patoloji-ders-notlari

Title

Serdar Balcı

Lung Tumors

Serdar BALCI, MD

METASTASIS TO THE LUNG

metastatic tumors form multiple discrete nodules scattered throughout all lobes

Autopsy Pathology: A Manual and Atlas

Metastases to the lung

diffusely infiltrating the lung parenchyma (lymphangitic spread)

Autopsy Pathology: A Manual and Atlas

PRIMARY LUNG TUMORS

Primary Lung Tumors

• 95% of primary lung tumors are carcinomas
• 5% →
  • Carcinoids
  • Mesenchymal malignancies, fibrosarcomas, leiomyomas
  • Lymphomas
  • Other benign lesions

Pulmonary Hamartoma

• Most common benign tumor
  • Spherical
  • Small (3 to 4 cm)
  • Coin lesion on chest radiographs
  • Mature cartilage, often admixed with fat, fibrous tissue, and blood vessels
  • Clonal cytogenic abnormalities show that it is a benign neoplasm
    • Misnomer as hamartoma

Lung cancer

• Carcinoma of the lung
• Single most important cause of cancer-related deaths in industrialized countries
  • Incidence among males is gradually decreasing, but it continues to increase among females
  • Women dying each year from lung cancer than from breast cancers
  • Causal relationship of cigarette smoking and lung cancer
• Peak incidence in 50s-60s
• >50% of patients already have distant metastatic disease
  • 1/4 have disease in the regional lymph nodes
• 5-yr survival rate for all stages 16%
  • Even localized to lung 45%

Smoking-related carcinomas

• Stepwise accumulation of a multitude of genetic abnormalities
• Sequence of molecular changes is not random
  • Follows a predictable sequence that parallels the histologic progression
• Early
  • Inactivation of the putative tumor suppressor genes on (3p)
  • Found in benign bronchial epithelium of persons with lung cancer
  • In the respiratory epithelium of smokers without lung cancer
  • **Field effect **
• Late
  • TP53 mutations or activation of the KRAS oncogene

Nonsmoking women of Far Eastern origin

Activating mutations of the epidermal growth factor receptor (EGFR)

Sensitive to agents that inhibit EGFR signaling

Smoking

90% of lung cancers occur in active smokers or those who stopped recently

Linear correlation has been recognized between the frequency of lung cancer and pack-years of cigarette smoking

60x greater among habitual heavy smokers (two packs a day for 20 years) than among nonsmokers

• Only 11% of heavy smokers develop lung cancer
  • Other predisposing factors must be operative in the pathogenesis of this deadly disease
• Mutagenic effect of carcinogens is conditioned by hereditary (genetic) factors
  • P-450 monooxygenase enzyme system
• Women have a higher susceptibility to carcinogens in tobacco than men
• Cessation of smoking decreases the risk of developing lung cancer over time
  • May never return to baseline levels
  • Genetic changes can persist for many years
• Passive smoking
  • 2x risk than nonsmokers
• Pipes and cigars also increases the risk
• Miners
  • Radioactive ores
  • Asbestos workers
  • Dusts containing arsenic, chromium, uranium, nickel, vinyl chloride, and mustard gas
• Exposure to asbestos
  • 5x risk in nonsmokers
  • 55x risk in smokers

LUNG CANCERS

Spread of Carcinoma of the Lung

Involvement of successive chains of nodes about the carina

Mediastinum

Neck (scalene nodes)

Clavicular regions

Distant metastases

Left supraclavicular node (Virchow node)

Pleural or pericardial space, leading to inflammation and effusion

Carcinoma of the lung

• Compress or infiltrate the superior vena cava
  • Vena cava syndrome
• Apical neoplasms may invade the brachial or cervical sympathetic plexus
  • Severe pain in the distribution of the ulnar nerve
  • Horner syndrome
    • Ipsilateral enophthalmos, ptosis, miosis, and anhidrosis
  • Pancoast tumors
    • Apical tumors
    • Pancoast syndrome
    • Destruction of the first and second ribs, thoracic vertebrae
• Metastatic spread
  • Brain
    • Mental or neurologic changes
  • Liver
    • Hepatomegaly
  • Bones
    • Pain
  • Adrenal
    • Insufficiency is uncommon
• NSCLCs carry a better prognosis than SCLCs

Paraneoplastic syndromes

• Hypercalcemia
  • Parathyroid hormone–related peptide
• Cushing syndrome
  • ACTH
• Syndrome of inappropriate secretion of antidiuretic hormone
• Neuromuscular syndromes
  • Myasthenic syndrome, peripheral neuropathy, and polymyositis
• Clubbing of the fingers and hypertrophic pulmonary osteoarthropathy
• Coagulation abnormalities
  • Migratory thrombophlebitis, nonbacterial endocarditis, and disseminated intravascular coagulation
• Hypercalcemia → squamous cell neoplasms
• hematologic syndromes → adenocarcinomas

Histologic Types of Lung Cancer

• Four major histologic types
  • Adenocarcinoma
  • Squamous cell carcinoma
  • Small cell carcinoma
  • Large cell carcinoma
  • Combination of histologic patterns
• Squamous cell and small cell carcinomas
  • Strongest association with smoking

Robbins Basic Pathology

Robbins Basic Pathology

Until recently there were two groups

• SCLC
  • metastasised at the time of diagnosis
  • no surgery
  • **chemotherapy w/wo radiotherapy **
• Non–small cell lung cancer (NSCLC)
  • surgery
• Now, targeted therapy has changed the field
  • Cannot give a drug of adenoca to sq cell ca

Personalized lung cancer therapy

• Mutations
  • EGFR, K-RAS
  • EGFR and K-RAS mutations are mutually exclusive
  • in 30% of adenocarcinomas
• Translocations
  • EML4-ALK tyrosine kinase fusion genes
  • ROS-1
• Gene amplifications
  • c-MET tyrosine kinase gene amplifications

4-6% of adenocarcinomas

Targeted with tyrosine kinase inhibitors

Carcinomas of the lung

• Begin as small mucosal lesions
• Firm and gray-white
• May arise as intraluminal masses
  • Invade the bronchial mucosa
• Form large bulky masses
  • Pushing into adjacent lung parenchyma
• Some large masses undergo cavitation
  • Secondary to central necrosis
  • Areas of hemorrhage
• May extend to the pleura
  • Invade the pleural cavity and chest wall
• Spread to adjacent intrathoracic structures
• Distant spread via lymphatics or hematogenous route

SQUAMOUS CELL CARCINOMAS

Squamous cell carcinomas

More common in men than in women

Closely correlated with a smoking history

Centrally in major bronchi

Spread to local hilar nodes

Disseminate outside the thorax later than other histologic types

Large lesions, central necrosis, cavitation

Preneoplastic lesions, may last for several years

central squamous cell carcinoma has completely obstructed the lumen of the right main-stem bronchus. Metastatic tumor deposits are evident in both lungs

Autopsy Pathology: A Manual and Atlas

• Dysplasia
  • Atypical cells may be identified in cytologic smears of sputum or in bronchial lavage fluids or brushings
  • Lesion is asymptomatic and undetectable on radiographs
• Tumor mass
  • Obstruct the lumen of a major bronchus
  • Produce distal atelectasis and infection

Robbins Basic Pathology

Goblet cell hyperplasia

Robbins Basic Pathology

Basal cell (reserve cell) hyperplasia

Robbins Basic Pathology

Squamous metaplasia

Robbins Basic Pathology

Squamous dysplasia

Robbins Basic Pathology

Carcinoma in situ

Robbins Basic Pathology

invasive squamous carcinoma

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

ADENOCARCINOMA

Adenocarcinoma

• Usually more peripherally located, many with a central scar
  • May occur as central lesions also
• Most common type of lung cancer in women and nonsmokers
• Grow slowly
• Form smaller masses than other subtypes
• Tend to metastasize widely at an early stage

Adenocarcinomas of the lung arise most commonly in the periphery

Autopsy Pathology: A Manual and Atlas

Bronchioalveolar stem cells

• At bronchioloalveolar duct junction
• Peripheral lung injury
• Multipotent BASCs undergo expansion
• Replenish the normal cell types
  • Bronchiolar Clara cells and alveolar cells
• Facilitate epithelial regeneration
• BASCs have initiating oncogenic event
  • Somatic K-RAS mutation
• Results in pulmonary adenocarcinoma

Adenocarcinoma

• Histologic examination
  • Acinar (gland-forming)
  • Papillary
  • Mucinous
    • Often multifocal and may manifest as pneumonia-like consolidation
  • Solid
    • Requires demonstration of intracellular mucin production by special stains
• Histologic examination
  • Acinar (gland-forming)
  • Papillary
  • Mucinous
    • Formerly mucinous bronchioloalveolar carcinoma
    • Often multifocal and may manifest as pneumonia-like consolidation
  • Solid
    • Requires demonstration of intracellular mucin production by special stains

Precursor of adenocarcinoma

• Squamous metaplasia and dysplasia may be present near adenocarcinomas
  • But they are not the precursor lesions for this tumor
• Precursor of peripheral adenocarcinomas:
  • Atypical adenomatous hyperplasia (AAH)
  • Progresses to adenocarcinoma in situ
• Minimally invasive adenocarcinoma
  • <3 cm and invasive component ≤5 mm
• Invasive adenocarcinoma
  • Tumor of any size, invaded >5 mm
• Squamous metaplasia and dysplasia may be present near adenocarcinomas
  • But they are not the precursor lesions for this tumor
• Precursor of peripheral adenocarcinomas:
  • Atypical adenomatous hyperplasia (AAH)
  • Progresses to adenocarcinoma in situ
    • Formerly bronchioloalveolar carcinoma
• Minimally invasive adenocarcinoma
  • <3 cm and invasive component ≤5 mm
• Invasive adenocarcinoma
  • Tumor of any size, invaded >5 mm

Atypical adenomatous hyperplasia

• Well-demarcated focus of epithelial proliferation
• Cuboidal to low-columnar cells
• Cytologic atypia of variable degree
  • Hyperchromasia, pleomorphism, prominent nucleoli
• Monoclonal
• K-RAS mutations

Robbins Basic Pathology

Adenocarcinoma in situ

• Involves peripheral parts of the lung, as a single nodule

• 3 cm or less

• Growth along preexisting structures, and preservation of alveolar architecture

• May be nonmucinous, mucinous, or mixed

• Grow in a monolayer along the alveolar septa

  • Lepidic growth pattern

• No destruction of alveolar architecture

• No stromal invasion with desmoplasia

• Formerly called bronchioloalveolar carcinoma

• Involves peripheral parts of the lung, as a single nodule

• 3 cm or less

• Growth along preexisting structures, and preservation of alveolar architecture

• May be nonmucinous, mucinous, or mixed

• Grow in a monolayer along the alveolar septa

  • Lepidic growth pattern

• No destruction of alveolar architecture

• No stromal invasion with desmoplasia

Robbins Basic Pathology

ADENOCARCINOMA

Gland-forming adenocarcinoma; inset shows thyroid transcription factor 1 (TTF-1) positivity, which is seen in a majority of pulmonary adenocarcinomas

Robbins Basic Pathology

Personalized lung cancer therapy

• Mutations
  • EGFR, K-RAS
  • EGFR and K-RAS mutations are mutually exclusive
  • in 30% of adenocarcinomas
• Translocations
  • EML4-ALK tyrosine kinase fusion genes
  • ROS-1
• Gene amplifications
  • c-MET tyrosine kinase gene amplifications

4-6% of adenocarcinomas

Targeted with tyrosine kinase inhibitors

LARGE CELL CARCINOMAS

Large cell carcinomas

• Undifferentiated malignant epithelial tumors
• Lack the cytologic features of small cell carcinoma
• No glandular or squamous differentiation
• Large nuclei, prominent nucleoli, and a moderate amount of cytoplasm
• On ultrastructural examination
  • Minimal glandular or squamous differentiation is common

NEUROENDOCRINE TUMORS

Pulmonary neuroendocrine neoplasms

• Typical carcinoid
• Atypical carcinoid
• Small cell carcinoma
• 5- and 10-year survival rates
  • Typical carcinoids: Above 85%
  • Atypical carcinoids: 56% and 35%
  • Small CLC: 5% in 10yr

Carcinoid Tumors

• Malignant tumors

• Dense-core neurosecretory granules in cytoplasm

  • Rarely, may secrete hormonally active polypeptides

• Typical (low-grade)

• Atypical (intermediate-grade) carcinoids

• Both are often resectable and curable

• Part of the multiple endocrine neoplasia syndrome

• Early age (mean 40 years)

• 5% of all pulmonary neoplasms

• Originate in main bronchi

  • An obstructing polypoid, spherical, intraluminal mass
  • A mucosal plaque penetrating the bronchial wall to fan out in the peribronchial tissue
    • Collar-button lesion
    • Broad front, reasonably well demarcated

• Peripheral carcinoids are less common

• 5-15% metastasized to the hilar nodes at presentation, distant metastases are rare

Robbins Basic Pathology

Robbins Basic Pathology

Typical carcinoids

Resemble the ones in the intestinal tract

Nests of uniform cells

Regular round nuclei

Salt-and-pepper chromatin

Absent or rare mitoses

Little pleomorphism

Atypical carcinoid tumors

• Higher mitotic rate
  • Less than small or large cell carcinomas
• Focal necrosis
• Higher incidence of lymph node and distant metastasis than typical carcinoids
• TP53 mutations in 20-40% of cases
  • Differ from typical carcinoid

Small cell lung carcinomas

• Pale gray
• Centrally located masses
• Extension into the lung parenchyma
• Early involvement of the hilar and mediastinal nodes
• Tumor cells
  • Round to fusiform shape
  • Scant cytoplasm
  • Finely granular chromatin
  • Mitotic figures are frequent

small cell neuroendocrine (oat cell) carcinoma developed in an asbestosis-scarred lung

Autopsy Pathology: A Manual and Atlas

• Neoplastic cells are usually twice the size of resting lymphocytes
• Necrosis is invariably present and may be extensive
• Tumor cells are markedly fragile
• Fragmentation and “crush artifact” in small biopsy specimens
• Nuclear molding
  • Close apposition of tumor cells that have scant cytoplasm
• Express a variety of neuroendocrine markers
• Secrete polypeptide hormones paraneoplastic syndromes

**deeply basophilic cells and areas of necrosis **

basophilic staining of vascular walls due to encrustation by DNA from necrotic tumor cells (Azzopardi effect)

Robbins Basic Pathology

Homework

Dr. Oberndorfer

Learn his life and his contribution to “Istanbul” and “Karzinoide”