Pathology - Block 3

Front 1

Aphthous ulcer (canker sore)

Back 1

Noninfectious ulcers or oral mucosa. unknown etiology. Extremely common (35-40% of pop). First 2 decades of life. Prevalent w/in certain families. Resolve in 7-10 days or persistent for weeks [painful ulcers covered by a shaggy gray membrane]

Front 2

Submucosal irritation fibroma

Back 2

localized proliferation of fibrous CT in response to tissue irritation. Bite or gingivo-dental line (also on side of tongue). common in 30-50yr. limited growth potential (up to 2 cm). Does NOT become malignant. Potential for recurrence if irritation persists. No ulcer. Have collagen tissue surrounding "like scar"

Front 3

Herpetic Stomatitis

Back 3

HSV type I. person-to-person transmission. virus persists in dormant state - asymptomatic. Reactivation --> <5 mm vesicles (cold sore). intraepithelial edema --> clear fluid --> rupture --> ulcer. Multinuleated giant cells w/ intranuclear viral inclusions (multinucleation, margination, molding. many neutrophils). Tzanck test (scrape ulcer --> stain --> microscope observation). usually localized.

Front 4

Candidiasis

Back 4

"thrush". Most common fungal infxn of Oral cavity. Immunocompromised ptn (common pre-AIDS-defining lesion), diabetes mellitus, steroids/prolonged antibiotic therapy. Widespread cancer. Gross - white plaque-like pseudomembrane. scraping --> erythematous base. Microscopic -- Fungal hyphae superficially attached to underlying mucosa. Special stain = GMS (silver)

Front 5

Squamous papilloma

Back 5

Benign epithelial hyperplasia. Associated with HPV (HPV-6, HPV-11). Not contagious. 30-50yrs. site - lingual, labial, buccal. Gross - soft, finger like projections. Micro - papillary hyperplasia of squamous mucosa with fibrovascular cores. [Most common benign tumor in oral cavity. Exophytic tumor w/ a fibrovascular core. May occur on the tongue, gingiva, palate, or lips]

Front 6

Leukoplakia

Back 6

Clinical, NOT pathologic dx. White patch caused by epidermal thickening or hyperkeratosis. Cannot be scraped off (unlike thrush). occasionally associated with epithelial dysplasia. risk of malignancy 5-25%

Front 7

Erythroplakia

Back 7

clinical, NOt pathologic dx. Red granular area that may or may not be elevated. poorly defined boundaries. Usually associated w/ epithelial dysplasia. risk of malignancy 50%

Front 8

Epithelial dysplasia of Oral cavity

Back 8

Proliferation of immature (basal) cells. Loss of cell polarity. Increased number of mitotic figures. Variation in nuclear size and shape. Hyperchromasia (darker than normal surrounding cells. Not yet cancerous. Not yet full thickness.

Front 9

Squamous cell carcinoma of OC

Back 9

95% of OC cancer is SCC. 3% of all cancers in USA. 50-70yrs. M>F. over past 25 yrs, no significant improvement in early dx of oral/pharyngeal cancers (lack of early detection). Associated w/ tobacco, alcohol (synergistic effect b/w alcohol & smoking), family hx, HPV infxn (serotype 6, 16, 18), leukoplakia (occasionally), erythroplakia (commonly). Site - mostly on tongue and floor of mouth, lower lip (vermilion border), also on gingiva, hard/soft palates, dorsal tongue, mucosa. Perineural invasion -- epithelial cells wrapping around nerve --> malignant cells can travel along the nerve (as well as LN). 5 yr survival: early stage oral SCC (80%), late stage oral SCC (20%). Site of metastasis -- regional LN (submental, cervical), distant (lung, liver, bone, mediastinal LN) [most common site is lower lip]

Front 10

Odontogenic Cyst

Back 10

large fluid filled cyst around crown of tooth. thin layer of squamous cell

Front 11

Odontogenic keratocyst

Back 11

developmental odontogenic cyst, believed to arise from dental lamina (not crown like Odontogenic cyst). Usually sporadic but may be associated w/ nevoid basal cell carcinoma syndrome (Gorlin syn), an AD disorder, secondary to mutations in PTCH (9q22). Usually benign but may exhibit locally aggessive clinical behavior. Morbidity is low, although high recurrence may require disfiguring surgery. 4-5 cells in thickness. Classic separation of artifact b/w mucosal layer & stroma

Front 12

Ameloblastoma (of OC)

Back 12

MC benign epithelial odontogenic tumor, arising from enamel organ or its progenitor cell lines. Majority (80%) occur in posterior mandible. Wide variety of clinical presentations w/ different tx and prognostic implications: Unicystic (13%) - younger pop, multicystic (86%) - more aggressive, Peripheral (1%) - confined to soft tissue. Locally aggressive, slow growing [do not metastasize], frequent recurrences. Tx with wide local surgical resection.["soap bubble" appearance]

Front 13

Vocal cord nodule/Polyp

Back 13

(Larynx) nodules are bilateral on opposing surfaces of the middle third of vocal cord. Polyps are single in teh ventricle or Reinke's space. Etiology - smoking, vocal abuse. M>F. Gross - smooth, rounded. NO cancer risk. Many fibrin, edema, mucin in stroma of polyps

Front 14

Carcinoma of Larynx

Back 14

decreasing incidence (attributed to decrease in tobacco use). 95% are SCC. associations - smoking, alcohol, GERD, HPV infxn [type 6 & 11], irradiation. Sequence of devo: Hyperplasia --> Dysplasia (progressiely increasing degrees of pleomorphism, hyperchromasia, increased nuclear size and nuclear/cytoplasmic ratio. With mild dysplasia, risk of carcinoma is 1-2% over 5-10 yrs. With severe dysplasia, risk of carcinoma is 5-10% over 5-10 yrs. dysplastic changes often regress after smoking stops.) --> Carcinoma. Clinical presentation: Glottis (true vocal cords) - ptn presents w/ hoarseness. most common location of laryngeal carcinoma. Dx at earlier stage because sx. Supraglottic or infraglottic - usually asymptomatic early in course. dx at later stages (sx secondary to mass). With spread into adjacent structures -- Hemoptysis or dysphagia. Tx - surgery (laryngectomy), radiation. 5-yr survival - Stage 1 (70%), stage 4 (30%)

Front 15

Rhinosinusitis

Back 15

Viral (common cold), allergic, obstructive process (ex. deviated septum). Gross - similar to Edematous nasal mucosa, turbinates enlarged. Microscopy - mixed inflammatory infiltrate, edema, thickened BM. Complication -- nasal polyps. Allergic sinusitis -- many eosinophils and plasma cells

Front 16

Schneiderian Papillomas

Back 16

Benign neoplastic papillomatous proliferations arising from Schneiderian membrane -- nasal mucosa consisting of ciliated columnar epi. Non-specific clinical sx -- nasal obstruction, headaches, epistaxis, rinorrhea, facial pressure. 3 types -- exophytic, endophytic (inverted) and cylindrical cell type. Associated with HPV (mostly 6 & 11). High occurance rate (60%), MC in inverted type (endothelic. tumor growing inside of stroma). Excellent prognosis if no malignant transformation.

Front 17

Olfactory Neuroblastoma (Esthesioneuroblastoma)

Back 17

Malignant.Arises in superior and laterla mucosa of the nose (olfactory mucosa) -- origin from neuroendocrine cells. 50yr median age. Sx -- epistaxis, nasal obstruction, headache. Composed of uniform cells with round nuclei, scant cytoplasm, "salt and pepper" chromatin. EM -- neurosecretory granules. Immunohistochemistry -- neuroendocrine markers (synaptophysin, chromogranin). Prognosis -- locally invasice. also metastasizes widely (local LN and lungs), 5-yr survival 50-70%

Front 18

Immunohistochemistry - Neuroendocrine markers

Back 18

Synaptophysin, chromogranin (pg 17)

Front 19

Nasopharyngeal carcinoma

Back 19

Geographic -- Africa, China (HK most frequent), rare in US, migration from high incidence locale to low incidence locale shows generational decline in incidence. Etiologic factors -- EBV infxn, environment (diet - salted fish, smoking), Heredity (consistently found molecular abnormalities). 2 Types -- Keratinizing SCC & Non-keratinizing SCC (undifferentiated -- Lymphoepithelial carcinoma; numerous lymphocytes (dark blue nuclei) b/w tumor cells obscuring the epithelial, cohesive, derivation. EBV stain & Cytokeratin stain (intermediate filament expressed by epithelial cells). Prognosis -- grow silently until they become unresectable. local regional LN (cervical) and distant metastasis. Radiotherapy is the standard modality of tx. 3-yr survival rate 50-70% [MC malignant tumor of nasopharynx. Male dominant. increased incidence in the Chinese and African pop]

Front 20

Major salivary glands

Back 20

Parotid gland (serous), Submandibular gland (mixed, mainly serous), Sublingual gland (mixed, mainly mucinous)

Front 21

Sjogren syndrome

Back 21

Autoimmune dz -- serology (anti-SS-B, anti-SS-A). Sicca syndrome -- Xerostomia (dry mouth, destruction of minor salivary glands), Keratoconjunctivitis (dry eyes, due to destruction of lacrimal glands). Often in assoc w/ other autoimmune dz (rheumatoid arthritis, lupus). Pathology -- lymphocytic infiltration of salivary and lacrimal glands w/ eventual gland destruction. Mikulicz dz (benign lymphoepithelial lesion) -- salivary & lacrimal gland inflammation of whatever cause. Biopsy minor salivary glands of lip. [Female dominant. Autoimmune destruction of minor salivary glands and lacrimal glands. Lab -- + serum ANA, RF, anti-ss-A/anti-Ss-B, lip biopsy confirms]

Front 22

Sicca syndrome

Back 22

Xerostomia and keratoconjunctivitis (Sjogren syndrome)

Front 23

Mikulicz dz

Back 23

Benign lymphoepithelial lesion. Salivary and lacrimal gland inflammation.

Front 24

Neoplasms of Salivary glands

Back 24

<2% of all human tumors, 65-80% arise in parotid gland -- 10% in submandibular gland. Remainder in minor salivary glands. Epidemiology -- adults mostly (5% in <16yrs), slight female predominance, benign tumors (50-70yrs), malignant tumors (slightly older). Likelihood of malignancy is inversely proportional to the size of gland -- 15% of parotid gland tumors malignant, 40% submandibular gland tumors malignant, 50% minor salivary gland tumors malignant, 70-90% sublingual gland tumors malignant. Benign - Pleomorphic adenoma (60%), Warthin Tumor (5-10%). Malignant -- Mucoepidermoid CA (15%), Adenoid cystic carcinoma (5%)

Front 25

Pleomorphic adenoma

Back 25

Benign. MC salivary gland tumor. 50-60% all salivary gland tumors. Wide age range. 75-85% occur in parotid. Benign mixed tumor -- epithelial cells (ductal), myoepithelial cells, mesenchymal components (myxoid, hyaline, chondroid). "Pleomorphic" -- variability (cell types and composition). "adenoma" -- proliferation of cells (epithelial and myoepithelial). Morphology -- well circumscribed, encapsulated, rubbery, firm (like cartilage). Shiny, gelatinous look (due to mucous). Solid part (epithelial components, cartilage). Clinical course -- painless, slow-growing. local recurrence rate 4%. Malignant transformation (carcinoma ex-pleomorphic adenoma) - 2% for tumors present < 5 yrs. 10% for tumors present > 10 yrs [painless, moveable mass at the angle of jaw. Facial nerve involvement is a sign of malignancy. female dominant]

Front 26

Warthin Tumor

Back 26

Benign. 2nd MC salivary gland tumor. Restricted to parotid gland. M>F. associated w/ smoking. MC bilateral salivary gland tumor. Gross -- often undergoes papillary cystic change. Microscopy -- bilayered oncocytic (pink, eosinophilic cytoplasm. looks granular. abundant mitochondria) epithelial cells and lymphocytes [Papillary cystadenoma lymphomatosum. Heterotropic salivary gland tissue trapped in a LN -- cystic glandular structures are located w/in benign lymphoid tissue]

Front 27

Mucoepidermoid Carcinoma

Back 27

MC malignant tumor of salivary glands -- 50% in parotid gland, 40% in minor salivary glands, occur in adults & kids. Mixture of squamoid, mucous, & intermediate cells. Prognosis/tx -- low grade tumors invade locally, rarely metastasize; 5 yr survival > 90%. High-grade/intermediate-grade tumors recur more frequently, metastasize in 30%; 5 year survival 50%. Surgical resection followed by radiation. Gross -- infiltrative growth pattern. cords, sheets, or cystic patterns. [mixture of neoplastic squamous and mucus-secreting cells]

Front 28

Adenoid Cystic carcinoma

Back 28

Malignant. 10% of all salivary gland carcinomas. Wide age range (peak 50-70yrs). Major and minor salivary glands. Microscopy -- perineural invasion. cribiform architecture. Local recurrence. wide to radical surgical resection.

Front 29

Thyroglossal duct cyst

Back 29

Midline developmental cyst. Presents prior to 4th decade. Always connected to the hyoid bone (move w/ swallowing). lined by respiratory or squamous epithelium. Thyroid tissue in wall of cyst. Mostly benign but rarely Papillary thyroid carcinoma follows

Front 30

Branchial Cleft cyst (Cervical lymphoepithelial cyst)

Back 30

Arises from the 2nd branchial pouch. 75% of ptn b/w 20-40yrs. laterally placed in neck along anterior border of SCM. may become infected. Gross -- thin walled, filled with cheesy, mucoid material. Micro -- Squamous lining, lymphoid tissue. Differential -- Metastatic SCC

Front 31

Pleural effusion definition

Back 31

Accumulation of fluid (>15ml) in pleural space secondary to increase in hydrostatic pressure (CHF), decreased oncotic pressure (nephrotic syn), increased vascular permeability (pneumonia), increased intrathoracic negative pressure (atelectasis), impaired lymphatic drainage (metastatic carcinoma, lung cancer)

Front 32

Pleural effusion: clinical manifestation, clinical mgmt, common causes, type

Back 32

1. clinical: Dyspnea, pleuritic pain, cough, enlarged hemithorax, dullness on percussion, decreased/absent breath sounds, attenuated/absent tactile fremitus, compression, collapse of lung and atelectasis leading to respiratory distress. 2. Clinical mgmt: Chest X-ray, Thoracentesis, analysis of pleural fluid (chemistry, culture), cytology, pleural biopsy (percutaneous, open), tx of underlying cause. 3. Common causes: CHF, bacterial pneumonia, malignant neoplasm, pulmonary embolization, viral dz, cirrhosis, nephrotic syndrome, collagen vascular dz, TB, Asbestosis, trauma. 4. Type: Inflammatory PF -- Serofibrinous, suppurative (empyema), hemorrhagis / non-inflammatory PF -- hydrothorax, hemothorax, chylothorax [CHF MC overall cause of PF]

Front 33

Inflammatory Pleural effusions

Back 33

1. Serous, fibrinous, and serofibrinous -- inflammatory conditions such as pneumonia, TV, lung infarcts, absecesses 2. Purulent exudate (empyema = pyothorax = suppurative pleuritis) -- localized accumulation of pus due to organisms. Purulent pleural effusions complicating lung infxn (pneumococci, staphilococci and streptococci). Pleural surface is coated by shaggy thick fibrin layer admixed w/ greenish purulent exudate. Organization produces adhesions adn loculation circumscribing the pusand limiting lung expansion. Surgical decortication is tx of choice. [PF exudate -- TB and malignancy MC case] 3. Hemorrhagic pleuritis -- coagulopathies, rickettsial dz, malignant neoplasm

Front 34

Non-inflammatory pleural effusions

Back 34

1. Hydrothorax -- clear serous fluid (cardiac failure, pulmonary congestion and edema, cirrhosis, uremia, renal failure) 2. Hemothorax -- hemorrhagic fluid (ruptured aortic aneurysm, trauma) 3. Chylothorax -- milky fluid (thoracic duct trauma or lymphatics occlusion secondary to malignancy -- malignancy is MC case) [due to chylomicrons (diet-derived TG. chylomicrons form a supranate in a test tube after refrigeration. PF triglyceride > 110 mg/dL is dx]

Front 35

Pneumothorax

Back 35

Presence of air or gas w/in pleural cavity. Types -- spontaneous traumatic, therapeutic. MC associated w/ emphysema, asthma, and TB. Sx -- chest pain, dyspnea, absent breath sounds on auscultation. Tympanitic percussion (hyper-resonance), Deviation of trachea on CXR. Compression and collapse of lung parenchyma w/ atelectasis. marked respiratory distress.

Front 36

Spontaneous pneumothorax

Back 36

encountered in young individuals secondary to rupture of small apical lung blebs. subsides spontaneously. may be idiopathic. lymphangioleiomyomatosis. CF. Emphysema. Bronchopleural fistula. [causes - primary idopathic. Chronic obstructive lung dz. Marfan syn. scuba diving. insertion of subclavian catheter. Trachea deviated ipsilateral to side of collapse. Loss of negative intrathoracic pressure. Sudden onset of dyspnea and pleuritic chest pain]

Front 37

Tension Pneumothorax

Back 37

Due to penetrating trauma to lungs. Produces increased pleural cavity pressure w/ compression and atelectasis. Flap-like pleural defects acts like a valve allowing air in but not out. Sudden onset of respiratory distress (medical emergency). Trachea deviated to contralateral side of pneumothorax [increase in pleural cavity pressure with each breath]

Front 38

Pleural neoplasms - types

Back 38

Benign -- Solitary fibrous tumor (pleural fibroma). Malignant -- Metastases from other organs. Malignant mesothelioma

Front 39

Solitary Fibrous tumor

Back 39

Benign. Polypoid, well-circumscribed, pedunculated. Composed of fibroblasts with abundant collagenized stroma. Benign tumor, cured by simple excision. Mostly asymptomatic and discovered incidentally on chest X-rays. ASsociated w/ hypoglycemia and clubbing of the fingers.

Front 40

Malignant Mesothelioma

Back 40

Neoplastic proliferation of mesothelial cells lining serosal surfaces. Affects 15-20 persons per million/per year in the general pop. MC in >50yrs. Etiology -- Asbestos exposure, smoking, radiation, chronic inflammation, Viral infxn (SV40 simian virus) idiopathic (up to 50%). Sx -- Insidious, slow growing neoplasm, recurrent pleural effusions, chest pain and dyspnea in more advanced stages, only 20% of patn have pulmonary fibrosis (asbestosis), fatal malignancy; median survival 18 mth. Morphology -- Tumor characteristically spreads along mesothelial surfaces. composed of bland-appearing cuboidal cells that resemble normal mesothelial cells (well-differentiated neoplasm)difficult fo pathologist to distinguish mesothelioma from metastatic carcinoma to the pleura. Can also involve other serosal surfaces like peritoneum, tunica vaginalis and pericardium. Cytogenetic studies have shown chromosomal deletions in 1p, 3p, 6q, and 22q. Histology -- epithelioid type, spindle cell type. Dx -- Immunohistochemistry (Positive markers -- CK5/6, calretinin, WT1 / negative markers -- CEA, TTF1, MOC31). EM (long slender surface microvilli).

Front 41

Asbestos-related mesothelioma

Back 41

Epidemiologic studies (coastal areas of US and GB and mining areas). Lifetime risk for developing mesothelioma is up to 10% in ptn with Hx. of heavy exposure. Long latency period (20-40yrs). occupational exposure -- millworkers, roofing materials, textiles, insulation, shipyard workers. Asbestos fibers look like dumbell

Front 42

Metastatic Tumors

Back 42

metastastatic tumors are more common than primary malignancies in the pleura. Lung is the most frequent source of metastasis to the pleura; other tumors include breast and ovarian cancer, pancreas, kidney. spread is by blood, lymphatics or direct extension. Metastases are often multiple and bilateral.

Front 43

Granulomatous mediastinitis

Back 43

Chronic disorder secondary to fungal or mycobacterial infxn. Hisoplasmosis. TB. Cryptococcosis. Atypical mycobacteria. Aspergillosis.

Front 44

Acute mediatstinitis

Back 44

Complication of conditions affecting neighboring organs (ex. esophageal perforation, perforation of lung abscess, sternal osteomyelitis)

Front 45

Mediastinal pathology -- inflammation

Back 45

Acute mediastinitis, Granulomatous mediastinitis, ideopathic mediastinitis

Front 46

COngenital/developmental mediastinitis

Back 46

Congenital thymic cysts, bronchogenic cysts, enteric duplication cysts, pericardial cysts, thymic hyperplasia, thymic hypoplasia or aplasia, thymolipoma (hamartoma)

Front 47

Congenital cyst

Back 47

usually unilocular. children 5-15yrs. lined by simple cuboidal epithelium. May be filled with serous fluid.

Front 48

Developmental cysts

Back 48

mediastinal cysts of non-thymic origin. Arise from ectopic or embryologically displaced elements. Bronchogenic and enteric types (foregut cysts). Pericardial cyst (mesothelial cyst)

Front 49

Thymic hyperplasia

Back 49

Thymic lymphoid follicular hyperplasia -- associated w/ myasthenia gravis and other autoimmune disorders. "true" thymic hyperplasia -- enlargement of the thymus with increase in volume but normal histology.

Front 50

Thymic hypoplasia

Back 50

Hypoplasia or aplasia of thymus seen in DiGeorge's syndrome (severe deficits in cell-mediated immunity and hypoparathyroidism)

Front 51

Primary thymic epithelial neoplasm

Back 51

Thymoma and Thymic carcinoma

Front 52

Myasthenia Gravis (related to Thymus dz)

Back 52

30-40% ptn w/ thymoma develop MG. Defect in ACh receptor in neuromuscular junction as a result of circulating autoAB. Autosensitization to AChR is initiated in thymus due to defective confrontation of ACh-secreting thymic myoid cells w/ T-lymphocytes. Sx -- weakness, fatigability, ptosis, diplopia

Front 53

Thymoma

Back 53

Neoplastic proliferation of thymic epithelial cells (NOT lymphoid tissue). Usually containt abundant immature T-lymphocytes (non-neoplastic). Frequently associated w/ myasthenia gravis and other paraneoplastic synd. May be composed of spindle cells or round epitheloid cells. Sx -- Asymptomatic in 30% ptn. couth, dyspnea, chest pain, SVC syn. Paraneoplastic syn (MG, pure red cell aplasia, Hypogammaglobulinemia, agranulocytosis; white blood cell aplasia, polymyositis; SLE, pemphigus vulgaris, disseminated herpes). Histology -- Difficult to classify. Currently use WHO classification. Based on cell type into type A (spindle cells), B (round cells), and AB (mixture of both). Immunophenotype -- Keratin, CD1a. Clinical behavior -- depends on the status of the capsule. encapsulated tumors are cured by complete surgical excision. Invasive tumors tend to recur repeatedly and may eventually metastasize. Recurrent tumors may progress to thymic carcinoma. [located in anterior mediastinum. Benign (70%), malignant (30%).

Front 54

Thymic carcinoma

Back 54

Histology -- many histologic variants that resemvle carcinomas in other organs (squamous, small cell, mucoepidermoid, basaloid, clear cell, papillary, mucinous adenocarcinoma). MC type is poorly-differentiated, non-keratinizaing SCC ("lymphoepithelioma-like carcinoma"). Dx of exclusion -- there is nothing pathognomonic that permits a specific histologic diagnosis.

Front 55

Lymphoid Malignancies (related to mediastinum)

Back 55

Lymphoblastic lymphoma/leukemia. Hodgkin lymphoma. Diffuse large cell lymphoma

Front 56

Lymphoblastic lymphoma/leukemia (related to mediastinum)

Back 56

children and adolescents. Rapidly enlarging, acutely symptomatic mediastinal mass (dyspnea, pleural effusion, SVC syn). Precursor lymphoid cells that express TdT (terminal deoxynucleotydyl transferase) in their nuclei. Majority are of T-cell lineage. Highly aggressive malignancy w/ poor survival. Genetics -- translocation so floci at 14q11.2 and 7q35 (30%), deletion 9p of TAL-1 locus (25%)

Front 57

Hodgkin lymphoma (related to mediastinum)

Back 57

60% all mediastinal lymphomas. often systemic (generalized lymphadenopathy). young, female predilection. 50% asymptomatic. Sx -- chest pain, dyspnea, SVC synd. Nodular sclerosing subtype is MC. Curable dz -- early stage ptn respond well to radiotherapy. More advanced stages require combintation chemotherapy. [Unknown pathogenesis -- B and T cells become neoplastic ReedSternberg cells]

Front 58

Diffuse large Cell Lymphoma (related to mediastinum)

Back 58

Distinctive type of lymphoma thought to be derived from native thymic B-lymphocytes. Young females 20-30yrs. Large mediastinal mass w/o evidence of tumor elsewhere. Sx -- chest pain, dyspnea, and SVC syndrome. Invasion of adjacent structures common. Common extrathoracic relapse in kidney, ovaries, liver, pancreas. Aggressive malignancy -- outcome based on clinical staging. Pathology -- B-cell neoplasm. Often displays sclerosing pattern (may resemble histologically carcinoma). thought to be derived form native population of thyic B-lymphocytes with overexpression of MAL gene.

Front 59

Germ cell tumors - type & characteristics.

Back 59

Benign teratomas. Malignant -- Seminoma, Yolk sac tumor, embryonal carcinoma, choriocarcinoma. mixed germ cell tumors. Most frequent in children and young adults. lg bulky masses with compression of adjaacent structures. Elevated serum levels of AFP, PLAP, HCG. respond well to sicplatinum-based therapy. YST, CC and embryonal carcinoma highly aggressive and commonly fatal. Malignant tumors almost exclusively seen in males.

Front 60

Yolk sac tumor

Back 60

[Malignant tumor. MC ovarian cancer in girls/testitular tumor in boys < 4yrs. Contain Schiller-Duval bodies (resemble yolk sac). increased alpha-fetoprotein (AFP).] pg 427, 460

Front 61

Mediastinal serminoma

Back 61

[MC germ cell tumor (40%) in male. Gray tumor w/o hemorrhage of necrosis.] pg. 427

Front 62

Posterior mediastinum - tumor?

Back 62

Neural tumors -- Schwannomas and neurofibromas, Malignant Schwannoma, Ganglioneuroma, Ganglioneurofibroma, Neurofibroma

Front 63

Neural neoplasms (related to mediastinum)

Back 63

Most often occur in younger individuals. Frequently assocaited w/ neurofibromatosis. Majority are benign but may occasionally be malignant.

Front 64

Stillbirth

Back 64

In utero demise. Major causes by gestational age: <24 wks -- infxn, malformation. 24-36 wks -- asphyxia, hydrops, anemia. >36 wks -- placental issues, unknown. Developmental cause (twin-twin transfusion, IUGR, chromosomal disorders, malformations) 40% of cause. Next is Circulatory cause (20%) -- placental abruption, cord accident, uteroplacental insufficiency.

Front 65

Spontaneous abortion

Back 65

occurs prior to 20 wks gestation. often caused by a karyotypic abnormality. Predisposing factors -- advanced maternal age, infxn, tobacco and alcohol use.

Front 66

Perinatal infection

Back 66

Ascending (transcervical) -- fetus aspirates infxted amniotic fluid or passes through an infcted birth canal. usually see chrioamnionitis. bacteria and some viruses (HSV-2). Hematologic (transplacental) -- agent passes through chorionic villi into fetal bloodstream. most viruses and parasites. some bacteria (TORCH). Early-onset -- acquired at or shortly before birth. symptomatic at 4-5 days of life. mostly group B Streptococcus. sepsis, meningitis, pneumonia. Late-onset -- latency period b/w infxn and symptoms. Listeria and Candida.

Front 67

Fetal Hydrops

Back 67

Accumulation of edema and fluid in the fetus, manifested by Soft tissue edema (anasarca), pleural effusion, pericardial effusion, ascites. 2 major types: 1. Immune Hydrops -- blood group incompatibility b/w mother and child. Usually Rh D antigen. Rh immune globulin is protective if administered appropriately. 2. Nonimmune Hydrops -- CV defects. chromosomal abnormalities (Turner - XO, Trisomies 18 and 21), fetal anemia -- thalassemia, parvovirus, thoracic pathology, twin-twin transfusion, infxn, urinary tract malformations, metabolic disorders.

Front 68

Anasarca

Back 68

Soft tissue edema

Front 69

Disorders of placenta

Back 69

infxn, meconium, cord accidents, infarction, maternal vascular dz, uteroplacental insufficiency, multiple gestation

Front 70

Placental infection

Back 70

Inflammation in cord ("Funisitis", fetal response). Inflammation of membranes ("Chorioamnionitis. maternal response). Predispose to premature rupture of membranes, fetal infxn and malformation, neonatal sepsis.

Front 71

Meconium

Back 71

Earliest stool of infant. Released by fetus during stress or in postdates gestation. If severe and prolonged, may cause placental vasculitis and thrombosis. Fetus at risk for meconium aspiration.

Front 72

Cord accidents

Back 72

Knots, Thrombi, Avulsion, Nuchal loops

Front 73

placenta - vascular problems

Back 73

Parenchymal infarction, intraprenchymal hemorrhage, maternal vasculopathy, abruption --> all may lead to uteroplacental insufficiency.

Front 74

Prematurity

Back 74

2nd MC cause of neonatal mortality. Gestational age < 37 wks. Limit of viability around 20 wks.Risk factors -- Preterm premature rupture of membranes (PPROM), intrauterine infxn, anatomic abnormalities of cervix, uterus, or placenta. multiple gestation pregnancy. Sequelae -- Hyaline membrane disease, Necrotizing enterocolitis, sepsis, intraventricular hemorrhage, developmental delay.

Front 75

Postmaturity

Back 75

Gestational age > 42 wks. Mortality/morbidity rises - Meconium aspiration, difficult deliveries due to large infant.

Front 76

Intrauterine Growth retardation (IUGR)

Back 76

Appropriate for gestational age (AGA) - 10th ~90th percentile. SGA <10th percentile. LGA >90th percentile. Contributing factors -- Fetal (symmetric) chromosomal disorders, congenital anomalies, congenital infxn (TORCH). Placental (asymmetric) - uteroplacental insufficiency. Maternal - vascular (HTN, pre-eclampsia), drugs, alcohol, cigarettes. Sequelae -- IUGR associated w/ a 5- to 30-fold increase in perinatal morbidity and mortality. Similar complications to prematurity, plus the potential for long-term developmental problems.

Front 77

RDS / Hyaline Membrane Dz

Back 77

incidence is inversely proportional to gestational age. Deficiency of pulmonary surfactant (synthesized by type II alveolar cells). Epithelial and endothelial damage leak to fibrin-rich exudative fluid (hyaline membranes). Prevention -- delaying delivery until lung maturation, measuring phospholipids in amniotic fluid, inducing maturation by steroid administration. Tx -- exogenous surfactant, oxygen via ventilation

Front 78

Necrotizing Enterocolitis

Back 78

occurs in premature infants shortly after initiation of oral feeds. Appears to be a combination of ischemia, baterial infxn, and inflammation. Pneumatosis intestinalis (gas w/in bowel wall) seen radiographically. May require antibiotics or resection. high mortality (progress to sepsis)

Front 79

Germinal Matrix Hemorrhage

Back 79

subependymal hemorrhage which can rupture into the ventricles. common in premature infants w/ episodic hypoxia. Graded on a 4 point system.

Front 80

Cystic Fibrosis

Back 80

MC lethal genetic dz in Caucasians (1:3000 live birth). AR. Preconception testing of women can be performed (if positive, test partner). Defect in CFTR protein (epithelial transport of chloride). MC mutation -- F508. Decreased CFTR fn --> pancreatic duct plugging, fibrosis, and eventual failure with loss of exocrine fn, Bronchial tree obstruction and recurrent infxn w/ fibrosis and pulmonary failure. Steatosis and cirrhosis, bilateral absence of the vasa deferentia, azoospermia, and (male) infertility

Front 81

SIDS

Back 81

Sudden death of infant < 1 yr which remains unexplained after a thorough case investigation, including autopsy, examination of death scene, and review of clinical history. Usually occurs at night during sleep, usually unwitnessed, rarely acute life-threatening events (ALTE) have occurred in siblings of SIDS victims -- suddently cyanotic, apneir, and limp, no struggling or gasping, if resuscitated, may go on to succumb to SIDS. Epidemiology -- leading cause of death in US b/w 1 mth - 1 yr. 90% occur before 6 mths, most occur b/w 2-4 mths. More common in African cmerican and native american pop. Known risk factors -- young maternal age, frequent child birth, poor prenatal care, smoking, prematurity, low birth weight, male sex, sibling dying from SIDS, prone (face down) sleeping position, overheating, sleeping on soft surfaces. "Triple Risk Model" - 1. vulnerable infant -- Delayed or abnormal devo of arousal and cardiorespiratory centers in the brainstem (arcuate nucleus hypoplasia, serotonergic dysregulation, muscarinic receptors, BDNF production), minority pop (genes vs. enviro) 2. Critical developmental period -- SIDS occurs b/w 1 month - 1 yr. highest risk 2-4 mths (reflects brainstem immaturity?) 3.exogenous stressors -- Infxn, Hypercarbia (hypercapnea)/hypoxia (sleeping position), hyperthermia (overbundling). Back to Sleep Campaign. Dx -- diagnosis of exclusion. possible findings (nonspecific hypoxic and agonal changes, brainstem gliosis or structural abnormalities, lack of evidence of other cause), must exclude traumatic child abuse. Mimickers -- subclinical infxn (bronchopneumonia, viral myocarditis), unexpected congenital anomaly (usually cardiac), Traumatic child abuse, Metabolic or genetic disorder (FA oxidation defects, Long QT interval syn, Histiocytoid cardiomyopathy, complemetn/inflammatory disorders)

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Cosleeping

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Most deaths are suffocations, but SIDS can still occur in an unsafe sleep enviro. Risk factors -- true prevalence of cosleeping is unknown. Deaths likely occur in only a minute fraction of the total incidents; injureies also occur. Proposed risk factors -- caregiver drug/alcohol use, fatigue, obesity, etc. Evaluation -- like SIDS. scene investigation, interviews, autopsy. Prevention -- different reasons for cosleeping. Offer alternatives. focus on ABCs (Alone, Back, Crib)

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Diagnosis of Genetic & Developmental Disorders

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Approach to diagnosis -- multidisciplinary approach is best, Hx, Examination (measurements, photos, autopsy when possible), Genetic studies, Labs (triple/quad screen), Radiology (prenatal US, "babygram").

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Genetic Analysis (genetic & devo disorders)

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Prenatally -- Amniocentesis, Chorionic villus sampling. Neonatally (and for parents) -- Fibroblast culture from skin punch biopsy. can do conventional karyotyping, PCR, RFLP,etc.

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Amniocentesis

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Transabdominal aspiration of amniotic fluid and fetal cells through a long 18-22 G needle. Preformed around 16 wks gestation. Increased risk of fetal loss (1%). Complications -- fetal puncture, hemorrhage, amniotic bands, blood antigen sensitization, infection

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Chorionic Villus Sampling

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Aspiration of placental cells (chorionic villi) via transcervical or transabdominal needle. Performed b/w 9 - 12 wks gestation. Increased risk of fetal loss (2-3%). Similar complications as Amniocentesis (fetal puncture, hemorrhage, amniotic bands, blood antigen sensitization, infxn). Faster results, more tissue, NO fluid.

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Laboratory studies of Infants - Triple screen, Quad screen, Penta screen

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Triple screen -- serium AFP, serum human chorionic gonadotropin (hCG), serum unconjugated estriol (uE3). Identifies 60% of Down Syn (decr AFP, incr hCG, decr uE3), identifies 90% of neural tube defects (incr AFP), 90% of positive results are false positive --> need follow up with ultrasound and genetic testing when appropriate. (Trisomy 18 -- dec AFP, dec hCG, dec uE3). Quad Screen -- adds inhibin A. Penta screen -- adds invasive trophoblastic antigen (ITA). Results for each analyte are reported as multiples of the mean (MOM), based on ptn age, weight, gestational age, multiple gestations, and ethnicity

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Radiology -- Prenatally & postnatally

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Prenatally -- Ultrasound, MRI. Postnatally -- ultrasound, MRI, CT

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Diagnostic method (for genetic and devo dz)

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multimodal and multidisciplinary approach is the best method for diagnosing congenital abnormalities.

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Congenital anomalies

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Present (although not necessarily detected) birth. May or may not have a genetic basis. about 3% of newborns have a major congenital anomaly - represents only the tip of the iceberg.

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Anomaly

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Deviation from the expected or avg type in structure, form, and/or fn which is interpreted as abnormal. Definition excludes normal variations (>5% prevalence), Major - surgical or cosmetic implications (cleft lip, accessory digits), Minor -- little/no impact on patient well-being (epicanthal folds, transverse palmar crease)

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Deformation

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Abnormal form, shape, or position of a part of the body caused by extrinsic mechanical forces. occurs after 9th wk. ex - Plagiocephaly, oligohydramnios, club foot.

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Disruption

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Morphologic defect of an organ, or larger region of the body resulting from the extrinsic breakdown of, or interference with an originally normal developmental process. Ex - Amniotic bands, drugs/toxins, environmental insults

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Dysplasia

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An abnormal organization of cells into tissues and its morphologic results. ex - Lisch nodules in NF, Osteogenesis imperfecta, Hamartomas

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Malformation

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A morphological defect of an organ, or large region of the body resulting from an intrinsically abnormal developmental process. Occur in 3-9 wks. ex -- Bifid great toe, Cleft lip/palate, congenital heart disease.

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Sequence

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Pattern of anomalies derived from a single known or presumed prior anomaly or mechanical factor.

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Syndrome

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Multiple anomalies thought to be pathogenetically related but that cannot be explained by a single defect (not respresenting a sequence). Ex - Trisomy 13, Goldenhar syndrome

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Syndromes & chromosomal disorders (genetic): 1. Down syn; 2. Edwards syn; 3. Patau syn; 4. Turner syn

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1. Down - Trisomy 21; 2. Edwards - Trisomy 18; 3. Patau -- Trisomy 13; 4. Turner -- Monosomy X

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Association

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Idiopathic occurrence of multiple congenital anomalies during blastogenesis. ex -- Schisis association, VATER/VACTERL, MURCS, CHARGE

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Developmental Field defect

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Result of (non-disruptive) disturbed devo of a morphogenic field or a part therof. Ex -- Sirenomelia, Cloacal defects, Branchial anomalies.

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Agenesis

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Complete absence of an organ and its associated primordium, Renal agenesis, agenesis of corpus callosum.

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Aplasia

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Absence of an organ due to failure of development of the primordium. Radial aplasia

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Atresia

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Absence of an opening, Esophageal atresia, duodenal atresia

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Hypoplasia

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Incomplete or underdevelopment of an organ w/ decreased number of cells. Pulmonary hypoplasia

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Hyperplasia

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Overdevelopment of an organ with increased number of cells, adrenocortical hyperplasia

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Hypertrophy

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Abnormality of an organ with increased size of cells, right ventricular hypertrophy

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Congenital Anomalies -- Causes: Genetic, Envir, Multifactorial, Idiopathic

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Genetic (10-25%), Environmental (10-15%), Multifactorial (20-25%), Idiopathic (40-60%)

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Congenital Anomalies -- Genetic causes

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Chromosomal syndromes -- 10-15% prevalence in Anomalous fetuses. usually sporadic. Down (21), Klinefelter (XXY), turner (45, XO), Patau (47,+13). Monogenic Disorders -- 2-10%. Mendelian (AD, AR, X-linked), Ex - Sonic hedgehog (holoproscencephaly), GLI3 (digital anomalies).

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Congenital Anomalies -- infections

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Tend to cause disruptions. Viruses -- Rubella, CMV, Herpes simplex, Varicella-zoster, influenza, mumps, HIV, enterovirus. Other -- Syphilis, toxoplasmosis.

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Rubella (related to congenital anomalies) - Rubella tetrad

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Pre-conception to 16th week of gestation. Rubella embryopathy (tetrad) -- cataracts, CV defects, deafness, mental retardation. Also, low birthweight, thromocytopenic purpura, diabetes mellitus, dental abnormalities, hepatomegaly, osteomyelitis.

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CMV

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MC congenital infxn, second trimester, Most affected infants are asymptomatic at birth (95%), can cause mental retardation, deafness, microcephaly, chorioretinitis, and hepatosplenomegaly.

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Congenital Anomalies -- drugs & toxins: Teratogens, Prescription drugs, Cigarettes

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Prescription drugs: pregnancy categoreis C,D, and X. Thalidomide (phocomelia), folate antagonists (methotrexate), androgens, anticonvulsants, warfarin, 13-cis-retinoic acid / Cigarettes -- not specifically teratogenic. Increase rate of miscarriage, premature labor, placenta abnormalities, IUGR, and SIDS

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Fetal Alcohol Spectrum disorders

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Required elements -- Prenatal and postanatal growth retardation, facial anomalies, CNS dynfn. Also seen -- joint, limb, and cardiac abnormalities.

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Congenital anomalies -- Environmental: Radiation, Hyperthermia, Hypothermia, Ultrasound & MRI

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Radiation -- CNS and eye defects. Hyperthermia -- CNS and musculoskeletal anomalies. Hypothermia -- increased miscarriage rate. Ultrasound and MRI -- seem to be OK.

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Congenital Anomalies -- Maternal conditions: Diabetes Mellitus, Lupus, Hypothyroidism (cretinism)

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Diabetes -- usually in type 1 and 2 diabetes, only rarely with gestational diabetes. increased risk of neural tube, heart, and renal defects. Macrosomia and visceromegaly. Lupus -- increased risk of thrombosis and miscarriage (via antiphospholipid AB), congenital heart block (via anti-Ro AB). Hypothyroidism (cretinism) -- Maternal AB, iodine deficiency, drugs, deafness, mental retardation.

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Congenital Anomalies -- Pathogenesis

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Embryonic period -- conception to 9 wks. active organogenesis, malformations occur here (esp 4-5 wks). Fetal period -- 9 wks to birth. Growth and maturation of developed organs, disruptions occur here. The same agent may have diff effects dependong on when exposure occurs.

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Homeobox (HOX) genes

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transcription factors (DNA-binding proteins), patterning of limbs, craniofacial structures, and vertebrae. Regulated by retinoic acid receptor pathways, target of several teratogens.

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Paired box (PAX) genes

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transcription factors. general embryonic patterning. PAX3 and PAX7 are proto-oncogenes in alveolar rhabdomyosarcoma

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Tumors of infancy and childhood - characteristics

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2% of malignant tumors occur in infancy and childhood. Neoplastic dz accounts for 9% of childhood deaths (only surpassed by accidents). Benign tumors > malignant tumors. MC neoplasms of childhood have a mesenchymal derivation ( vs. epithelial origin in adults). Frequent relationship b/w abnormal development and neoplasia. Potential for spontaneous regression and/or cytodifferentiation. Familial/genetic aberrations play an important role.

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Heterotopia

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microscopically normal cells/tissue present in an abnormal location. ex. Pancreatic tissue in stomach or intestinal wall; gastric mucosa in the esophagus or intestines.

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Hamartoma

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excessive localized overgrowth of mature cells/tissue normally present in an organ but produce an abnormal arrangement; may represent link b/w malformation and neoplasia. Ex -- vascular, rhabdomyoma of the heart, angiomylipoma of kidney, chondromatous hamartoma of lung

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Benign tumors or tumor-like lesions of infancy/childhood

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Vascular anomalies, Fibrous tumors, Teratoma

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Vascular Anomalies - infancy/childhood: classification

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1. Tumors (proliferative lesions) -- i) Reactive conditions (pyogenic granuloma), ii) Benign Neoplasms (infantile hemangioma), iii) Malignant neoplasms; 2. Malformations (Developmental errors in vascular morphogenesis) -- i) Simple (capillary, venous, lymphatic, arterial), ii) combined (venulocapillary, arteriovenous, venous-lymphatic)

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Infantile Hemangioma

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MC tumor in infancy (4%). Frequencly located in skin of face or scalp. Flat to elevated irregular red-blue masses. Variably cellular small vessel proliferation ("oma"), glut-1 positive. Enlarges quickly, then regresses with time (vs. malformation which grows commensurately with child). wide clinical spectrum --> unified by Perinatal presentation and proliferation, Inevitable slow involution

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Vascular malformations - infancy/childhood

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Congenital errors in devo of embryonic vasculature that, in general grow slowly and commensurately with the overall growth of child and persist throughout life. NOT tumors -- unlike vascular tumors, endothelial cells of vascular malformations do NOT show increased mitotic activity.

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Fibrous tumors of infancy/childhood (type)

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Fibrous hamartoma of infancy, fibromatosis, Congenital-infantile fibrosarcoma. Myofibromatosis

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Fibrous Hamartoma of infancy

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Benign fibrous groth in dermis or subcutis. most often develops in first 2 yrs, M>F. Rapid growth --> then slows. MC location is anterior/posterior axillary fold. "organoid pattern" with fibrous traveculae, islands of loosely arranged spindle-shaped cells and mature fat (distinct from fibromatosis). cured by Local excision.

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Fibromatosis

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Hypocellular locally infiltrative proliferation of fibroblastic cells, does NOT metastasize. Superficial fascial vs. deep musculo-aponeurotic forms (more aggressive). deep (desmoid tumor) forms may occur in the setting of familial adenomatous polyposis (FAP). Risk for recurrence depends on age, location, size and mode of therapy. Wide resection most effective, adjuvant radiation tx for recurrent. [non-neoplastic proliferative CT disorder. Fibrous tissue infiltrates tissue (usually muscle)]

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Infantile Fibromatosis (lipofibromatosis)

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Solitary firm poorly circumscribed deep-seated mass, skeletal muscle of head/neck, shoulder/upper arm, thigh. MC before age 2yrs. Rapid growth pattern in wks/mths prior to presentation resulting in pain or dysfn. Consists of mixture of fibroblasts and myofibroblasts. Tx -- Wide local excision.

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Congenital-infantile Fibrosarcoma - (characteristic translocation)

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Non-tender poorly circumscribed mass often in the extermeties (lower leg/forarm). at birth or usually in 1st yr. Hypercellular fibroblast-like proliferation resembling adult fibrosarcoma (needs to be distinguished from cellular fibromatoses and high grade sarcomas of childhood). Characteristic translocation (12;15), (p13;q25). Tx - Wide local excision (excellent prognosis)

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Myofibroma/myofibromatosis

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Solitary or multifocal myofibroblastic proliferation involving skin, soft tissue, bone, visceral organs. Occurs at birth (often multifocal) but also infant to older. M>F. Solitary, MC in skin dermis or subcutis of head/neck followed by trunk and extermeties. Clinically benign, often spontaneous regression. Morbidity/mortality associated with impingement on vital organ fn in multifocal type.

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Teratoma

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Range from systic/mature to solid/immature lesions to malignant lesions. Usually consits of derivaties from all 3 germ layers. May include elements of malignant germ cell neoplasm. Sacrococcygeal -- MC location in childhood, F>M. 10% associated w/ congenital anomalies (hindgut/cloacal region and midline defects such as meningocele and spina bifida). Other sites -- gonads, midline structures (mediastinum, retroperitoneum, head/neck)

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Malignant tumors - of infancy/childhood

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Malignant pediatric neoplasms often have a primitive or embryonal morphology and are designated "blastomas". Demonstrate features of organogenesis (attempt to microscopically recaptulate organ devo of site of origin). Because of primitive appearance of pediatric small round blue cell tumors, adjunctive studies (special stains, EM and cytogenetic analysis) are often required for diagnosis and prognosis purposes. Types: Hematopoietic sys (leukemia/lymphoma), Nervous tissue (central -- posterior fossa juvenile astrocytoma, ependymoma, medulloblastoma; Sympathetic/adrenal medulla -- neuroblastoma; retina -- retinoblastoma), Soft tissue (rhabdomyosarcoma), Bone (Ewing sarcoma, osteosarcoma), Kidney (Wilm's tumor or nephroblastoma), Liver (Hepatoblastoma)

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Neuroblastoma

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sheets of small primitive cells (neuroblasts) with dark nuclei, scanty cytoplasm, background pale eosinophilic fibrillary material (neuropil), Homer Wright rosettes, mitoses, ultrastructure (EM) cytoplasmic dense core granules (catecholamine containing secretory granules) [primary located in adrenal medulla. Neoplasm of postganglionic sympathetic neurons. Commonly metastasize to skin and bone (70% metastasize at time of dx).

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Ganglioneuroblastoma

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mixture of neuroblasts and larger cells with more abundant cytoplasm, large vesicular nuclei, prominent nucleolus (ganglion cell differentiation), schwannian stroma (organized fascicles of neuritic processes, Schwann cells, fibroblasts)

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Ganglioneuroma

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ganglion cells (matured neuroblasts) and schwannian stroma

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Neuroblastic tumors -- type, clinical presentation, Prognostic features, Risk groups

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Neuroblastoma, Ganglioneuroblastoma, Ganglioneuroma. Tumors of sympathetic ganglia (paravertebral, posterior mediastinum) and adrenal medulla, derived from NC cells. 2nd MC childhood solid malignancy following brain tumors. 7-10% all pediatric tumors (50% of infant malignancies). median age - 22 mths. F>M, Caucasian. AGE and STAGE most important for prognosis. Most sporadic, few familiarl w/ AD transmission. Cx -- Lg abdominal mass, fever, <2 yrs weight loss; >2 yrs often have metastatic dz w/ bone pain or respiratory, GI and bladder complaints. Metastatic to LN, liver, lung, bone (periorbitalproptosis, ecchymosis), bone marrow. "Blueberry muffin baby" - neonate w/ multiple cutaneous metastases producing deep blue discoloration. 90% neuroblastomas produce catecholamines, Dx -- incr blood levels of catecholamines and elevated urine levels of metabolies (Vanillymandelic acid - VMA, Homovanillic acid - HVA). Prognosis -- AGE/STAGE (most important determinants of outcome. < 1yr have excellent prognosis regardless of stage (most are low, >90%, 5yr survival). STAGE 4S (special stage for infants < 1yr. defined as localized primary tumor with dissemination limited to skin, liver, and/or bone marrow (not bone), 80% 5 yr survival with only minimal therapy. Neuroblastoma staging system -- Stage 1,2A, 2B, 4S (favorable) vs. STage 3,4 (unfavorable). most children present with Stage 3 or 4 tumors. Morphology -- independent prognostic variable linked to age and characterized as favorable and unfavorable depending on degree of differentiation (Schwannian stroma/gangliocytic differentation), mitotic rate, mitotic-karyorrhexis index, calcification). DNA ploidy -- hyperploidy/near-triploidy (good prognosis). diploidy, near-diploidy, near tetraploidy (poor). N-myc oncogene - located on Chr. 2. N-myc amplication is most important genetic abnormality used in risk stratification and is UNFAVORABLE. Chr 17q gain, 1p loss (absence is favorable). Other favorable factors -- presence of Trk-A/CD44 expression, absent MRP/telomerase expression, normal serum ferritin and low lactate dehydrogenase. Risk groups -- 1. Low risk - infants w/ low stage (1,2A,2B) or 4S, hyperdiploid/near-triploid DNA content, high TRK-A, absent N-myc amplication, no 17q gain or 1p deletion, >90% cure rate. 2. Intermediate risk - infants or older with high stage (3 or 4), favorable histologic features, absent N-myc amplification, low Trk-A, 25-50% cure rate. 3. High risk - multiple unfavorable features, usually >1 yr. advanced stage, unfavorable histology, N-myc amplication, <20% cure rate

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Ecchymosis

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a small hemorrhagic spot in the skin or a mucous membrane, larger than a petechia, forming a nonelevated, rounded, or irregular blue or purplish patch.

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Wilm's Tumor (WT) - Nephroblastoma: Classification, Clinical presentation, incre risks of WT, protnosis and tx.

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Embryonic tumor derived from metanephris blastemal tissues of developing kidney. Characteristic "triphasic" morphology -- undifferentiated (blastemal), stromal and epithelial elements. Nephrogenic rests present 25-40%(often) -- (persistence of nephrogenic cells beyond 36wks gestation), precursor lesion of Wilms, incr risk of contralateral Wilms.Favorable histology (absence of anaplasia) -- Mixed (59%), Blastemal predominant (23%), Epithelial predominant (12%), Stromal predominant (6%). Unfavorable histology -- Diffuse anaplasia ("Anaplasia" -- 3 fold nuclear enlargement compared w/ adjacent nuclei of same cell type; hyperchromasia of enlarged nuclei; atypical enlarged usually multiplolar mitoses p53 mutations. "Diffuse" -- > 10hpf), Clear cell sarcoma, Rhabdoid tumor. 5% of all childhood malignancies. mean/med age -- 3-3.8 yr. 86% unilateral. Clinical -- asymptomatic mass (unilateral or when very large may cross midline/extend into pelvis), 20-30% associated signs and symp (malaise, pain, micro/macroscopic hematuria), HTN (25%) related to incr renin activity, pulmonary metastases. Increased risk of WT -- 1. WAGR syndrome (Wilms-aniridia-genital anomaly retardation) - constitutional deletion in 11p13 (WT-1 gene and contiguous aniridia gene PAX6), 2. Denys-Drash syndrome (gonodal dysgenesis with male pseudohermaphroditism, nephropathy, WT) - germline abnormal 11p13 (dominant negative missense mutaiton, affects DNA binding properties); 3. Beckwith-Wiedemann syndrome (microglossia, organomegaly, hemihypertrphy, renal medullary cysts, adrenal cytomegaly, omphalocele) - abnormal 11p15.5 (WT-2); 4. Familial nephroblastoma - loss of heterozygosity on long arm of Chr 16. Prognosis and Tx -- metastases (regional LN, lung, liver bone inrequenc <1%), Tx -- 90% long term survival w/ combined surgery/chemo/radiation. Recurrences (treatable), least favorable prognosis (diffuse anaplasia - extrarenal spread) - increased survival-increased risk of 2nd malignancy.

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Anaplasia

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Diffuse anaplasia ("Anaplasia" -- 3 fold nuclear enlargement compared w/ adjacent nuclei of same cell type; hyperchromasia of enlarged nuclei; atypical enlarged usually multiplolar mitoses p53 mutations. "Diffuse" -- > 10hpf),

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Frequency of solid malignancy in children

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1. CNS tumors; 2. Neuroblastoma; 3. Malignant lymphoma; 4. Wilms tumor (nephroblastoma)

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Wilm's tumor -- Conditions increasing risk of WT

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Increased risk of WT -- 1. WAGR syndrome (Wilms-aniridia-genital anomaly retardation) - constitutional deletion in 11p13 (WT-1 gene and contiguous aniridia gene PAX6), 2. Denys-Drash syndrome (gonodal dysgenesis with male pseudohermaphroditism, nephropathy, WT) - germline abnormal 11p13 (dominant negative missense mutaiton, affects DNA binding properties); 3. Beckwith-Wiedemann syndrome (microglossia, organomegaly, hemihypertrphy, renal medullary cysts, adrenal cytomegaly, omphalocele) - abnormal 11p15.5 (WT-2); 4. Familial nephroblastoma - loss of heterozygosity on long arm of Chr 16.

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Gene WT-1 (the Wilms tumor associated)

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Location -- Chromosome 11p13, Protein/fn -- Transcription factor; Embryonic expression -- Early (intermediate mesoderm, mesenchyme of metanephros, epithelial cells of nephric tubules), Late (mesothelium, spinal cord, brain, derivatives of urogenital ridge); Developmental anomalies -- WT-1 (homozygous gross deletion, Renal agenesis (mice). Heterozygous gross deletions --> WAGR syndrome (WT susceptibility, aniridia, genitourinary malformations, mental retardation), Dominant point mutations (Deny's-Drash syndrome -- ambiguous genitalia, streak gonads, renal failuare, incr susceptibility to Wilm's tumor). Cancer -- WT (WT1 mutation -- 15% sporadic WT)

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Pulmonary disorder -- chief complaints

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1. dyspnea -- cardiac or pulmonary, Anemia, Acidosis, Pregnancy; 2. Cough -- acute vs. chronic (>6 weeks). Chronic -- 1. post nasal drip, 2. reflux, 3. asthma; 3. Chest pain; 4. hemoptysis -- Source (pulmonary - low pressure; Bronchial -- high pressure). Degree - mild, major, Massive (600ml/day). Common conditions - lung infxn, Bronchitis, PE, cancer, Mycetoma (fungus ball in caviry - inflame wall of lung), Vasculitis)

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Mycetoma

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Fungus ball in cavity --> inflame lung wall

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Lung dz - commonly associated with Smoking

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COPD, lung cancer, Interstitial lung dz -- progression in IPF/UIP, DIP, RBILD, Eosinophilic granuloma

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lung dz - Familial

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Asthma & allergies, CF, Emphysema (alpha 1 antitrypsin deficiency), Pulmonary embolism (thrombophilias). Less common -- sarcoidosis, pulmonary fibrosis, pulmonary HTN, Bronchiectasis

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Pulmonary fn test: Spirometry vs. Flow-volume loops / predicted value differences in sex, height, age, ethnicity / normal values

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Spirometry -- only measures expiratory flow. Flow-volume loops -- measure inspiratory & expiratory. / Sex - 12-15% difference, Ethnicity - 15%, Height - 3-5% change/inch, Age - <0.5% change/yr. / normal value -- FVC (>80%), FEV1 (>80%), FEV1/FVC (>70%).

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Pulmonary fn test (PFT) classification of common pulmonary disorders: 1. Airway dz (obstructive disorders); 2. Interstitial chest wall dz (restrictive disorders)

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1. Airway dz -- Asthma, COPD (chronic bronchitis, emphysema), CF, Bronchietcasis, Bronchiolitis; 2. Interstitial chest wall dz -- Idiopathic pulmonary fibrosis, Sarcoidosis, occupational disorders, drug induced disorders, kyphoscoliosis

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Venous Thromboembolism

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Common, often fatal, idopathic. Risk factors -- Thrombophilias (Protein C, S, ATIII, Factor V leiden, prothrombin gene mutation, MTHFRl factor VIII), Virchow's triad -- Stasis, hypercoagulability, injury (need all 3). Medical risk factors -- hip, knee surgery, immobility, CHF, obesity, malignancy (idopathic), aquired hypercoagulabilityMany preventable (DVT prophylaxis). 60-90% of PE orginate in proximal deep veins of legs.

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Virchow's triad

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Sepsis, injury, hypercoagulability -- related to venous thromboembolism

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Pulmonary embolism

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30% mortality if untreated, 2.5% in-hospital mortality -- due to recurrent, acute PE, Massive obstruction of vessels, RV failure, infarct. Majority resolve w/ tx. 1-3% with Chronic PE -- main risk factor is recurrent events. Sx -- nonspecific. Dyspnea, acute or subacute. Dizziness, Syncope (large PE, massive, "saddle"), Chest pain (pleuritic, infarct, bloody effusion), Palpitations, tacycardia, hemoptysis (infarct).

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* Pulmonary Artery Hypertension -- 3 main pathways targeted for tx

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Pathogenesis & tx -- 1. increased Endothelin (vasoconstriction and proliferation) --> give Endothelin receptor antagonist (Bosentan) ; 2. decreased Nitric oxide (vasodilation and antiproliferation) --> give exogenous nitric oxide OR Phosphodiesterase type 5 inhibitor (because phosphodiesterase type 5 inhibits cGMP!) ; 3. decreased Prostacyclin pathway (vasodilation and antiproliferation) --> give exogenous prostaclycin derivatives.

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* MC dz associated w/ Alveolar Hemorrhage syndromes (Capillaritis)

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Antibasement Membrane AB dz (Goodpasture's syndrome), ANCA associated vasculalitis (Wegener's dz), Idiopathic pulmonary Hemosiderosis, Collagen vascular dz (SLE)

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Pulmonary Hypertension - classification, definition, Dx, prognosis, Sx

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Thromboembolic obstruction of proximal pulmonary arteries (surgical candidates). obstruction of distal pulmonary arteries. Classification -- Group 1 (PAH - Pre-Capillary), Group 2 (Pulmonary venous HTN - MC), Group 3 (Pul. HTN Respiratory disorders -- FVC<70%), Group 4 (pulm HTN Thromboembolic disorders), Group 5 (Pulm HTN direct effect on pulmonary vessels). Definition -- pulmonary arterial pressure > 25mmHg at rest, or >30 mmHg during exercise, with normal PCWP. Associated w/ adverse changes in pulmonary vasculature (vasculopathy) and at the level of RV. Dx -- Echocardiogram -- best noninvasive test, RA & RV changes (D shaped sign - RV overload affecting LV performance), Estimate PA pressure, Congenital Ht Dz (PFO shunt - bubble study), Pericardial effusion (prognosis). Hemodynamic & prognosis -- Decresed RV fn -- RA P >10mmHg, Cardiac index <2.2 L/min m2. Poor prognosis (determined by elevated RAP and low CO parameters). Sx -- nonspecific, breathlessness, fatigue, syncope, chest pain (angina), palpitations, hemoptysis, hoarseness (paralyzed left VC)

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Pulmonary Hemodynamics - normal pressures & resistance: RA, PA, PWP pressures. PUlmonary Vascular resistance & Systemic Vascular resistance?

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RA - 0-5, PA 30/12 mean 18, PWP 5-12 mmHg. Pulmonary Vascular resistance - 1-2 Wood units & Systemic Vascular resistance - 10-20 Wood units.

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PAH (Pulmonary Arterial Hypertension) - Group 1 PHtn: pathogenesis, sx/dx, Tx

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Idopathic = IPAH (sporadic, primary = PPH). Hereditable (in PPH, IPAH, familial PAH) -- BMPR2 (Bone morphogenic protein receptor 2) genetic mutations, 10% IPAH (PPH) is familial. mapped to long arm Chromosome 2, BMPR2 -- 55% familial PHT have mutations in this gene, AD with low penetrance, TGF-beta superfamily of receptors, Exon mutations (stop codons, bue more than 40 distinct mutations identified), 25% sporadic IPAH (PPH) have BMPR2 mutations. Assoc with CVD (Scleroderma, SLE, RA), CHD, Portal HTN, HIV, drugs, other disorders. Persistent Fetal circulation, PAH w/ Capillary or venule involvement (Pulm. veno-occlusive dz, capillary hemangiomatosis). Different classes (Class I - IV) -- think PAH if young man has limitation in exercise capacity, new condition. Pathogenesis -- Large Pulm. artery thickening, Medial wall smooth muscle hypertrophy, "plexiform" lesion in small vessel. Chronic disorders -- Endothelial cell defects -- Increased Endothelins, decreased nitric oxide and prostacyclin. Platelet defects (thromboxane, serotonin), Smooth m. cells (distal muscularization), CT matrix, Genetic studies (BMPR2 Gene). Tx -- IV prostacyclin, Sildenafil (NO pathway, increase cGMP), Bosentan (endothelin receptor antagonist)

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Pulmonary vasculitis

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Pulmonary and Alveolar hemorrhage (Goodpasture synd), lung infiltrates (nodular, cavitary lesions, assoc ILD, acute, bilateral, diffuse), Pulmonary HTN

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Alveolar (capillary) hemorrhage syndrome

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Classification -- Antibasement membrane AB dz (goodpasture's syn), ANCA associated Vasculitis (Wegener's), Idiopathic pulmonary hemosiderosis, Collagen vascular dz (SLE). Classic triad -- hemoptysis, pulmonary infiltrates, anemia. Life-threatening complications -- respiratory failure, acute renal failure, severe anemia. Dx -- sputum, tracheal aspirate, UA, other organ problems, Serial Hgb (2 gm in 24 hr), Serial chest x-rays (DLCO), Seriologies (ABMAb, ANCA, ANA), Bronchoalveolar lavage, open lung biopsy ("Siderophages" -- hemosideran laden macrophages), Other organs (skin biopsy, renal biopsy -- RPGN, ABMAb dz - linear Ab staining on BM)

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Alveolar (capillary) hemorrhage syndrome - classic triad

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hemoptysis, pulmonary infiltrates, anemia

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Wegener's Granulomatosis

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Systemic vasculitis - granulomatous inflammation. Pulmonary involvement -- perivascular, necrotizing granulomatous inflammation, lung necrosis and cavitation, hemorrhage. Capillaritis, Alveolar Hemorrhage. Nodules, Cavitary lesions. large airways, COP, BOOP, ILD, Pleuritis, PFT (obstructive/restrictive) Organ involvement -- Upper (73%) before lower (45%) respiratory tract, and kidney (18%). Dyspnea, obstructive PFT (55%). infiltrates, cough, hemoptysis (45%). Athralgias (45%). Skin (40%), Neuro (40%), DVT. Sx -- nasal, sinus, otitis, cough, hemoptysis, constitutional (joint, fever). 50yrs. M>F. Dx -- Tissue biopsy, ESR, ANA, RF, ANCA (c-ANCA)

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Atelectasis

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state in which part or whole lung is collapsed or without air. (loss of lung volume due to inadequate expansion of airspaces. Types -- Resorption, Compression, Contraction and Neonatal (loss of surfactant)

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Resorption Atelectasis

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Consequence of complete airway obstruction -- obstruction from bronchi, subsegmental bronchi or bonchioles, prevents air form reaching the alveoli, resorption of air trapped in distal airspaces through the pores of Kohn, lack of air in distal airspaces, collapse. Cause of obstruction -- Mucus/mupurulent plug following surgery, aspiration of foreign material, bronchial asthma, bronchitis, bronchiectasis (narrowing of airway), bronchial neoplasms (caveat - total obstruction). Clinical -- fever and dyspnea (within 24-36 hrs of collapse -- commonest cause of fever 24-36 hours of following surgery), Ipsilateral deviation of trachea, Ipsilateral diaphragmatic elevation, Absent breath sounds and absent vocal vibratory sensation (tactile fremitus), Collapsed lung does not expand on inspiration.

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Compression atelectasis

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Air or fluid accumulation in pleural caviry - increase pressure - collapse underlying lung (pushes it). Ex -- tension pneumothorax, pleural effusion. Trachea and Mediastinum shift AWAY from the atelectatic lung.

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Neonatal atelactasis (loss of surfactant)

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Surfactant -- lipoprotein - Phosphatidylcholine (lecithin), phosphatidylglycerol, proteins (Surfactant proteins A&D - innate immunity; B&C - reduction of surface tension at air liquid barrier in alveoli), synthesized by Type II pneumocytes (syn begins at 28th wk. stored in lamellar bodies). Role of Surfactant -- reduces surface tension in small airways and prevents collapse on expiration. syn is modulated by different hormones - increased by cortisol and thyroxine vs. decreased by insulin. RDS in newborns -- decreased surfactant in fetal lung -- prematurity, maternal diabetes, C-section. Collapsed alveoli are lined by Hyaline membranes (fibrin-rich membr). Clinical -- respiratory distress w/in few hours of birth, Hypoxemia and respiratory acidosis, "ground glass appearance" on chest x-ray. Complications -- Intraventricular hemorrhage, PDA (persistent hypoxemia), Necrotizing enterocolitis (intestinal ischemia), Hypoglycemia (excessive insulin release), O2 therapy (damage to lungs, bronchopulmonary dysplassia, and cataracts)

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Contraction Atelectasis

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fibrotic changes in lung or pleura prevent full expansion (not reversible).

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Acute lung injury

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Endothelial or epithelial injury (at level of alveolar septum), initiated by numerous factors. Non-heritable & heritable (some genetic components). Mediators -- Cytokines, oxidants, Growth factors (TNF, IL-1,6,10, TGF-beta). Manifestation -- pulmonary edema, diffuse alveolar damage (ARDS)

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Pulmonary Edema

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Acute lung injury. 1. Edema due to alterations in Starling pressure -- increased hydrostatic pressure in pulmonary capillaries (Left heart failure, volume overload, mitral stenosis, cardiogenic pulmonary edema), decreased oncotic pressure (nephrotic syndrome, liver cirrhosis), transudate, edema fluid accumulation in alveolie with "heart failure" cells and "brown induration". 2. Microvascular or alveolar injury -- increase in capillary permeability. Infxn, aspiration, drugs, shock, trauma, high altitude. undetermined origin, therapy and outcome depend on underlying etiology.

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ARDS

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noncardiogenic pulmonary edema resulting from acute alveolar capillary damage. Direct lung injury, indirect lung injury (systemic dz), Risks -- Gram negative sepsis (40%), aspiration (30%), severe trauma (10%), pulmonary infxn, heroin, smoke inhalation. >50% of ARDS from 4 causes -- Sepsis, Diffuse lung infxn (viral, mycoplasma, PCP, MTb), Gastric aspiration, Physical injury/trauma. Clinical -- dyspnea, severe hypoxemia NOT responsive to O2 therapy. respiratory acidosis. Pathogenesis -- acute injury to alveolar epi or endo cells --> alveolar macrophages and other cells release cytokines (Neutrophilic chemotaxis, transmigration of neutrophils from capillaries into alvoeli, leakage of protein - fibrin - rich exudate forming Hyaline embranes, damage to pneumocytes causing surfactant deficiency leading to atelecatasis. Repair by type 2 pneumocytes. Progressive interstitial fibrosis. Prognosis -- Poor (60% mortality rate)

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* 4 main conditions associated with >50% of ARDS causes

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Sepsis, Diffuse lung infxn (virus, mycoplasma, PCP, MTb), physical injury/trauma, Gastric aspiration

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Acute lung injury - phases

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24 hrs -- edema --> 3-4 days -- hyaline membrane --> 1st wk -- hyaline membr reduced. Interstitial inflammation and interstitial fibrosis

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Pneumonia - host defense, impairment of host defense, classification

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3% of all hospitalizations. 6th leading cause of death with Flu. 13% of hospitalized ptns -- nosocomial pneumonia. Host defense -- 10,000 microorganisms inhaled daily. distance traveled is inversely proportional to microbe size. Mucociliary system clears most organisms in URT and larger airspaces. only organisms < 5um reach alveoli. Humoral/cellular immunity clear small microbes. Impairment of host defense -- Loss of cough reflex (clearance defect - anesthesia, coma, neuromuscular disorders (Guillain barre), drugs (EtOH)), Injury to mucociliary sys (smoking, viral infxn, genetic (immotile cilia syndrome), intubation), interference w/ phagocytic or bactericidal fns of macrophages, pulmonary congestion and edema, accumulation of secretions (CF). Epidemiological classification -- Community acquired (typical vs. atypical), Nosocomial, aspiration (necrotizing pneumonia / lung abscess), Chronic (TB/fungi), Immunocompromised host

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Typical community acquired pneumonia

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Majority by bacterial pathogens (streptococcus pneumoniae, H. influenza, Moraxella catarrhalis, Staph Aureus, Klebsiella pneumoniae, Pseudomonas Aeruginosa, Legionella pneumophilia), usually due to aerosol inhalation from infxted ptn. aspiration of nasopharyngeal flora during sleep. Sx -- fever, chills, productive cough, hemoptysis, chest pain, tachycardia, shortness of breath, fatigue, headache, loss of appetite, confusion, elevated White cell counts (pretty broad symp. need additional testing). Gross morphology (2 patterns) -- Lobar pneumonia (entire lobe) & Bronchopneumonia (patchy areas around Bronchioles). Pleuritis -- pleural fibrinous rxn to underlying inflammation (resolution, Fibrinous organization -- plaque formation). Complications -- abscesses, Empyema (spread into pleural space), Organization (organizing pneumonia), Bacteremic dissemination (septic emboli, endocarditis arthritis).

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Lobar pneumonia

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Pattern of community acquired pneumonia. 4 stages -- 1. Congestion -- Vascular engorgement (capillary leak), neutrophil migration, Intra-alveolar fluid; 2. Red hepatization -- confluent exudate with RBCs, Red, firm and airless lung, "liver-like" consistency, many neutrophils; 3. Gray hepatization -- Fibrinosuppurative exudate, disintegration of red cell; 4. Resolution -- enzymatic degradation (resoprtion, expectoration, macrophage ingestion, fibroblastic organization)

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Pleuritis

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Pleural fibrinous rxn to underlying inflammation: Resolution & Fibrinous organization (plaque formation)

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Streptococcus pneumoniae (Pneumococcus)

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MC cause of CAP. Sputum examination -- Gram Positive, lancet shaped diplococcus within neutrophils. Endogenous flora in 20% adults --> false positives. (Gold standard -- have it cultured)

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Atypical community acquired pneumonia

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"Atypical" -- moderate to no sputum, no physicla findings of lung consolidation, moderate to no elevation in WBCs, lack of alveolar exudate. Characteristics -- Droplet infxn (inhalation), varied clinical course, appear as severe URI's or chest colds, cough may be absent. Numerous extrapulmonary abnormalities may help key in to diagnosis. Atypical organisms -- mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydia trachomatis (newborns), Viruses (RSV, influenzavirus, adenovirus)

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Mycoplasma pneumoniae

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atypical community acquired pneumoniae. smallest free living organism (200nm). No cell wall, No gram staining. Cell wall inhibiting antibiotics are not effective. 10-20% of all pneumonias and at least 50% in children and young adults. No seasonal variation. Insidious onset w/ tracheobranchitis (75%) w/ progression to pneumonia in 5%. Early, sputum may have neutrophils but no bacteria. Peribronchial and peribronchiolar inflammation w/ occasional organizing pneumonia (histology is quite nonspecific). Extrapulmonary manifestation are common -- 1. Rashes (trunk, extremeties): 10-20%. MC cause of a rash and pneumonia; 2. Hematologic effects are common -- anemia (hemolytic), cold agglutinins (up to 70% of ptn) -- IgM AB directed at the I antigen on RBCs, may cause hemolytic anemia if high titers are present, appear at 2 wks, at 4 wks, gone in 2 mth

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Nosocomial Pneumonia

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Risk factors -- severe underlying dz (immunosuppression), Antibiotic therapy, respirators. Pathogens -- Pseudomonas aeruginosa (respirators), E.Coli, MRSA

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Aspiration pneumonia

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Occurs in -- markedly debilitated ptn (stoke), repeated vomiting, intubated ptns. Result of both gastric acid irritating lung parenchyma, and bacteria from oral flora. More often polymicrobial, aerobes > anaerobes. Often a necrotizing pneumonia with abscess formation.

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Lung Abscess

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Localized suppurative process within the lung, characterized by necrosis of lung tissue. Cavitary lesion -- few mm to > 6cm. Cavity filled with suppurative material composed of neutrophils adn necrotic debris. More common in right lung (because of steep angle). Clinical -- copious foul-smelling sputum in cough, fever, weight loss, chest pain, clubbing of digits. Mechanism -- Aspiration (altered consciousness), antecedent primary bacterial infxn (pneumonia), septic embolism (hematogenous spread), neoplasia (10-15% of abscesses), direct traumatic penetration. Organism -- frequently mixed (polymicrobial dz), Anaerobes common -- streptococci, Bacteriodes, Fusobacterium, peptococcus.

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TB

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Mycobacterium TB. Microbial characteristics -- strict aerobe, Acid-fast test due to mycolic acid in cell wall. Screening -- PPD (purified protein derivative), Positive with both active and inactive dz. 1. Primary TB -- asymptomatic, low-grade fever, cough, rarely fatigue, pharyngitis, arthralgias, controlled w/o progression in 90% of cases. inhalation of contaminated droplets. MTB taken up by alveolar macrophages. Subpleural lesion -- lower part of upper lobe, peripheral 1-2 cm nodule with central caseous necrosis -- Gohn focus. Granulomatous inflammation with necrosis. MTB goes to lymphatics -- hilar lymphadenopathy + Ghon focus --> Ghon complex. Majority lesions may resolve and heal with normal tissue. Small portion of lesion may become fibrotic and/or calcify. Organisms remain viable -- can reactivate and cause secondary TB 2.Secondary TB -- Reactivation of primary site. Apical involvement (ventilation - oxygenation) is highest in upper lobes, Cavitary lesion. Clinical -- fever, night sweats, weight loss. Complications -- massive hemoptysis, Bronchiectasis, scar carcinoma, Miliary pulmonary spread due to bronchial or lymphatic invasion, Miliary extrapulmonary spread due to pulmonary venous invasion (kidney is common site), Granulomatous hepatitis, vertebral involvement (Pott's spine). Granulomatous inflammation with necrosis -- Epitheloid histiocytes, Multinucleate giant cells, lympohcytes, macrophages, Bacteria found in necrotic material. (Periphery -- histiocytes)

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Primary TB

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1. Primary TB -- asymptomatic, low-grade fever, cough, rarely fatigue, pharyngitis, arthralgias, controlled w/o progression in 90% of cases. inhalation of contaminated droplets. MTB taken up by alveolar macrophages. Subpleural lesion -- lower part of upper lobe, peripheral 1-2 cm nodule with central caseous necrosis -- Gohn focus. Granulomatous inflammation with necrosis. MTB goes to lymphatics -- hilar lymphadenopathy + Ghon focus --> Ghon complex. Majority lesions may resolve and heal with normal tissue. Small portion of lesion may become fibrotic and/or calcify. Organisms remain viable -- can reactivate and cause secondary TB

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Secondary TB

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Secondary TB -- Reactivation of primary site. Apical involvement (ventilation - oxygenation) is highest in upper lobes, Cavitary lesion. Clinical -- fever, night sweats, weight loss. Complications -- massive hemoptysis, Bronchiectasis, scar carcinoma, Miliary pulmonary spread due to bronchial or lymphatic invasion, Miliary extrapulmonary spread due to pulmonary venous invasion (kidney is common site), Granulomatous hepatitis, vertebral involvement (Pott's spine). Granulomatous inflammation with necrosis -- Epitheloid histiocytes, Multinucleate giant cells, lympohcytes, macrophages, Bacteria found in necrotic material. (Periphery -- histiocytes)

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Miliary TB

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Organisms seed pulmonary venous return and enter systemic circulation. Seed other organs -- liver, kidney, bone marrow, spleen, adrenals, fallopian tubes, epididmis. Numerous gray-white nodules in affected organs.

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Atypical Mycobacterial infxn

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Mycobacterium Avium-intracellulare complex (MAC). Commonly seen in AIDS (CD4 TH counts < 50 cells/microL)

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Fungal infxn (pneumonia related)

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Inhalation. Granulomatous inflammatory rxn w/ or w/o necrosis.

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Pneumonia in immunocompromised host

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HIV/AIDS and bone marrow transplant ptn. Common pathogens -- CMV, Pneumocystis jiroveci (tx and prophylaxis -- bactrim (trimethoprim-sulfamethoxazole)), Aspergillus fumigatus

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Interstitial lung dz

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Def -- lung parenchymal disorders w/ common clinical, radiologic, physiologic, adn pathologic features; "involvement of interstitium". Usually have additional components besides interstitium involved (like alveoli, epithelial cell). Synonyms -- infiltrative lung dz (infiltration of cellular and non-cellular elements w/in alveolar septa and alveoli), DPLD (diffuse parenchymal lung dz), Restrictive lung dz (characterized by reduced total lung capacity in presence of a normal or reduced expiratory flow rate. Types -- Acute interstitial lung dz (ARDS), Chronic interstitial lung dz (Pneumoconiosis - fibrosing lung disorders, Sarcoidosis - Granulomatous disorders, ILPs), Chest wall disorders in presence of normal lungs (Kyphoscoliosis, obesity, pleural dz). Pathogenesis -- Alveolitis (damage to pneumocytes and endothelial cells), leads to leukocytes releasing cytokines which mediate and stimulate interstitial fibrosis. Interstitial fibrosis (decreases lung compliance and elasticity, decreased lung expansion during inspiration). Clinical -- dry cough and dyspnea, late inspiratory crackles, bibasilar (Velcro crackles), Cor pulmonale, Chest radiography (bilateral reticulonodular infiltrates)

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Pneumoconiosis

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Def -- non-neoplastic lung dz in response to inhalation of mineral dusts inhaled in the workplace. Now expanded to induce dz induced by organic and inorganic particulate matter/chemical fumes/vapors. Coal dust, silica, asbestos, beryllium. 25% cases of chronic interstitial lung dz. Pathogenetic -- devo depends on amt of dust retained in lung parenchyma and airways. SIZE, SHAPE and buoyancy of particles (1-5 microm reach bifurcation of respiratory bronchioles and alveolar ducts, < 0.5 microm reach alveoli and are phagocytosed by alveolar macrophages. Particle solubility and physicochemical reactivity. possible additional effects of other irritants (tobacco smoking). 1. Fibrogenic -- CWP, Silicosis, Silicatosis, Asbestosis, Rare forms (metalloconiosis - Berylliosis, Hard metal lung dz, Aluminosis / Thesaurosis - hair spray). 2. Nonfibrogenic -- Siderosis (iron oxide), Baritosis (barium sulfate or barytes), Stannosis (tin dioxide or cassiterite), Zirconium lung dz, Antimony lung dz.

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CWP

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Coal worker's pneumoconiosis. Anthracotic pigment -- coal mines, urban centers, tobacco smoke, Pulmonary anthracosis (NOT really a dz. rather, a condition of Anthracosis in lung), Simple CWP (< 1cm) vs. Complex CWP (>1cm) (progressive massive fibrosis)

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Anthracosis

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Asymptomatic. Anthracotic (accumulation of carbon pigment) in interstitial compartment and LN. Type of CWP.

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Simple CWP

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Fibrous opacities < 1cm. upper lobes and upper portions of lower lobes. Characterized by -- coal dust deposits adjacent to respiratory bronchioles (produce centrilobular emphysema)

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Complex CWP

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Progressive massive fibrosis. Fibrous opacities > 1cm. with or without central necrosis. Massive fibrosis -- crippling lung dz (black lung dz). Complication -- Cor pulmonale (RV failure). Caplan syndrome -- CWP w/ rheumatoid nodules in lung. NO increased incidence of TB or cancer.

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Silicosis

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MC occupational dz worldwide. Crystalline silicon dioxide (quartz) -- foundries (metal casting), sandblasting, silica mines. Quartz activates alveolar macrophages after engulfment --> cytokine release --> fibrogenesis. Silicosis = chronic exposure -- Nodular opacities with concentric layers of collagen, Polarizable quartz particles can be sign, "egg-shell" calcification in hilar LN. Complications -- cor pulmonale, associationg with Caplan syndrome. Incre risk for TB (silicotuberculosis) and cancer.

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Asbestos-related dz

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Asbestos forms -- 1. Serpentine (chrysotile) - curly and flexible; 2. Amphibole (crocidolite) - straight and rigid. more common form. more likely to cause dz as they enter lung better. Deposition site -- respiratory bronchioles, alveolar ducts and alveoli. Sources -- insulation around pipes in old naval ships, roofing material used over 20 years ago, demolition of old buildings. Tissue appearance -- Ferruginous bodies (macrophages phagocytose asbestos fibers and coat them with ferritin (iron and protein), golden-brown color. Benign pleural plaques (NOT precursor of mesothelioma), diffuse interstitial fibrosis (asbestosis), Bronchogenic carcinoma (additional risk w/ smoking, 20 yrs after first exposure), Methothelioma (NO relationship to smoking, arises from lining mesothelial cells of pleura. 25-40 yrs after first exposure). NO increased risk for TB. Complications -- Cor pulmonale, Caplan syndrome

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Mesothelioma (related to asbestos)

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NO relationship to smoking, arises from lining of mesothelial cells of pleura. 25-40 yrs after first exposure.

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Berylliosis

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Beryllium - nuclear and airspace industry. Granulomatous inflammation -- TB and sarcoidosis (differential diagnosis). Complications -- cor pulmonale, and lung cancer

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Sarcoidosis

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Multisystem GRANULOMATOUS dz of u/k etiology. 25% cases of chronic interstitial lung dz. AA> Whites, F>M, 70% < 40 yrs, NON-SMOKERS. Disorder of immune regulation. Unknown antigen --> interaction w/ CD4 TH cells --> cytokine release --> recruitment of monocytes/histiocytes --> non-necrotizing granuloma formation. Dx of exclusion. Organs infected -- Lung (90-100%), LN (75-80%), spleen (75%), Skin (nodular granulomatous lesions, Lupus pernio, Erythema nodosum), Eye (Uveitis), liver (granulomatous hepatitis), other (enlarged salivary and lacrimal glands, diabetes insipidus, bone marrow and splenic involvement). Lab -- increased ACE (marker of dz activity and response to steroids), Hypercalcemia (5% cases), polyclonal gammopathy, Cutaneous anergy (lack of response to common skin antigens - candida - due to consumption of CD4 Th cells), CXR -- Bilateral hilar adenopathy, Reticulonodular shadows in lung (meshwork). Langhan's giant cells, Epitheloid histiocytes. Prognosis -- variable (spontaneous remissions and relapses), Progressive interstitial fibrosis w/ cor pulmonale and death in 10-15 % cases.

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Granulomas in lung -- 3 dz?

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Infection, Sarcoidosis, HS pneumonitis

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HS pneumonitis

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Inhaled antigen (known or u/k) producing granulomatous interstitial pneumonitis (extrinsic allergic alveolitis). Type III HS rxn -- 1st exposure (IgG AB in serum), 2nd exposure (AB combine w/ inhaled antigens to form immune complexes --> inflammatory response in lung - interstitial), Chronic exposure (Granuloma formation -- Type IV HS response). Types -- Farmer's lung (moldy hay, thermophilic actinomycetes bacteria -- saccharopolyspora rectivirgula), Silo filler's dz (inhalation of gases from plant material - oxides of nitrogen), Byssinosis (cotton, linen, hemp, textile factory workers, Monday morning blues). Clinical -- acute, subacute, chronic. Interstitial and alveolar infiltrates of inflammatory cells, peri-bronchiolar accentuation, ill-defined granulomas. Clinico-pathologic diagnosis -- sx and physical findings, x-ray abnormalities, PFTs, immunologic features (Abs to suspected Ags). lung biopsy may be needed.

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HS pneumonitis types

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Farmer's lung, Silo filler's dz, Byssinosis

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IPF

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Idiopathic Pulmonary Fibrosis. 15% of cases of chronic interstitial lung dz. Broad and all encompassing term including a number of types of Idiopathic interstitial pneumonias. M>F. 40-70 yrs. Avg duration of sym -- 18-24 mth. Clinical -- dyspnea, non-specific constitutional sx such as fever, weight loss, fatigue, arthralgias, cough. Repeated injury to lung --> alveolitis --> cytokine release --> interstitial fibrosis (NOT an inflammatory condition instead). Interstitial fibrosis --> irregular dilatation of adjacent airways --> honeycomb lung (end stage interstitial fibrosis). Appearance -- Honeycomb cyst, Patchwork appearance (normal and abnormal areas), Fibroblastic plug. Course -- unpredictable; proegressive dz - end-stage lung, cor pulmonale.

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Collagen vascular dz

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10% cases of interstitial lung dz. SLE, RA, Scleroderma (systemic sclerosis).

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SLE - related to lung

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Interstitial lung dz in 50% ptn. Wide spectrum of pulmonary changes -- common manifestation is pleural effusion (Unexplained pleural effusion in young woman liketly to be SLE)

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Rheumatoid arthritis - related to lung

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Wide spectrum of pulmonary changes -- Rheumatoid nodules (when associated w/ pneumoconiosis -- Caplan syndrome). Interstitial fibrosis. Pleural effusions.

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Systemic sclerosis (scleroderma)

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Interstitial fibrosis w/ pulmonary vascular hypertrophy. Commonest cause of death. "sclerosis" -- stiffening of structure.

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COPD

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Dz that cause obstruction to airflow out of the lungs.Types -- Emphysema, chronic bronchitis, asthma, Bronchietasis

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* obstructive vs. restrictive lung dz

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Obstructive -- airway disorder (trachea to terminal bronchiole), increased resistance to air flow and limited expiratory rates on forced expiration. reduced FEV1:FVC ratio. Restrictive -- parenchymal disorder - respiratory bronchiole alveoli, and alverolar duct. decreased expansion with reduced TLC, O2 diffusing capacity, LVs and compliance. Maintained FEV1:FVC ratio

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Emphysema

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def -- 1. permanent enlargement of all or part of respiratory unit (resp. bronchiole, alveolar duct, alveoli) accompanied by 2. wall destruction w/o obvious fibrosis. Causes -- smoking, alpha1-antitrypsin deficiency. Types -- Centriacinar (95%) cases, Panacinar (Paraseptal, irregular). Pathogenesis -- increased numbers of macrophages, CD8+ T lymphocytes and neutrophils. Neutrophils and macrophages are recruited due to cigarette smoke (chemotaxis). Elastase and free radicals derive from neutrophils and macrophages (incr elastase, decr antielastase -- alpha1-antitrypsin / incr oxidants, decr antioxidant). Destruction of elastic tissue. incr compliance and decr elasticity. Patho -- Elastic tissue --> keeps airway lumens open by applying traction --> elastic destruction causes collapse of airways on expiration --> prevents exit of air --> trapped air distends part of respiratory unit that has lost elastic support --> dilatation and destruction of alveoli and alveolar duct. Types -- Centroacinar (oxidant) & Panacinar (alpha1-antitrypsin). Clinical -- severe and early onset of dyspnea. Pink puffers. Coexistance w/ chronic bronchitis (smokers' emphysema). Cor pulmonale (less common than in chronic bronchitis). Diminished breath sounds due to hyperinflation. CXR -- incr AP diameter, hyperlucent lung fields, vertical heart, depressed diaphragm. May look like honeycomb lung of interstitial dz BUT LACKS FIBROSIS

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Panacinar emphysema

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Alpha1-Antitrypsin deficiency (protease-antiprotease imbalance) -- genetic (AD) or acquired. Total lack of antiproteases throughout the acinus. Susceptibility to chronic low-level proteolysis from transient neutrophils. Lower lobes -- Lower lung distribution where perfusion and neutrophil numbers are greatest, all parts of the respiratory unit are affected by elastic tissue destruction. Smoking accelerates process. Serum electrophroesis -- absent alpha1 globulin peak.

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Centriacinar emphysema

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smoker's emphysema. Apical segments of upper lobes. Sites of elastic tissue destruction -- distal terminal and respiratory bronchioles. Air trapped behind collapsed distal terminal bronchioles distends respiratory bronchioles. Oxidant-antioxidant imbalance -- tobacco smoke contains free radicals that deplete antioxidants, Oxidative injury also inactivates native antiproteases - functional alpha1-antitrypsin deficiency (But oxidative injury is the MAJOR cause).

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Paraseptal emphysema & Irregular emphysema

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Paraseptal emphysema -- subpleural involvement, spontaneous pneumothorax, NO COPD. Irregular emphysema -- localized, scar associated, NO COPD

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Chronic Bronchitis

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Productive cough for at least 3 mths for 2 consecutive yrs. Causes -- smoking, CF. Pathogenesis -- Inhaled smoke (irritant) --> mucous hypersecretion in bronchi --> airflow obstruction in terminal bronchioles (more proximal than in emphysema) --> irreversible fibrosis of terminal bronchioles. Infxn (maintenance of dz, Acute exacerbations). Bronchospasm. Cause of Airway narrowing -- mucus secretion & constriction of wall. Clinical -- productive cough, Cyanosis (due to decr O2 saturation from hypoxemia), Blue bloaters, dyspnea, expiratory sheezing and rhonchi, Cor pulmonale (frequent early sign, more prevalent in chronic bronchitis > than emphysema). Morphology -- hyperemia, swelling and edema of mucous membrance, increased mucous glands (hypertrophied), thickening of walls (narrowing of bronchiolar lumnia). Reid index -- ratio of thickness of mucous gland layer to thickness of wall b/w epithelium and cartilage.

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Asthma

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Episodic and reversible airway dz characterized by bronchospasm. Affects bronchi and terminal bronchioles. MC chronic respiratory dz in children. Extrinsic and intrinsic. Mainly related to wall of bronchi (vs. Chronic bronchitis -- lumen related). Extrinsic asthma -- immune mediated, exposure to external allergens, IgE. Intrinsic asthma -- Non-immune mediated. Virus induced respiratory infxn. Morphology -- Gross -- overdistention of lungs, small areas of atelectasis, thick mucous plugs causing occlusion. Microscopic -- Curschmann spirals, eosinophils, Charcot-Leyden crystals, thickening of bronchial BM, Edema and inflm of bronchial walls, increased size of submucosal glands, Hypertrophy of bronchial wall muscle.

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Extrinsic Asthma

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Extrinsic asthma -- Immune mediated, exposure to external allergens, children w/ family hx of allergies, Release of IgE (Type I HS - anaphylactic rxn). Inhaled antigen --> CD4+TH2 cells --> IL4 (--> mast cell growth, B cells) & IL5 (--> B cells, Eosinophil activation) --> IgE --> Mast cells --> vasoactive mediators, Cytokines, GF, Proteases --> Smooth m. proliferation --> Stem cell factor --> Chemoattractant GF --> Mast cell (cycle). Mast cell mediator release --> 1. Acute response (min) -- bronchoconstriction, edema, mucus secretion, influx of PMNs, monocytes, lymphocytes, basophils and eosinophils. 2. Late phase rxn (4-24 hrs) -- eosinophils, epithelial damage, airway constriction. Clinical -- episodic expiratory wheezing, nocturnal cough, barrel chest. Lab -- eosinophilia, positive skin test for allergens. Airway Remodeling -- Hypertrophy of bronchial Smooth m. Deposition of epithelial collagen. linkage of ADAM-33 gene to asthma (polymorphisms may accelerate proliferation of bronchial smooth m. cells and fibroblasts). Morphology -- Curschmann spirals, eosinophils, Charcot-Leyden crystals (casts of bronchioles). Clinical -- in ptns w/ severe dz, sx may be present at a low level all the time. Status asthmaticus (severe acute asthma that cna persist for days to weeks and can cause death.

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Status asthmaticus

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Severe acute asthma that can persist for days-wks and can cause death.

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Morphology -- Curschmann spirals, eosinophils, Charcot-Leyden crystals. Thickening of bronchial BM

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Asthma

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Intrinsic Asthma

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Non-immune mediated. Virus induced respiratory infxn (respiratory syncytial virus, rhinovirus, influenzavirus). Air polutants (ozone). Drug induced -- aspirin. Stress, exercise. cigarette smoke.

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Bronchiectasis

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Permanent destruction and dilatation of bronchi and bronchioles. Destruction involves cartilage and elastic tissue. Causes -- CF, infxn (TB, Adenovirus, H Influenzae, Staph Aureus), Bronchial obstruction, Primary ciliary dyskinesia, allergic bronchopulmonary aspergillosis. Clinical -- Copious sputum, Hemoptysis, digital clubbing, Cor pulmonale. CXR -- bronchial markings extending to the periphery of the lungs. Gross -- Bilateral lower lobes, distal bronchi and bronchioles. Dilated airways which can be followed out to the pleural surfaces. On cut surface the dilated bronchi appear as cysts filled with mucopurulent secretions. Microscopic -- intense acute and chronic inflammatory exudate in bronchial walls, necrotizing ulceration, squamous metaplasia of bronchial epithelium, lung abscesses may be present, fibrosis of bronchial walls leading to bronchiolitis obliterans, Cultures are usually positive.

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CF - related to Bronchiectasis

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AR. Pathogenesis -- deletion of chromosome 7 (3 nucleotides that code for phenylalanine), defective CFTR. --> dehydration of body secretions due lack of NaCl -- bronchioles, pancreatic ducts, bile ducts, meconium, seminal fluid. Clinical -- (systemic) Nasal polyps, Respiratory infxn --> respiratory failure (Pseudomonas aeruginosa, S. aureus, H influenza, Cor pulmonale), Malabsorption (exocrine pancreatic deficiency, glandular atrophy from thick secretions blocking lumen), Type I diabetes mellitus (chronic pancreatitis), Infertility in males (Vas deferens atresia), Meconium ileus (small bowel obstruction in newborns), Secondary biliary cirrhosis (Bile ductular obstruction by secretions).

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Lung - tumor types

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Bronchogenic carcinoma (90-95%), Carcinoids (5%), Other tumors (2-5%)

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Bronchogenic Carcinoma

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Incidence -- decr in men and incr in women. MC visceral malignancy in males. 1/3 cancer deaths in males / 7% of cancer deaths in both sexes. M>F. Most frequent fatal malignancy in men and women. Dz of middle & late adult life (peak in 50s-60s). <2% below 40yrs. Etiology -- Tobacco smoking, Industrial hazards, air pollution, molecular genetics, scarring. Clinical -- 50yrs. 7 mths avg duration of sx. Major presenting complaints -- cough (75%), wt loss (40%), chest pain (40%), dyspnea (20%). increased sputum production. Pancoast tumor (tumor at extreme apex of lung. Superior cervical sympathetic ganglion -- Horner's syn. SVC syn). Classification -- SCC, NonSCC (Squamous cell carcinoma, Adenocarcinoma, Large cell carcinom, adenosquamout carcinoma). Metastasis -- Hilar LN, Adrenal gland (50%), Liver (30%), Brain (20%), Bone. Paraneoplastic syndromes (Cushing's syn, hyponatremia, carcinoid syn, hypercalcemia, myasthenic syn), Course -- Overall outlook is poor, 5 yr survival is 9% (10% for SCC and AdenoCa, 3% for small cell Ca)

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Carcinoid Tumors

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1-5% of all lung tumors. ptn < 40yrs. M=F. 20-40% non-smokers. Low-grade malignant neoplasms (biologically all benign tumors but may behave like low-grade malignant fashion). Microscopic -- nests/cords/masses. uniform cells w/ round nuclei. Salt & pepper chromatin. IHC (NSE, chromogranin, synaptophysin). Clinical & prognosis -- hemoptysis, cough, obstructive sx (due to intraluminal growth), infxns, bronchiectasis, atelactasis or emphysema. Carcinoid syn (intermittent diarrhea, flushing, and cyanosis). Metastases occur rarely (1-5%). usually follow a benign course for long periods and are amenable to resection. 5 and 10 yr survival (87%).

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Bronchogenic Carcinoma -- Tobacco smoking

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Assoc b/w frequency of lung Ca & amt of daily smokine -- Smokers X10 risk, Heavy smokers X20. Pack year -- # packs/day X # years. Other association -- lip, tongue, mouth, pharynx, larynx, esophagus, UB, pancreas, kidney. Clinical evidence -- histologic changes in the respiratory tract of smokers. 96.7% smokers have atypical changes in bronchial epithelium (preneoplastic changes). However Experimental evidence is NOT that strong.

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Bronchogenic carcinoma -- Industrial hazard & Air polution

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Radiation, Uranium miners, Asbestos -- + smoking (X 50-90 risk), - smoking (X5 risk). Latent period (10-30 yrs). 1/5 deaths Lung Ca. 1/10 deaths Mesothelioma. 1/10 deaths GI Ca. Other hazards -- Nickel, chromates, coal, mustard gas, arsenic, beryllium, iron. / Air pollution -- indoor air pollution (Radon exposure), ubiquitous radioactive gas -- lung cancer in non-smokers may be attributed to radon exposure. Miners exposed to higher concentrations.

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Bronchogenic carcinoma -- Molecular genetics

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1. Oncogenes -- C-myc (SCC), K-ras (Adenocarcinoma), EGFR (Adenocarcinoma), EML4-ALK (adenocarcinoma); 2. Tumor suppressor genes -- p53, Retinoblastoma; 3. Benzopyrene (in cigarette) causes DNA damage at the same codons of p53 gene; 4. Familial clustering and variable risk among heavy smokers suggest genetic predisposition.

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Bronchogenic carcinoma -- Scarring

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"scar cancers" -- cancers occuring in the vicinity of pulmonary scars. Usually adenocarcinomas. In most cases, the scar is a response to the tumor. Sometimes, scar precedes cancer (old infarcts, wounds, granulomatous infxn).

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Pancoast tumor (Bronchogenic carcinoma related)

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Tumor at extreme apex of lung. 1. involvement of superior cervical sympathetic ganglion -- Horner's syndrome (ipsilateral lid lag, miosis, ipsilateral anhydrosis); 2. SVC syndrome -- compression of SVC. primary lung cancer. "puffiness" - blue to purple discoloration of face, arms, shoulders. retinal hemorrhage, stroke.

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Bronchogenic carcinoma -- classification

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SCC -- Oat cell (lymphocyte-like), Intermediate cell (polygonal), Combined (usually with squamous). Non-SCC -- Squamous cell (epidermoid_ carcinoma. Adenocarcinoma (Glandular with mucin, papillary, solid, Lepidic Bronchioloalveolar). Large cell carcinoma (Neuroendocrine, undifferentiated, Giant cell, clear cell). Adenosquamous carcinoma. (based on response to chemotherapy). Cytology -- acurate in distinguising small from non SCC.

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Squamous cell carcinoma - (Bronchogenic carcinoma)

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25-40%. MC type in males. Cigarete smoker. Central cavity necrosis. Arise centrally (main or lobar bronchi) -- usually endobronchial, polypoid growth. Histology -- Keratin formation, intracellular bridges, atypia and invasion. well/moderately/poorly differentiated subtypes depending on degree of squamous differentiation.

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Adenocarcinoma - (Bronchogenic carcinoma)

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25-40%. MC type in women and non-smokers (most patients are smokers). MC form of lung carcinoma in USA. Peripheral w/ pleural retraction or puckering. Associated with scarring. Grow more slowly, metastasize more frequently than Squamous cell carcinoma. Asymptomatic (peripheral tumor) -- late diagnosis. Histology -- Glandular (acinar) w/ mucin. Papillary, solid. (Lepidic) Bronchioalveolar.

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Bronchioloalveolar carcinoma - (type of bronchogenic carcinoma)

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1-9%. Subset of adenocarcinoma. Gross -- single peripheral nodule, Multiple nodules (several lobes/bilateral) - multifocal/aerogenous spread, diffuse pneumonia-like infiltrate. Histology -- Lepidic spread (tumor cells spread along alveolar septa - sneaky). Nonmucinous (Clara cells, type 2 pneumocytes. 2/3 cases). Mucinous (tall columnar mucinous cells, worse prognosis) Need to rule out Lepidic spread in lung by metastases of other tumor like colon cancer.

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Adenocarcinoma classification

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1. AIS (Adenocarcinoma in situ) - nonmucinous and rarely mucinous, <3cm; 2. MIA (Minimally invasive adenocarcinoma) - nnonmucinous and rarely mucinous <3cm; 3. Lepidic predominant adenocarcinoma - nonmucinous, > 3cm; 4.5. Invasive mucinous adenocarcinoma (formerly mucinous BAC) >3cm.

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Small cell Carcinoma - (type of Bronchogenic carcinoma)

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20-25%. predominantly in males, smokers, central location. Worst prognosis. highly malignant, median survival 4mths. Submucosal/circumferential infiltration; rare endobronchial polypoid growth. Subclassification -- oat cell, intermediate cell, Mixed (small/large cell), Combined (small cell/adeno or squamous). Extensive necrosis, crush artifact. Secretory granules of neuroendocrine type. Metastasis by time of diagnosis (70%) ptn seen at advanced stage. Ectopic hormone production (paraneoplastic syn). Excellent response to chemotherapy.

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Large cell carcinoma - (type of Bronchogenic Ca)

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10-15%. undifferentiated. Pleomorphic, large cells w/o differentiation. Ultrastructural evidence of glandular or squamous differentiation. 5-yr survival 6%. Giant cell carcinoma -- highly malignant, mostly peripheral, < 10 month survival

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Adenosquamous carcinoma - (type of Bronchogenic Ca)

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1-3%. squamous cell carcinoma and adenocarcinoma in same neoplasm. Peripheral tumor, associated with scar. Clinical presentation and behavior similar to Adenocarcinoma. Majority ptns are smokers.

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Paraneoplastic syndromes - related to Bronchogenic carcinoma

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Def -- symptom complexes in ptn with cancer that 1. cannot be readily explained by local or distant spread; or by 2. elaboration of hormones by tumor cells. Importance -- earliest manifestation of occult neoplasm, significant clinical problems, May mimic metastases and be difficult to treat. Clinically significant syndromes -- 1-10%. Syndromes -- Cushing's syn (ACTH; SCC), Hyponatremia (inappropriate ADH secretion; SCC), Carcinoid syn (serotonin, SCC), Hypercalcemia (parathormone, Squamous cell Ca), Myasthenic syn (Eaton-lambert syn, SCC)