion ★Pheochromocytoma -rare tumor, begins in chromaffin cells in adrenals -increased secretion of adrenaline and noradrenaline -benign (5% malignant), but still life-threatening -80% occur in one adrenal, 10% in both, 10% outside adrenals -soft, spherical, variable in size, well demarcated, cut section brown. ★Merkel cell carcinoma -highly aggressive, fast growing rare skin cancer -starts in hormone-producing cells below skin in hair follicles -usually in head and neck region -people over 70, more in men and caucasions -painless, firm, shiny lump on skin -may spread to lymphatics, distant

Leukemia

Leukemias are neoplastic proliferative disorders of WBC. There are two types of proliferation of white cells: ★Reactive proliferation (physiological) -WBC increase in reaction to infection, inflammation, trauma, stress etc. -Leukocytosis: mild-moderate increase of WBC. -Leukemoid reaction: high increase of WBC, up to 30 000-50 000/ul. ★Neoplastic proliferation (pathological) -can lead to leukemia or lymphoma (difference in where and how they spread, behave and present clinically) -Leukemia: neoplastic proliferation of hematopoietic precursor cells. if the hematopoietic precursor cells undergo malignant transformation and spill (behave like a fluid) into circulation. the neoplastic cells diffusely infiltrate the bone marrow. ="milk" -Lymphoma: also neoplastic proliferations of hematopoietic precursors. these cells, however stick together, making a well defined clear cut mass in any tissue. the lymphoma cells dont come into the blood in very high numbers. ="butter" Neoplastic proliferations of WBC can be divided into: ★Lymphoid neoplasms -neoplastic cells derived from lymphoid precursors cells, either from B-line or T-line mileage or NK mileage. -include NHL, HL, lymphocytic leukemia, plasma cell neoplasms ++. ★Myeloid neoplasms -arise from progenitor cells that give rise to granulocytes, RBC, platelets. ★Histiocytic neoplasms -include proliferative lesions of macrophages and dendritic cells.

Non- Hodgkin lymphoma

Lymphomas are accumulations of T/B lymphocytes. NHL is more common than HL. -80% of NHL are B-cell lymphomas - half follicular, half diffuse -20 % of NHL are T-cell lymphomas - only diffuse Non hodgkins can be divided into low grade, intermediate grade and high grade. ★Low grade: -Small lymphocytic lymphoma (B cell) -Mycosis fungoides of skin (T cell) -Follicular small cell lymphoma (B cell) -Extranodal lymphoma ★Intermediate grade: -Follicular large cell lymphoma (B cell) -Diffuse large cell lymphoma (B cell) ★High grade - LASSI -Lymphoblastic lymphoma (T cell) -Adult T cell lymphoma -Sezary syndrome (T cell) -Small, non-cleaved lymphoma/Burkitt lymphoma (B cell) -Immunoblastic lymphoma (T/B cell)

Malignant epithelial tumors

Malignant epithelial tumors -either carcinoma (squamous) or adenocarcinoma (glandular, columnar) -characterized by invasive, locally destructive growth with possible dissemination via lymphatics (local metastasis) and hematogenic (distant metastases - lung, liver, bone, other) ★Cytological signs: -loss of polarity -increased NC ratio -pleomorphism: anisocytosis, anisokaryosis, hyperchromatism nucleolar changes -increased mitotic activity There are several ways to distinguish between the different types of malignant epithelial tumors. One way is according to their growth pattern, tendency to develop necrosis, and stroma. ★Papillary carcinoma - resemble papillomas but have larger surface area ★Polypoid carcinoma - resemble benign polyps, but usually larger than 2cm ★Ulcerated carcinoma - exhibit central necrosis that has created an ulcerated crater surrounded by a ring-like wall ★Cystic carcinoma - arise due to malignant degeneration of cystadenoma ★Scirrhous carcinoma - exhibit stromal proliferation around tumor villi, leading to diffuse tumor growth. ★Medullary carcinoma - soft pulpy tumors with little stroma that resemble bone marrow ★Multicentric carcinoma - develop simultaneosly at several sites in the epithelium of origin. Classification according to stroma: ★Scirrhotic carcinoma - Epithelium < Stroma (eg diffuse tumor of stomach) ★Simple carcinoma - Epithelium = Stroma ★Medullary carcinoma - Epithelium >> Stroma (in breast, thyroid gland)

Poorly differentiated tumors

Medulloblastoma -the most common pediatric malignant primary brain tumor -located in cerebellum -spreads via CSF and frequently metastasize to different locations along the surface of brain and spinal cord.

Meningiomas

Meningiomas -predominantly benign tumors of adults arising from the meninges (arachnoid cells) -can be located along any of the external surfaces of brain as well as within the ventricular system. -occurs more frequently in women, can be hormone sensitive -subtypes include: psammomatous meningioma, transitional meningioma, meningiothelial meningioa, fibroblastic meningioma.

Mesenchymal tumors

Mesenchyme -loosely organized, undifferentiated (pluripotent), supporting tissue derived from embryonic mesoderm and give rise to CT, blood, lymphatics, bone, cartilage, adipose tissue and muscle. Mesenchymal tumors -consist of tissue that originate from mesenchyme -vimentin is the major cytoskeletal component of mesenchymal cells, thus a clinical marker for mesenchymal tumors -basic component of the tumor: reactive stroma (blood vessels, lymphovytes, CT, macrophages) and proliferating neoplastic cells. Benign mesenchymal tumors -and with -oma -far more frequent than malignant sarcomas -most do not evolve from benign to malignant Sarcomas -mainly spread hematogenously (eg to lungs, liver, bones). ★Fibrous: Fibroma -> Fibrosarcoma ★Bone: Osteoma -> Osteosarcoma (+ Ewing sarcoma) ★Cartilage: Chrondroma -> Chondrosarcoma ★ Muscle: Leiomyoma, Rhabdomyoma -> Leiomyosarcoma, Rhabdomyosarcoma ★Blood vessels: Hemangioma -> Angiosarcoma, Kaposi sarcoma ★Fat: Lipoma, Hibernoma -> Liposarcoma ★Other: -myxoma, -GIST (malignant)

Oncogenes

Proto-oncogenes are essential for cell growth and differentiation. Mutation of proto-oncogenes form oncogenes that lead to unregulated cell growth. Categories of oncogenes: ★Growth factors - induce cell growth -PDGFB -> Astrocytoma ★Growth factor receptors - mediates signals from GF -FRBB2 ->Breast carcinoma -RET -> sporadic medullary carcinoma of thyroid - KIT -> GIT stromal tumor ★Signal transducers - relay receptor activation to nucleus -RAS - carcinoma, melanoma, lymphoma ★Nuclear regulators -C Myc - Burkitt lymphoma -N Myc - Neuroblastoma -L Myc - Lung carcinoma (small cell) ★Cell cycle regulators - mediate progression through cell cycle - Cyclin D1 - Mantle cell lymphoma - CDK 4 - Melanoma

Myxoma

Myxoma -benign tumor where myxoid ground substance (mucous or gelatinous) predominates, embedding various cells of mesenchymal origin. -most common primary tumor of the adult heart -almost always single, 80% occur in left atrial cavity (arising in the region of oval fossa) -tumor can be small or massive, sessile or pedunculated. -pedunculated: often mobile and able to swing into mitral or tricuspid valve during systole, damaging the valve leaflets -myxomas are intravascular, accounting for most cases of tumor embolism. -can be familial and transmitted in AD fashion, however most are sporadic.

Pseudo tumors / Tumor like lesions

Pseudotumors aka tumor-like lesions = enlargement of tissues that resembles tumors. -may result from inflammation, accumulation of fluid or other causes - may regress spontaneosuly Enlargement of tissue due to: -multiple growth by hormones (hyperplasia) -enlargement of cells (hypertrophy) -more intestinal tissue -combinations. Examples: -Hyperplasia (prostate gland) -Hypertrophy (muscle) -Hamartoma -normal tissue in disorganized manner (chondrohamartoma) -Choristoma -normal tissue in abnormal location (pancreatic heterotopia) -Cyst - cavity with epithelial lining -Pseudocyst - cavity without epithelial lining -Deposits of pathological material -Inflammatory pseudotumors - IgG4 related disease -Polyps

Endocrine tumors

Pituitary ★ Pituitary adenoma -prolactin, GH, ACTH secreting tumor -range in size, spherical, soft and encapsulated -composed of predominantly one cell type (acidophil, basophil or chormophores) -diffuse, sinusoidal or papillary pattern. Adrenal ★Adrenocortical adenoma -benign slow growing, small, usually nonfunctional -may be part of MEN type 1 -small, solitary, spherical and encapsulated (bright yellow cut) -arranged in trabeculae, resemble zona fasciculata. ★Adrenocortical carcinoma -uncommon, mostly in adults -invades locally, spreads distally -most secrete excessively hormones -large spherical, well demarcated (yellow, Hem, Necr, Calc) Thyroid ★Follicular adenoma -most common benign tumor of thyroid, in adult women -solitary, encapsulated, small, spherical(grey-white to redbrown) -benign follicular cells form follicles of various size, may show trabeculae, solid and cord patterns. -microfollicular, normofollicular, macrofollicular, Hurtle cell, atypical cells may be seen ★Thyroid cancer -95% are carcinoma of primary tumors -4 types: Papillary, Follicular, Medullary and Anaplastic -risk factors: radiation, iodine excess, genetics -★Papillary carcinoma -most common, higher in advancing age, 3x more in female -slow growing malignant, most often asymptomatic solitary -nodule up to 10 cm, cut surface grey white, hard, scar-like -papillary pattern, cells with clear cytoplasm -psammoma bodies in stroma -good prognosis Parathyroid ★Parathyroid adenoma -most common PT tumor, occur at any age -mostly adults -excessive secretion of PTH -> hyperparathyroidism -small encapsulated, OVAL nodule up to 5g -chief cells arranged in sheets or cords -rim of normal PT parenchyma outside capsule=not diffuse hyperplasia ★Parathyroic carcinoma -rare, more pronounced hyperparathyroidism -irregular in shape, adhere to tissue, most well.diff -difference from adenoma: local invasion, distant metastases

Precancerous lesions and conditions

Precancerous condition: a generalized state of the body, which is associated with significantly increased risk of cancer. Precanceroses: any pathologic change that can lead to formation of malignant tumors. in this tissue we can see a change of structure, impairment of differentiation or cytologic alterations of cells. Precancerous lesions: state of disordered morphology of cells, which is associated with an increased risk of developing cancer. -histopathological abnormality in which cancer is more likely to occur. -fex. dysplasia, metaplasia, hyperplasia, inherited defect or acquired -usually caused by persistent stress on the tissue, in form of chronic tissue injury or inflammation. -even though precancerous lesions increase risk of malignancy, very few actually turn malignant. individual risk depend on tissue and type of lesion.

Bone tumors

Primary bone tumors are less common than bone metastasis from other primary sites. ★Osteoma -most common in neck, head and paranasal sinuses -mostly solitary, slow growing, hard, exophytic masses -multiple lesions in Gardner syndrome (Familial colorectal polyposis) -can cause mechanical problems, obstruction in sinus, cosmetic deform -not locally aggressive, do not undergo malignant transformation ★Osteoid osteoma and Osteoblastoma -benign neoplasm with very similar histological features. -both lesions typically occur in late adolescence -osteoid sarcoma is smaller, causes localised pain in the night(aspirin work) -osteoblastoma causes diffuse pain often in vertebrae (aspirin doesnt) ★Osteosarcoma -primarily in long bones in adolescents -most common primary bone malignancy after myeloma and lymphoma -most common type is Primary, solitary, intramedullary and poorly differentiated, producing predominantly bony matrix. -several syndromes associated - eg Li Fraumeni syndrome, Rb syndrome, bone infarcts, chronic osteomyelitis, Pagets disease, irradiation. -Secondary osteosarcoma occur in elderly, is highly aggressive(like primary) and do not respond well to therapy, usually fatal ★Ewing sarcoma -primary undifferentiated malignant small round cell tumor of bone and soft tissue. -affects mostly people under 20y -second most common pediatric bone sarcoma (after osteosarcoma) -usually manifest as painful palpable mass on long tubular bones or pelvic flat bones. -reciprocal translocation between Chr.11 and 22 are also seen in primitive neuroectodermal tumors.

Mesothelioma

Rare malignant cancer of mesothelial cells. Usually arise in parietal or visceral pleura, but can occur in peritoneum or pericardium. -related to occupational exposure to asbestos. 50% of patients history of asbesos exposure. -latent period is long, 25-40 years after initial asbestos exposure, suggesting multiple somatic genetic events required for conversion to mesothelial tumor cell. -asbestos remain for life in the body, prefer to gather near mesothelial cell layer where they generate ROS, cause DNA damage and can lead to oncogenic tranformation. -Somatic mutations of 2 TSG have been observed: p16/CDK2A, NF2 Malignant mesothelioma often preceeded by extensive pleural fibrosis and plaque formation. -begin in localized area before spread widely over time either by contact growth or diffusely seeding to pleural surfaces -autopsy: lung is yellow-white, firm, sometimes gelatinous layer of tumor covering pleural space. -distant metastases rare (invade thoracic wall or subpleural tissue) Normal mesothelial cells give rise to pleural lining and the underlying fibrous tissue - gives 3 patterns: 1. epithelial - cuboidal cells line tubular and microcytic spaces in which small papillary buds project. most common pattern. (often confused with pulmonary adenocarcinoma) 2. sarcomatoid - spindled and sometimes fibroblastic-appearing cells grow in non-distinctive sheets 3. biphasic - having both sarcomatoid and epithelial areas.

Polyps

Small growth, usually benign with a stalk protruding from a mucous membrane. -May be tubulous, villous or tubulovillous. -shape and structure can determine risk of invasiveness. -formed by inflamed stroma, edematous, collagen CT, blood vessels and normal mucosa. -if it is chronic, it can lead to metaplasia. -causes include inflammation, foreign object, cyst, tumor, mutation in genes of colon cells, chronic stomach inflammation, excess estrogen. Examples ★Hyperplastic polyp -very common in colon, may coexist with benign neoplastic polyps and malignant polyps. -most of them do not have malignant potential -exception: hyperplastic polyposis syndrome -> invasive adenocarcinoma ★Peut Segher polyps -polypoid hamartoma ★Inflammatory pseudopolyp -seen in ulcerative colitis. -non-ulcerated area that protrudes above ulcerated area ★Nasal polyp -associated with chronic rhinitis.

Staging of cancer

Staging of cancer is based on size of primary lesion, its extent of spread to regional lymph nodes and the presence or absence of metastases. -Assessment based on clinical (lab tests other procedures) and radiographic examination (Xray, CT, MRI) and in some cases surgical exploration. -Staging help understand how serious the cancer is and survival chances. Also to plan the best treatment and identify clinical trials that may be treatment options. -Cancer is always referred to by the stage it was given at diagnosis, even if it gets worse or spreads. New information about how a cancer changes over time gets added on to the original stage. Staging vocabulary ★In situ: abnormal cells present but not spread to nearby tissue ★Localized: cancer limited to the place it started, no sign of spread. ★Regional: cancer spread to nearby LN, tissues or organs. ★Distant: cancer has spread to distant part of body. ★Unknown: not enough information to figure out stage. TNM system and AJC system used.

Regulators of Apoptosis

They prevent apoptosis in normal cells, promote apoptosis in mutated cells whose DNA cannot be repaired. ★Bcl 2 (anti-apoptotic gene) -normally stabilizes MIT membrane, blocking release of cytochrome c -disruption of Bcl2 allow cytochrome c to leak and cause apoptosis -Follicular lymphoma: Bcl2 is overexpressed. -Translocation t(14;18) moves Bcl2 (Chr18) to Ig heavy chain locus (Chr14) resulting in increased Bcl2 -> inhibiting apoptosis -B cells don´t under go normal apoptosis because of mutation, causing accumulation in germinal center leading to lymphoma. ★BAX (pro-apoptotic gene) -mutation: decreased activity

Vascular mesenchymal tumors

Tumors of blood vessels and lymphatics include ★Common benign hemangiomas ★Locally aggressive intermediate neoplasm that rarely metastasise ★Rare, highly malignant angiosacroma Vascular neoplasm can arise from endothelium (hemangiima, lymphangioma, angiosarcoma) or from suppporting cells (glomus tumor, hemangiopericytoma) Benign tumors -usually contain obvious vascular channels filled with blood and lymph, lined by a monolayer of endothelium. Malignant tumors -more cellular and proliferate, usually do not form well-organized vessels Benign ★Hemangioma ★Lymphangioma ★Glomus tumor Intermediate ★Hemangioendothelioma ★Hemangiopericytoma ★Kaposi sarcoma Malignant ★Hemangiosarcoma ★Lymphangiosarcoma

Tumors of oral cavity

Tumors of oral cavity ★Fibroma -fibrous proliferative lesion -submucosal nodular lesions arising due to chronic irritation in buccal mucosa along bite line (reactive CT hyperplasia) ★Pyogenic granulomas -fibrous proliferative lesion -pedunculated in gingiva of young adults, children, pregnant -richly vascularized and usually ulcerated. ★Leukoplakia and erythroplakia -chronic irritation of oral mucosa, hygiene, tobacco. -can lead to precancerous conditions -erythroplakia is vascularized leukoplakia (higher pre-malignant potential) ★Squamous cell carcinoma -95% of oral cancers are squamous. -aggressive, six most common neoplasm in the world. -long term survival less than 50% -multiple primary tumors may be present -alcohol, tobacco, HPV infection -most often in floor of mouth, gingiva, soft palate -often ulcerate, range from well differentiated keratinized to anaplastic. -spread first to cervical LN - mediastinal, lungs, liver -Tongue very aggressive, Lip better prognosis

Lipoma, Liposarcoma, Hibernoma

★Lipoma -benign tumor of fat, most common soft tissue tumor in adults -most are solitary. multiple lipomas suggest presence of rare hereditary syndromes. -can be subclassified into: fibrolipoma, myelolipoma, angiolipoma, myolipoma and angiomyelolipoma ★Liposarcoma -malignant neoplasms with adipocytic differentiation -mostly arise in deep soft tissue or in retroperitoneum -can be divided into low grade well-differentiated liposarcoma and high grade myxoid/round cell liposarcoma - in most cases: lipoblast present as malignant cell ★Hibernoma -benign neoplasm of brown adipose tissue -lipoma of immature fat -commonly occur in interscapular area

Malignant PNS tumors

★Malignant PNS tumors Typically also show differentiation from Schwann cells. -Seen in adults mostly -about 50% occur de novo, other arise from malignant transformation of preexisiting NF1 associated Neurofibroma (dont arise from Schwannomas!) -present as large, poorly defined tissue masses with anaplasia, necrosis, infiltrative growth, pleomorphism and high mitotic activity.

CT: Fibrohistiocytic tumors - Dermatofibroma, Dermatofibrosarcoma protuberans, Malignant fibrous histiocytoma

★ Dermatofibroma -small, circumscribed, motile nodules -in dermis or subcutaneous tissue -cured by simple excision ★ Dermatofibrosarcoma protuberans -cutaneous soft tissue sarcoma, very rare -intermediate malignancy, behaving like a benign tumor -can in rare cases metastase -lesions often in thorax, abdomen, extremeties, head and neck -bednar tumor is a rare variant with melanin pigment within cells. ★Malignant fibrous histiocytoma -undifferentiated, extremely aggressive tumor -high metastatic potential -includes poorly differentiated leiomyosarcoma and leiomyoma, and is therefor called pleomorphic fibroblastic sarcoma

High grade NHL - LASSI

★ Lymphoblastic lymphoma -can transform to leukemia -T cell lymphoma in 40% of childhood lymphomas -can affect CNS, skin, mediastinal LN ★ Adult T cell lymphoma -CD4 T cells -HTLV-1 encodes Tax protein that activate NF-kB enhancing survival -rapidly progressive, fatal witihin months-1year despite chemo -cells small -only seen in adults affected with human t-cell leukemia retrovirus 1 -skin lesions, generalized lymphadenopathy, hepatosplenomegaly, peripheral lymphocytosis, hypercalcemia (unknown reason) ★Sezary syndrome -more aggressive form of mycosis fungoides (T cell) -spread from skin ★Small, noncleaved lymphoma aka Burkitt lymphoma -origin: germinal center B cell -mainly in children and young adults -translocation of c-myc gene on chromosome 8 resulting in increased c-myc expression t(8,14) -very aggressive -very high rates of proliferation + apoptosis. Macrophages surrounded by clear space: starry sky pattern -extranodal sites of tumors: african - mass in mandible, sporadic - peritoneum -curable, radiosensitive ★Immunoblastic lymphoma -T cell/ B cell. 50% from immunological disorder. could be from NHL -50% cure rate

Tumors of parenchymatous organs - Pancreas

★ Mucinous cystadenoma ● In itself benign, but can be associated with an invasive carcinoma ● Male:Female ratio: 95% arise in women ● Location: usually arise in the body or tail of the pancreas ● Morphology: The cysts are larger than those formed in serous cystadenomas, and are filled with thick mucin and lined by a columnar mucin-producing epithelium with an associated dense stroma similar to ovarian stroma ● Progressiveness: 1/3 of surgically resected mucinous cystadenomas harbor an associated invasive adenocarcinoma. The best way to distinguish the entirely benign form (mucinous cystadenoma) from its malignant counterpart (invasive adenocarcinoma arising in association with a mucinous cystic neoplasm) is pathologic assessment after complete surgical removal, usually by distal pancreatectomy ● Clinical presentation: Present as painless, slow-growing masses ★ Mucinous cystadenocarcinoma -various differentiation -70 % head, (body10% and tail 10%) -fibroproduction -Trosseau syndrome - migratory thrombophlebitis is associated in 10% of cases

Tumors of parenchymatous organs - Lung

★ Non small cell carcinoma ★ Small cell carcinoma -strongly related to smoking -frequently hilar or central location -most often associated with neurosecretory granules in majority of tumor cells (NET markers: chromogranin, NSE, synaptophysin) -Three subtypes 1) Oat cell carcinoma-small,uniform cells with sparse cytoplasm form pseudorosettes (ribbons of small BV) 2)Small cell carcinoma -intermediate cell type with cells slighly larger, abundant cytoplasm. cells organized into lobules. 3) Combined oat cell carcinoma -oat cell + squamous cell. Clincal: cough, hemoptysis, dyspnea, pain wheeze A number of paraneoplastic syndrome are associated with lung cancer: Ectopic hormone production (SCC most often associated) - ACTH producing Cushings, ADH inducing hyponatremia, PTH causing hypercalcemia, Calcitonin causing hypocalcemia, Gonadotropins causing gynecomastia and Serotonin associated with carcinoid syndrome.

Rhabdomyoma, Rhadbdomyosarcoma

★ Rhabdomyoma -very rare benign tumor of striated muscle -most often found in the heart - -★Cardiac rhabdomyoma -most common primary tumor of heart in infants, children -frequently discovered due to valvular or outflow obstruction -occur in patients with tuberous sclerosis (mutated TSC1, TSC2 =TSG) -often regress spontaneosly ★Rhabdomyosarcoma -most common soft tissue sarcoma of childhood and adolescence. -usually occur places where there is little or no skeletal muscle -eg. head, neck, genitourinary tract. -histologically classified into variants: 1. embryonal - Sarcoma botryoides (soft, grape-like mass in bladder, vagina in children) 2. alveolar 3. pleomorphic -rhabdomyoblasts found in all variants, the malignant cell used for diagnostics.

Lymphoid neoplasms

★Acute Lymphoblastic Leukemia (ALL) -clonal proliferation of lymphoid stem cells; lymphoblasts -primarily involving BM, LN, other lymphoid organs -extranodal spread to brain, testis -85% B cell, 10% T cell, <5% pre-B and pre-T cell -TdT - terminal deoxynucleotidyl transferase (DNA polymerase in immature lymphoid cells) -> DNA variations - peak incidence in children 4 yo, also occur in adults -survival rate used to be 2 mnths before chemo -90% complete remission, 2/3 permanentlu cured -abrupt onset, fatige, fever, bleeding, bone pain and tenderness -generalized lymphadenopathy, splenohepatomegaly, testicular enlargement, headache, vomiting, nerve palsies ( meningeal spread) ★Chronic Lymphocytic Leukemia -malignant clonal expansion of well-differentiated lymphoid cells resembling B lymphocytes with CD20 marker -asymptomatic, peak incidence 60 yo M:F 2:1 -lymphocytosis, BM involvement, generalized lymphadenopathy and hepatosplenomegaly -anemia, thrombocytopenia, increased susceptibility to bact infection -protracted course, variable survival 6-10 or more years -Richter syndrome - transformation to DLBCL (rare) ★Adult T cell Leukemia /Lymphoma -neoplasm of cd4 t cells caused by retrovirus HTLV-1 (Human T cell leukemia virus type 1) -skin lesions, lymphadenopathy, hepatosplenomegaly, HYPERCALCEMIA along with variable number of malignant CD4+ cells in blood. -in most cases extremely aggressive, not responding to chemo ★Hairy cell Leukemia -rare, indolent neoplasm. -consist of small mature B cells with oval nuclei, abundand cytoplasm with hairy projections. -invade blood and diffusely infiltrate BM, splenic red pulp -middle age - old people M/F 5:1 -treated by chemo, survival rate 92% PLASMA CELL DYSCRASIAS ★Multiple myeloma (Monoclonal gammopathy) -most common malignant plasma cell dyscriasis -multifocal lytic in skeletal system caused by neoplastic proliferation of myeloma cells. -usually occurs in adults, 50-60 -most common M protein produced is IgG (60%), followed by IgA(20%) -in 15 % of cases, plasma cells produce only kappa or gamma light chains, because of their low MW - excreted in urine (Bence Jones proteins) ★Localised plasmacytoma ★Waldenstom+s macroglobulinemia ★Heavy chain disease (only heavy chains - mostly IgA)

Myeloid neoplasms - types

★Acute myeloid leukemia (AML) -neoplastic disease resulting in replacement of normal BM with more than 20% blasts. -hematopoiesis suppression - anemia, neutropenia, thrombocytopenia -represent 20% of all leukemias in western countries mainly 15-30 yo -20% of childhood leukemias -most have mutation in genes encoding transcription factors required for normal myeloid cell differentiation -risk factors: preleukemia (myelodysplastic syndrome, myeloproliferative neoplasm), chemical exposure, radiation, genetics -diagnosis: based on clinical, BM biopsy with more than 20% blasts -secondary hematopoietic organ involvement - spleen, liver, LN -chromosomal translocations, deletions or monosomies typical -fatigue, fever, spontaneous mucosal and cutaneous bleeding, intravascular coagulation, infection of oral cavity, skin etc -in tumors with monocytic differentiation, infiltration of skin and gingiva -CNS involvement - less common than in ALL -poor response to chemo, AML with t(8,21) 50% chance of longterm remission ★Myelodysplastic syndromes -bone marrow partly or wholly replaced by clonal progeny of a transformed multipotent stem cell that retains the capacity to differentiate into red cells, granulocytes or platelets - but ineffective, disorented manner. -as a result: BM is hyper- or normocellular, but in peripheral blood shows one or more cytopenias. Idiopathic or primary MDS -most common, older than 50 -develops insidiously Therapy-related MDS -complication of previous myelosuppressive drug or radiation therapy -risk of transforming to AML!! -variable chemotherapy with variable survival rate according to age, type ★Chronic myeloproliferative disorders -CML, PV, Primary myelofibrosis

Malignant - Angiosarcoma, Lymphangiosarcoma

★Angiosarcoma -malignant endothelial neoplasm range from highly differentiated tumors to widely anaplastic lesions. -typically affects older people and can occur anywhere on the body, especially on skin, soft tissue, breast and liver. ★Lymphangiosarcoma -develop in the ipsilateral upper extremity several years after radical mastectomy (with LN resection) after breast cancer

Precancerous lesions in squamous epithelium

★Barrett´s esophagus -metaplasia of stratified squamous epithelium in lower esophagus into gastric columnar epithelium. -this transition typically occurs due to chronic gastro-esophageal reflux -risk factor for esophageal adenocarcinoma ★Oral leukoplakia -seen as white patches of keratosis on oral mucosa that can not be scratched off. -multifactorial causes: tobacco major factor -risk for squamous cell carcinoma -leukoplakia also seen on vulva and penis ★Actinic keratosis -progressive dysplastic changes leading to patches of thick, scaly, crusty skin due to hyperkeratosis. -caused by damage from UV light (more in light people) -if left untreated - 10% develop into squamous cell carcinoma -more rarely turns into basal cell carcinoma (most common skin cancer) ★Schistosomiasis and carcinoma of bladder -Schistosomiasis infection can cause squamous metaplasia ->dysplasia -> squamous cell carcinoma of urinary bladder

Tumors of parenchymatous organs - Prostate

★Benign prostatic hyperplasia (Nodular hyperplasia) -is hyperplasia of prostatic stromal and epithelial cells, resulting in large discrete nodules in periurethral region of prostate. -The can compress and narrow the urethral canal to cause partial or complete obstruction of urethra. Very common in 50+. ★Prostate carcinoma -product of some critical combination of acquired somatic mutations and epigenetic changed. ★Gleason grading system - Grad 1: well-diff tumor, neoplastic glands are uniform and round in well circumscribed nodules. Grade 5: tumor with no glandular differentiation, infiltrate storm. Most tumors contain more than one pattern, where primary grade assigned to dominant pattern, and secondary grade to most frequent pattern. They are added to obtain Gleason grade.

Examples of cyst in organs

★Bone -often occur in proximal humoral and femoral metaphases in children with cysts with thin fibrous lining. increased risk of bone fractures. -aneurysmal bone cyst filled with blood is often seen near osteoarhtitic joints. ★Brain -taenia solium (larva) may cause cyst in brain and epilepsy. -hydatid cyst in brain by embryos of echinococcus granulosus. ★Breast -fibrocystic change due to duct obstruction leading to dilation of ducts and acini. the lining epithelium show apocrine metaplasia. ★Kidney -adult polycystic disease (AD)is quite common, cause cyst formation and pressure atrophy of nephrons. -infantile polycystic disease is rare (AR) with normal number of nephrons, cyst is located in terminal branches of collecting tubules. ★Ovary -follicular cyst may be single or multiple and may be several cm in diameter. multiple follicular cysts are usually small and associated with endometrial hyperplasia. -theca lutein cysts from disappearing granulosa cells leaving cysts surrounded by luteinized thecae tissue. ★Vagina -bartholin glands on each side of vaginal opening, lubricate vagina -if openings are obstructed, the fluid backup into glands. -painless swelling: bartholin cyst may become infected resulting in pus by inflamed tissue (abscess)

Types of cancer

★Carcinoma -most commonly diagnosed cancer -originate in skin, lung, breast, pancreas and other organs and glands. ★Melanoma -cancer arising in cells that make pigment in skin ★Sarcoma -relative uncommon -arise in bone, muscle, fat or cartilage ★Lymphoma -cancers of lymphocytes ★Leukemia -cancers of blood, does not usually form solid tumors

Neuroblastoma, Ganglioneuroblastoma

★Neuroblastoma -malignant tumor derived from neural crest cells. -most frequently starts from one of the adrenals -can develop in neck, chest, abdomen, spine -most common cancer in babies -most occur sporadically (90%), but some familial, AD. -tumor secrete catecholamines. -small tumor cells forming pseudorosettes. -secondary maturation of tumor cells may occur, resulting in ganglioneuroblastoma or ganglioneuroma. -spontaneous remission may occur. -symptoms: bone pain, faigue, loss of appetite, fever, lump in abdomen, neck or chest (swollen belly), constipation ★ Ganglioneuroblastoma -variant of neuroblastoma, surrounded by ganglion cells.

Tumors of cartilage - Chrondroma, Chondroblastoma, Chondrosarcoma, Osteochondroma

★Chondroma -neoplasm of hyaline cartilage -when arise in medulla, it is called enchondromas -when on bone surface: juxtacortical chondroma -Ollier disease, Maffucci syndromes are characterized by multiple chondromas due to a point mutation. ★Chondroblastoma -rare, benign, locally aggressive bone tumor -typically affects epiphysis or apophyses of long bones -arise from an outgrowth of chondroblasts from secondary ossification centers. ★Chondrosarcoma -slow growing cancer arising from chondrocyte precursors. -tends to develop during mid-late adulthood -affect trunk, limb girdles, proximal long bones -subclassified into: intramedullary or juxtacortical -according to histological features: myxoid, dedifferentiated, clear cell or mesenchymal. -commonly occur in pelvis, shoulder and ribs -common metastases are lung and skeleton. ★Osteochondroma -relatively common benign cartilage-capped tumors attached to skeleton by body stalk -solitary(adult) or multiple (childhood) -autosomal dominant disorder: multiple hereditary osteochondroma -develop only in bones of endochondrial origin arising at the metaphysis near the growth plate. -tend to stop growing once the normal growth of skeleton is completed.

Myeloproliferative neoplams - examples

★Chronic myeloid leukemia -BCR/ABL fusion gene - balanced 9:22 translocation - philadelphia chromosome (also present in smaller fraction in ALL, AML) -leukocyte count elevated (granulocytes, metamyelocytes, myelocytes) ★Polycytemia vera -proliferation of erythrocytes, granulocytes and megakaryocytes (Panmyelosis) -differs from normal polycytemia by its low level of Erythropoietin -polycythemia -> increase blood volume and viscosity -> thrombosis and infarctions in heart, spleen and kidney. -hemorrhage most often affect oropharynx, GIT and brain -might find fibrosis in BM of some patients ★Primary myelofibrosis -fibrosis of BM - eventually extramedullary hematopoiesis in spleen, liver and lymph nodes - inefficient -> anemia, thrombocytopenia -hepatosplenomegaly -erythrocytes with strange shape (poikilocyses, tear drop cells), nucleated erythroid precursors and immature white blood cells are present in the peripheral blood -> leukoerythroblastosis -most common cause of Budd-Chiari syndrome (rare, occlusion of hepatic vein leading to abd pain, ascites and liver enlargement) ★Systemic mastocytosis -CD117 positive -clonally derived mast cell infiltration in bone marrow, skin, GIT, liver, spleen

Parenchymatous organs - Uterus

★Endometriod carcinoma (70-80%) -estrogen stimulation -anovulating cycles, infertility, late menopause -obesity, hyperlipidemia -hormonal receptor expression -premenopausal or perimenopausal -precursor - hyperplasia -ovary - endometriosis ★Non-endometroid carcinoma (15-20%) -High grade carcinoma -multiparity (given birth to eg. twins) -no obesity, no estrogen stimulation -highly invasive, bad prognosis, high mortality -no hormonal receptors -precursor: atrophic endometrium

Precancerous conditions

★FAP - Familial adenomatous polyposis -inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. -polyps start out benign, but malignant transformation into colon cancer occurs when they are left untreated. -caused by APC gene defect (Chr5) ★Lynch syndrome -Hereditary non-polyposis colorectal cancer syndrome -caused by germline mutation of DNA mismatch repair genes, which cause microsatelite instability. -increase risk of many types of cancer, particularly colorectal cancer. ★Gardner´s syndrome - Familial colorectal polyposis -AD form of polyposis characterized multiple polyps in colon together with tumors outside the colon. -caused by mutation in APC gene

CT: Fibroblastic tumors - fibroma, fibrosarcoma

★Fibroma -quite common, can arise almost everywhere -renal medulla, ovary, skin etc. -tumor composed of proliferating fibroblasts -depending on collagen content, they can be soft (molle) or hard(durum) ★Fibrosarcoma -slow growing cancer -often presented in thigh, knee and retroperitoneum -composed of fibroblasts -in half of cases, it recurs locally after excision -most commonly metastases to lungs -often contain hemorrhage, necrosis and form "herring bone" pattern

Intermediate grade NHL

★Follicular large cell lymphoma -translocation t (14,18) - overexpression of antiapoptotic Bcl2 -large cells, indolent cancer, -BM involved in 85% of cases -nodular growth pattern -principal cells: centrocytes, centroblasts, immunoblast -centrocyte:centroblast ratio (grade 1,2,3 -worse prognosis) -usually develop in LN, extranodal: skin, duodenum -painless, generalized lymphadenopathy -can transform into DLBCL -incurable, palitative chare with low dose chemo/ immunotherapy (anti-CD20) ★Diffuse large B-cell lymphoma -most common form of NHL in adults -dysregulation of Bcl6 (can silence p53), also t(14,18) -aggressive tumor, appear as rapid growing mass at nodal or extranodal site, fever, night sweats, fatigue, weight loss -BM involvement late in the course -large cells (3-4x resting lymphocyte) -diffuse growth pattern - 60% nodal, 40% extranodal -waldeyers ring commonly involved -rapidly fatal without treatment (chemo) -rarely can form into leukemia.

Ganglioneuroma, Paraganglioma

★Ganglioneuroma -rare and benign tumor of autonomic nerve fibres, arising from neural crest sympathogonia (undiff. cells of SNS) -fully differentiated solid neuronal tumors composed of ganglion cells, schwann cells and fibrous tissue. -white (can be seen with naked eye) -neoplastic ganglionic cells - large with vesicular nuclei, eosinophilic cytoplasm, surrounded by a clear ring. -arise most frequently from paravertebral sympathetic chains or adrenal medulla. -malignant form: Ganglioneuroblastoma, Neuroblastoma -typically asymptomatic, depending on location -treatment may not be necessary. ★ Paraganglioma -rare neuroendocrine neoplasm -originate from paraganglia in chrommafin negative glomus cells (chemoreceptors in BV: carotid body and arch) -derived from neural crest -can develop from various body sites -97% are benign and cured by surgical removal. -sharply circumscribed mass, firm consistency, highly vascular (deep red) -includes pheochromocytoma (secrete catecholamines) and chemodectoma (no hormones)

Neurofibroma

★Neurofibroma -benign schwann cell tumor arising from craniospinal and peripheral nerves. -Three subtypes: 1) Cutaneous neurofibroma - superficial nodules, sometimes hyperpigmentation, may grow to be large and become pedunculated - cosmetic concern. -Occur either as solitary lesion or multiple in ass. with NF1 2) Plexiform neurofibroma - may arise along a nerve, but large nerve trunks are the most common sites. -Multiple lesions in ass with NF1. -Can involve major nerve trunks - diffucult to remove -Potential for malignant transformaion 3) Diffuse neurofibromas - infiltrative proliferations often taking form as large subcutaneous masses.

Intermediate - Hemangioendothelioma, Hemangiopericytoma, Kaposi sarcoma

★Hemangioendothelioma -wide spectrum of borderline tumors arising in medium-large veins. -tumor cells cuboidal, dont form well defined vascular channels -variable clinical course; exicision may be curable, in some cases tumor metastase, in few cases it is fatal. ★Hemangiopericytoma -rare tumor derived from pericytes (contractile cells that wrap around endothelial cells) -painless, slow growing tumor that occur anywhere, esp in LE, retroperitoneal space -may recur after excision, about half metastase - lung, bone, liver ★Kaposi sarcoma -vascular neoplasm caused bu Kaposi sarcoma herpes virus (HHV-8) -very common in patients with AIDS -virus transmitted through sex, oral secretions, cutaneous exposure Types of KS: 1. Classic KS -disorder in older men in and around europe, not ass. with HIV. -manifest as lesion on distal LE and spread proximally -typically asymptoatic, remains localised to skin and subcut. tissue -cutaneous lesion can progress through 3 stages: 1)pathces (pink-purple macules typically on distal LE) 2) plaques (raised lesions spread proximally and become larger) 3) nodules (accompanied with hemorrhage, hemosiderin deposition and sometimes mitotic figures) 2. Endemic African KS -younger population - severe form seen in prepubertal children, LN and visceral involvement -very bad prognosis 3. Transplant associated KS -occurs due to Tcell immunosupression, causing 100-fold increased risk -follows an aggressive course - LN, mucosa and viscera involved -lesions often regress in case of increased immmune response 4. Epidemic AIDS associated KS -the incidence in HIV patients are 1000-fold higher than general population, thus the most common AIDS-related malignancy -involves LN and viscera in early course

Benign - hemangioma, lymphangioma, glomus tumor

★Hemangioma -very common tumor composed of blood filled vessels -often in children, infants - mostly present at birth -may increase in size or spontaneously regress Types of hemangioma 1. Capillary Hemangioma -most common type, in skin, subcut and mucous membranes of oral cavity, lips or spleen, liver, kidneys. -composed with thin-walled capillaries with little stroma 2. Juvenile hemangioma -can be multiple, extremely common on newborn skin -grow rapidly the first years, then regress by age of 7 3. Pyogenic granulomas -capillary hemangiomas that manifest as rapidly growing red pedunculated lesions on the skin, gingiva and oral mucosa. bleed easily and ulcerate. -can occur as a result of trauma, or during pregnancy. 4. Cavernous hemangioma -composed of large, dilated vascular channels. -more infiltrative, frequently involve deep structures and don´t spontaneously regress (compared to capillary hemangioma) -one component of von Hippel-Lindau disease where vascular lesions commonly found in cerebellum, brain stem, retina, pancreas, liver. ★Lymphangioma -lymphatic equivalent of hemangioma. 1. Simple capillary lymphangioma -slightly elevated lesions found in head, neck and axillary subcut. tissue. 2. Cavernous lymphangioma -cystic hygroma typically found in neck and axilla of children. -commonly seen in Turner syndrome -composed of massively dilated lymphatic spaces with endothelial lining ★Glomus tumor -painful tumor arising from specialized smooth muscle cells of glomus bodies (arteriovenous structures involved in thermoregulation). -most commonly found in the distal portion of digits, esp. under fingernails.

Hodgkin lymphoma vs Non-Hodgkin lymphoma

★Hodgkin lymphoma -more often localised to a single group of LNs -orderly spread by contiguity (bordering areas or in contact) -mesenteric nodes and waldeyer ring rarely involved -extranodal involvement is uncommon ★Non-Hodgkin lymphoma -more often involve multiple LNs -non-contiguous spread -mesenteric nodes and waldeyer ring comonly involved -extranodal involvementis common

Stages of carcinogenesis

★Initiation -carcinogen act usually in the form of enzyme interaction with DNA, producing genetic damage and cell necrosis. -complete carcinogens cause malignant transformation of target cell without the aid of other cofactors. -incomplete carcinogens cause malignant transformation of target cell only by the help of cofactors. -various carcinogens influence each others effect in one of two ways. -complete and incomplete carcinogens can have an additive effect, whereas the effect of a weak carcinogen can be significantly enhanced by cofactor. ★Promotion -process triggering proliferation of initiating cells, causing genetic error to become established in daughter cells and produce dysplasia with polypoid cells. ★Latency -follows promotion, varies in duration. ★Progresssion -first step in tumor development and involves irreversible transition from a single preneoplastic cell to neoplastic cell. -this neoplastic cell becomes the mother cell of a proliferating cell clone. -this clone grows into macroscopic visible tumor nodule that is initially benign and later malignant. ★Metastasis -with increasing progression, transformed cells lose their surface differentiation antigens and with them their cohesiveness. Cells leave primary cell mass, migrate and colonize other tissues and organs, where they form secondary tumors (metastases) -lymphatic spread is characteristic of carcinomas, initial spread is to regional draining LN. -hematogenous spread is characteristic of sarcomas and some carcinomas. (Renal CC - invade renal vein, HepatoCC -invade hepatic vein, Follicular carcinoma of thyroid, Choriocarcinoma)

Leiomyoma, Leiomyosarcoma

★Leiomyoma -benign smooth muscle tumors are common, well circumscribed, can arise anywhere in the body. -most frequently found in uterus, intestinal tract, vascular walls and skin (erector pili) -Clinically called fibrinoids due to to their firm consistency -they may occur single, but more often as multiple -almost never transform to sarcomas, and the presence of multiple lesions does not increase the risk of malignancy. -★Uterine leiomyoma -most common benign tumor in females (30-50% in reproductive age) -occuring in smooth muscle cells of myometrium -growth potentiated by estrogen (more accelerated during pregnancy/pill) -in menopause, estrogen decrease - tumor stop growing, regress -regressive changes: hyalinisation, calcification, ossification -places it can occur: submucosal, intramural, subserosal, myoma nascent -most frequently found: intramural tumor ★Leiomyosarcoma -malignant tumor of smooth muscle -commonly affect skin and deep soft tissues of extremities and retroperitoneum (inferior vena cava) -can also occur in uterus -arise de novo from mesenchymal cell -appear almost always singular -most often occur in postmenopausal women -it usually presents necrosis -superficial or cutaneous sarcomas are usually small, with good prognosis -retroperitoneal tumors are large and bad prognosis

Nodular fasciitis, Myositis ossificans

★Nodular fasciitis -benign reactive soft tissue lesion, often secondary to trauma -spindle cells (fibroblasts, myofibroblasts) in loose matrix -in adulthood, usually on forearm, chest, back -occasionally painful ★Myositis ossificans -fibroblastic proliferation with presence of metaplastic bone -usually develops in proximal muscles of extremities in athletics and young adults after trauma -initially swollen and painful -> painless, hard

HL - types

★Nodular sclerosis HL (65-70%) -most common, frequently found in young women -often involve lower cervical, supraclavicular, mediastinal LNs -Lacunar cells, Lymphohistiocytic (Popcorn) cells presence -presence of collagen dividing the LN into circumscribed nodules -relative good prognosis -rarely associated with EBV ★Mixed cellularity HL (20-25%) -most common in older patient over 50 -commonly associated with EBV -often contains areas of necrosis and fibrosis -plenty diagnostic lymphohistiocytic cells -inflammatory infiltrate containing lymphocytes, eosinophils, plasma cells and macrophages ★Lymphocyte rich HL -associated with EBV ★Lymphocyte depletion HL -associated with EBV -rarest subtype of HL ★Lymphocyte predominance HL -No association with EBV -large number of lymphocytes -very difficult to find RS cells, if found: lymphohistiocytic RS variant

Schwannoma (Neurinoma)

★Schwannoma -benign soft tumor -usually occur in peripheral nerve as a result of proliferation of Schwann cells and perineural fibroblasts -well circumcribed, encapsulated masses that usually attach to the nerve, but can be separated from it -forms gray masses, can also have cystic change -often attach to vestibular branch of CN8 (patient presnt with tinnitus and/or hearing loss) -> "acoustic neuroma" -can be sporadic or in association with NF2, causing multiple lesions. -Bilateral vestibular schwannoma = hallmark of NF2 -mixture of 2 growth patterns: 1) Antoni A: composed of spindle cells with pink cytoplasm, forming characterstic palisades = verocay bodies 2) Antoni B: formed during degeneration of tumor and results in loosely arranged vacuolated big tumor areas *"Malignant Schwannoma" - if its overgrowing the pyramids its not able to be resected!

Hallmarks of cancer

★Self sufficiency in growth signals -mutation of proto-oncogenes -> oncogenes (gain of function, 1 hit) -promotes cell proliferation when there is no need -RAS most common proto-oncogene mutation -> Colon Carcinoma -ABL mutation -> Chronic myeloid leukemia -Myc gene mutation (C - Burkitt lymphoma, L-lung cancer, N-Neuroblastoma) ★Insensitivity to growth inhibitory signals -mutation of tumor suppressor genes (loss of function, 2hit) -cell continue to proliferate -APC -inhibit Beta catenin - if mutation ->-> E2F-> cell cycle -> Familial adenomatous polyposis, Colorectal cancer -P53 - most common mutation in cancer -> inhibit CDK--> E2F-> cell cycle -> Most common, Li Fraumeni syndrome -Rb - mutation -> E2F -> cell division -> Retinoblastoma, Osteosarcoma ★Impaired DNA repair mechanism -Mismatch repair system defect - Hereditary Non Polyposis Colon cancer -Nucleotide excision repair system defect - Xeroderma Pigmentosum -Homologus recombination system defect - BRCA 1, 2 ★Evading Apoptosis -mutation of apoptosis genes activating caspases -increased Bcl-2 (anti-apoptotic), decreased BAX (pro-apoptotic) ★Unlimited replication capacity -telomerase elongate telomeres ★Angiogenesis -VEGF (vascular endothelial GF), PDGF ★Invasion and metastasis ★Evasion of immune system ★Reprogramming of energy metabolism

Low grade NHL

★Small lymphocytic lymphoma -the same as CLL, but in LNs instead of blood stream (4000 cells/ul) -B or T cell precursors, small cells, slow progressing lymphoma -deletion of chromosome 13,11,17 or trisomy of chromosome 12 -often asymptomatic -possible transformation to DLBCL (Richter syndrome) -treatment: chemo, immunotherapy, BM transpant for young people ★ Mycosis fungoides -CD4 T cells -lazy indolent tumor of skin, medium cell size -extracutaneous spread, to LN and BM. -progress in 3 stages: 1) red spots, 2) plaques 3) ulcerous tumor mass *Sezary is a aggressive variant of mycosis fungoides -generalized rash, lymphadenopathy, atypical t cells in blood, hepatosplenomegaly -possible transformation to aggressive T cell lymphoma as terminal event ★Follicular small cell lymphoma -translocation 14,18 - overexpression of antiapoptotic Bcl 2 -can transform into larger and diffuse

Precancerous lesions in columnar epithelium

★Squamous metaplasia of bronchial mucosa -change of respiratory epithelium in bronchus into stratified squamous epithelium due to chronic stress from eg. smoking. -risk factor for developing lung cancer. ★Endometrial hyperplasia (non-inflammatory hyperplasia) -excessive proliferation of endometrium due to high levels of estrogen and low levels of progesterone. -may occur in eg. obesity, polycystic ovary syndrome, estrogen-producing tumors. -significant risk factor for endometrial cancer. necessary for careful monitoring and treatment. ★Villous adenoma of colon -benign neoplasms, as neoplastic colonic villous adenoma, are also at risk for malignant transformation. -if polyps left untreated - 50% progress to colorectal cancer -adenoma arise due to epithelial proliferation and dysplasia and thought to be connected with high fat and low fiber diet. -polyps can be villous, tubular, tubo-villous (villous most dangerous and most often linked to carcinogenesis) ★Atrophic gastritis -chronic inflammation of stomach mucosa, which can be caused by persistent infectection with helicobacter pylori, or can be autoimmune. -leads to loss of gastric glandular cells and will eventually be replaced by intestinal epithelium. -this metaplasia increase risk for developing gastric adenocarcinoma (intestinal type), but also MALT lymphoma Other precancerous lesions and conditions: -Cirrhosis-> hepatocellular carcinoma -Chronic UC -> colorectal carcinoma -Erythroplakia -> squamous cell carcinoma -Bowen´s disease -> squamous cell carcinoma -CIN -> cervical squamous cell carcinoma

Other features of tumor development

★Telomerase necessary for cell immortality. - elongate telomeres that are normally shortened during cell division. ★Angiogenesis necessary for tumor survival and growth -FGF and VEGF (angiogenic factors) produced by tumor cells. ★Avoiding immune surveillance necessary for tumor survival. -mutations often result in production of abnormal proteins, which are expressed on MHC 1: CD8 T cells detect and destroy such mutated cells. -so tumor cells downregulate expression on MHC 1. -immunodeficiency (primary and secondary) increases risk of cancer.