PATHOLOGY LABORATORY: RESPIRATORY TRACT NEOPLASIA Chi Lai, MD, FRCPC

Plan Concepts & nomenclature Lung cancer Epidemiology Risk factors Histologic subtypes Malignant mesothelioma Upper respiratory tract / head & neck cancer

NOMENCLATURE

Nomenclature Epithelial cell Normal cell Blood cell Mesenchymal cell Sporadic Viral Infection Radiation Chemical agents Carcinoma MutationsNeoplastic cell Lymphoma/leukemia Sarcoma

LUNG CANCER

Epidemiology Most frequently diagnosed major cancer worldwide Most common cause of cancer-related mortality Occurs most often between 40 & 70 years of age (peak incidence in 50s/60s) Only 2% of all cases occur before 40 years of age Most lung cancers associated with well known carcinogen (e.g. cigarette smoke)

Risk Factors Cigarette smoking ~80% of lung cancers occur in active or recent former smokers Almost linear correlation between frequency of lung cancer and pack- years of cigarette smoking Only 11% of heavy smokers develop lung cancers ?other factors Cessation of smoking decreases risk of lung cancer over time, but never returns to baseline (nonsmokers) No safe level of exposure of secondhand smoke which contains numerous human carcinogens

Risk Factors Genetic predisposition Specific p-450 polymorphisms: increased capacity to activate procarcinogens in cigarette smoke Mutagen sensitivity genotype: increased susceptibility of lymphocytes to chromosomal damage after exposure to carcinogens in cigarette smoke Industrial hazards Ionizing radiation Uranium (nonsmokers: 4X vs. smokers: 10X) Asbestos (nonsmokers: 5X vs. smokers: 50-90X) Chromium, arsenic, nickel, vinyl chloride, mustard gas ?Environmental pollution (e.g. air pollution, radon gas)

Squamous cell carcinoma Small cell carcinoma Large cell carcinoma Adenocarcinoma Central LesionsPeripheral Lesions = Tobacco Adapté de Sternberg, S., Histology for pathologist, 2nd ed.

Central Neoplasms Peripheral Neoplasms

Neuroendocrine cells

Histological Subtypes Adenocarcinoma (40%) Derived from glandular epithelium Squamous cell carcinoma (25%) Derived from squamous epithelium Small cell carcinoma (20%) Derived from neuroendocrine cells Large cell carcinoma (10%) Neither glandular or squamous epithelium Other (5%)

Small Cell Carcinoma Characteristics Invasive growth along submucosa Consequences Negative chest x-ray Marked cellular proliferationGood response to chemo/rad tx Lymphatic vessel invasion Lymph node metastases & superior vena cava syndrome Blood vessel invasionEarly distant metastases Production & secretion of neuroendocrine peptides Paraneoplastic syndromes

Small cell carcinoma Relatively small cells with scant cytoplasm, ill-defined cell borders, hyperchromatic & pyknotic nuclei (red arrows), “salt & pepper” chromatin, nuclear molding

Non-Small Cell Carcinoma Squamous cell carcinoma Adenocarcinoma Non-invasive (in situ adenocarcinoma or bronchiolo-alveolar carcinoma) Invasive Large cell carcinoma Other

Squamous Cell Carcinoma > 90% associated with cigarette smoking Precursor lesions / synchronous lesions Cavitation / local invasion ↑ Lymphatic metastases ↓ Peripheral presentation: 20 to 30% Relatively "better" prognosis than other types of NSCLC

Metaplasia - Dysplasia Thickened mucosa NormalMetaplasia Mild dysplasia Severe dysplasia

In Situ – Microinvasive Carcinoma Abnormal Microinvasive focus

Invasive Squamous Cell Carcinoma Keratin pearl Tumour

Squamous cell carcinoma

Adenocarcinoma Invasive Solid nodule Stromal invasion Lymph-vascular invasion Lymph node metastases Distant metastases 5-yr survival: 10 to 15% Non-invasive AKA bronchioloalveolar ca (adenocarcinoma-in-situ) Ground-glass opacity/consolidation Aerogenous spread/multicentric No stromal or vascular invasion No lymph node or distant metastases 5-yr survival: 100%

Adenocarcinoma Vascular invasion FDG avid spot on PET scan

Bronchioloalveolar carcinoma (adenocarcinoma- in-situ)

Large Cell Carcinoma Undifferentiated malignant epithelial neoplasm exhibiting neither glandular or squamous cell differentiation Large pulmonary masses Peripheral > central Aggressive behaviour

Large cell carcinoma

AdenocarcinomaSquamousLarge CellSmall Cell Incidence40% (↑)25% (↓)10%20% SexF > MM > FM = F Cigarette+++ PresentationPeripheral Met ++ Central Met + Peri / Central Met ++ Central Met +++ Paraneopl. syndromes RarePTH (↑Ca)Rare+++ (ADH, ACTH) TreatmentSurg (RT/CT) Chemo/radio Prognosis5-yr: % 2-ryr: 0% (D), 20-30% (L) SCLCNSCLC

MALIGNANT MESOTHELIOMA

Malignant Mesothelioma Rare malignant tumor of mesothelial derivation arising from visceral or parietal pleura Strongly associated with asbestos exposure Lifetime risk of developing mesothelioma in heavily exposed individuals: up to 7 to 10% Long latent period (>20 years) between asbestos exposure & development of asbestos-related mesothelioma) No increased risk of mesothelioma in asbestos workers who smoke Patients yrs, M > F Concurrent pulmonary asbestosis present in only 20% of individuals with pleural mesothelioma Diffuse unilateral nodular pleural thickening Consumptive symptoms, dyspnea, thoracic pain (contraction of hemithorax)

Gross features Diffuse nodular pleural thickening involving either visceral or parietal pleura or both Direct invasion of lung parenchyma & chest wall may be present Affected lung eventually becomes surrounded by thick layer of firm, white-to-tan tumor tissue Presence of fibrous pleural plaques

Microscopic features Epithelioid (60%) Cuboidal, columnar, or flattened cells forming tubular or papillary structures Sarcomatoid (20%) Spindle cells Biphasic (20%) Both epitheloid & sarcomatoid patterns Epithelioid variant is most common & morphologically indistinguishable from metastatic carcinomas

Mesothelioma vs Carcinoma Metastatic carcinomas >>> mesotheliomas No definitive morphological criteria to distinguish them Immunohistochemistry & electron microscopy Clinical information is most important! Search of primary carcinomas: lung, breast, ovaries etc Detailed occupational history to detect previous asbestos exposure (no asbestos exposure = unlikely mesothelioma)

UPPER RESPIRATORY TRACT / HEAD & NECK TUMORS

Malignant Head & Neck Tumours Oral cavity: Squamous cell carcinoma, salivary gland tumours, lymphoma Upper respiratory tract: Squamous cell carcinoma, nasopharyngeal carcinoma (EBV) Ears: Squamous cell carcinoma Neck: Metastatic squamous cell carcinoma, lymphoma (cervical lymph nodes)

Squamous Cell Carcinoma Most common head & neck cancers (~95%) 6 th most common neoplasm, 500,000 cases worldwide Multifactorial pathogenesis Chronic abusers of tobacco & alcohol (North America & Europe) Chewing betel quid & paan (India & Asia) Actinic radiation & pipe smoking (lower lip cancer) HPV (esp. HPV-16): 70% of oropharyngeal SCC (tonsils, base of tongue) 5-yr survival: overall <50%, early stage 80%, late stage 20% Field cancerization: chronic exposure of mucosa to carcinogens Rate of 2 nd primary tumors: 3% to 7% per year 35% chance of developing at least 1 new primary tumor within 5 years Frequent development of multiple primary tumors markedly decreases survival (poor prognosis)

Precancerous Lesions of Oral Cavity Leukoplakia White patch or plaque that cannot be scraped off & cannot be characterized clinically or pathology as any other disease (WHO) Must rule out other entities (chronic irritation, lichen planus, candidiasis) Incidence: ~3% of world’s population 5 to 25% of leukoplakic lesions are premalignant Spectrum of thickened, hyperkeratotic, orderly mucosal epithelium to markedly dysplastic changes sometimes merging into carcinoma in situ Erythroplakia Much less common than leukoplakia Red & velvety, possibly eroded area Almost all (~90%) show severe dysplasia, carcinoma-in-situ, or micro- invasive carcinoma Risk of malignant transformation much higher than leukoplakia Usually in patients 40 to 70 years of age (M:F ratio = 2:1) Multifactorial, tobacco use common antecedent

Leukoplakia

Progression of Premalignant to Malignant Normal Hyperplasia/H yperkeratosis Mild/moderate dysplasia Severe dysplasia/CIS SCC

Squamous cell carcinoma of tongue Well-differentiated SCC (on left): Polygonal cells with dense eosinophilic cytoplasm & distinct cell borders; intercellular bridges; keratin pearls (asterisks); dyskeratotic cells (arrow); moderate pleomorphism; mitoses * *

Squamous Cell Carcinoma of Larynx Most commonly seen in men, 60 yrs of age Most often related to smoking Smoking + alcohol increases risk substantially Spectrum of changes from hyperplasia to dysplasia to CIS to invasive SCC Progression from dysplasia to carcinoma within 5-10 yrs 1%-2% with mild dysplasia 5%-10% with severe dysplasia Usually develops on vocal cords

Squamous Cell Carcinoma of Larynx