lung cancer - unibo.it · lung cancer prof. pier paolo piccaluga department of experimental,...
TRANSCRIPT
1
Pathologic Anatomy
Lung Cancer
Prof. Pier Paolo Piccaluga
Department of Experimental, Diagnostic and Specialty Medicine, Bologna University
Department of Pathology JKUAT, Nairobi
Estimated age-standardized incidence and mortality rates (Europe and World) in 2018,
worldwide, both sexes, all ages
EUCAN, IARC/WHO November 2014
2
Cancer Word Incidence
Breast 46,3
Prostate 29,3
Lung 22,5
Colorectum 19,7
Cervix uteri 13,1
Stomach 11,1
Liver 9,3
Corpus uteri 8,4
Thyroid 6,7
Ovary 6,6
Cancer World Mortality
Lung 18,6
Breast 13
Colorectum 8,9
Liver 8,5
Stomach 8,2
Prostate 7,6
Cervix uteri 6,9
Thyroid 4,2
Ovary 3,9
Corpus uteri 1,8
IARC/WHO
Estimated number of incident cases and deaths worldwide, both sexes, all ages
IARC/WHO
Estimated number of incident cases and deaths, both sexes, all ages in Italy
IARC/WHO
Epidemiology
• Most common cancer in both men and women
– 2nd in USA (In men, prostate cancer is more common, while in women breast cancer is more common.
– 3rd in Europe (prostate, breast, colorectal)
• About 13% of all new cancers are lung cancers in USA.
• Leading cause of cancer: more people die of lung cancer than of colon, breast, and prostate cancers combined.
American Cancer Society, 2019
Epidemiology
• Lung cancer mainly occurs in older people.
• Most people diagnosed with lung cancer are 65 or older;
• A very small number of people diagnosed are younger than 45.
• The average age of people when diagnosed is about 70.
American Cancer Society, 2019
Risk factors
Risk factors you can change
• Tobacco smoke
– 80% of deaths in smokers
– Number of cigarettes/day
– Total time of exposure
– Cigar and pipe = cigarettes
– Light cigarettes = standard cigarettes
• Secondhand smoke
• Exposure to radon
– Second cause and first in non-smokers
• Exposure to asbestos
– Synergistic with tobacco smoke
Risk factors 2
Risk factors you can change
• Exposure to other cancer-causing agents in the workplace– Radiocatives (uranium)
– Inhaled chemicals such as arsenic, beryllium, cadmium, silica, vinylchloride, nickel compounds, chromiumcompounds, coal products, mustard gas, and chloromethyl ethers
– Diesel exhaust
• Taking certain dietary supplements– Avoid Beta carotene in smokers
• Arsenic in drinking water– Asia, South America
Risk factors 3
Risk factors you cannot change
• Previous radiation therapy to the lungs
• Air pollution– 5% of lung cancer deaths
• Personal or family history of lung cancer
Factors with uncertain or unproven effects on lung cancer risk
• Smoking marijuana
• Talc mills
• E-cigarettes
Direct effects of nicotine on cell proliferation
Classificazione WHOWHO Classification 2015
J T
ho
rac
On
col.
20
15
;10
: 12
43–
12
60
Epithelial tumors
1.Adenocarcinoma
•Lepidic adenocarcinoma
•Acinar adenocarcinoma
•Papillary adenocarcinoma
•Micropapillary adenocarcinoma
•Solid adenocarcinoma
•Invasive mucinous adenocarcinoma
– Mixed invasive mucinous and non-mucinous adenocarcinoma
•Colloid adenocarcinoma
•Fetal adenocarcinoma
•Enteric adenocarcinoma
•Minimally invasive adenocarcinoma
– Nonmucinous
– Mucinous
•Preinvasive lesions
– Atypical adenomatous hyperplasia
– Adenocarcinoma in situ
• Nonmucinous
• Mucinous
2. Squamous cell carcinoma
• Keratinizing squamous cell carcinoma
• Nonkeratinizing squamous cell carcinoma
• Basaloid squamous cell carcinoma
• Preinvasive lesion
– Squamous cell carcinoma in situ
3. Neuroendocrine tumors
• Small cell carcinoma
– Combined small cell carcinoma
• Large cell neuroendocrine carcinoma
– Combined large cell neuroendocrine carcinoma
• Carcinoid tumors
– Typical carcinoid tumor
– Atypical carcinoid tumor
• Preinvasive lesion
– Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
4. Other types
• Large cell carcinoma
• Adenosquamous carcinoma
• Sarcomatoid carcinomas
• Salivary gland-type tumors
– Mucoepidermoid carcinoma
– Adenoid cystic carcinoma
– Epithelial-myoepithelial carcinoma
– Pleomorphic adenoma
• Papillomas
• Adenomas
Mesenchymal tumors
Lymphohistiocytic tumors
Tumors of ectopic origin
Metatstatic tumors
Staging
• Stage I: cancer is located only in the lungs and has not spread to any lymph nodes.
• Stage II: The cancer is in the lung and nearby lymph nodes.
• Stage III: Cancer is found in the lung and in the lymph nodes in the middle of the chest, (locally advanced disease)
– stage IIIA: cancer has spread only to lymph nodes on the same side of the chest where the cancer started.
– stage IIIB: cancer has spread to the lymph nodes on the opposite side of the chest, or above the collar bone.
• Stage IV: advanced disease. Cancer has spread to both lungs, to fluid in the area around the lungs, or to another part of the body, such as the liver or other organs.
• Limited stage: In this stage, cancer is found on one side of the chest, involving just one part of the lung and nearby lymph nodes.
• Extensive stage: In this stage, cancer has spread to other regions of the chest or other parts of the body.
Non small cell lunga cancer (NSCLC) Small cell lunga cancer (SCLC)
Staging and Survival
SEER stage 5-year relative survival rate
Localized 60%
Regional 33%
Distant 6%
All SEER stagescombined
23%
EER stage 5-year relative survival rate
Localized 29%
Regional 15%
Distant 3%
All SEER stages combined
6%
Non small cell lunga cancer (NSCLC) Small cell lunga cancer (SCLC)
J Thorac Oncol. 2015;10: 1243–1260
Adenocarcinoma
Adenocarcinoma
• Def: invasive, malignant, epithelial tumor with glandular differentiation or mucin production
• 2° in the world by frequency; 1st in USA
Atypical adenomatous hyperplasia
Smll lesion (<5mm): dysplastic
pneumocytes lining alveolar walls,
that are mildly fibrotic.
It can be single or multiple
(sometimes close to a cancer area)
Adenocarcinoma
Adenocarcinoma Morphology
• Different growth patterns
– Acinar
– Lepidic
– Papillary
– Micropapillary
– Solid
With mucin
production
Adenocarcinoma Morphology
• From well differentiated
(obvious glandular
elements) to papillary
(resembling other
cancers) or solid masses
with occasional mucin
production
Colloid adenocarcinoma
• Tissue architecture effaced by large mucous «lakes»
• Small aggregates of neoplastic cells
• DD vs. metastatic lesions
Minimally invasive adenocarcinoma (MIA)
J Thorac Oncol. 2015;10: 1243–1260
Adenocarcinoma in situ (AIS)
J Thorac Oncol. 2015;10: 1243–1260
Spread Through Air Spaces
• An additional pattern of invasion is now clearly recognized consisting of spread through air spaces (STAS).
• STAS consists of micropapillary clusters, solid nests, or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma
• It probably contributes to the significantly increased recurrence rate for patients with small stage 1 adenocarcinomas who undergo limited resections and the worse prognosis observed by others.
• STAS is now incorporated into the definition of invasion that is used to separate lepidic adenocarcinomas from MIA and AIS.
• STAS is a pattern of invasion to be reported similar to visceral pleural and vascular invasion
Spread Through Air Spaces
Invasion of adenocarcinoma in the pattern of spread through air spaces (STAS).
A, Tumor cells are presentwithin airspaces in the lung parenchyma beyond the edgeof the tumor (arrows).
B, These consists of micropapillaryclusters and single cells (arrows).
J Thorac Oncol. 2015;10: 1243–1260
Squamous cell Carcinoma
Squamous cell Carcinoma
• Def: invasive, malignant, epithelial tumor with squamous differentiation
• Most commonly in males
• Strong association with tobacco smoke
• Central lesion (segmental/subsegmental)
Sqamous cell metaplasia/dysplasia
• Squamous metaplasia of the airway epithelium is characterized by replacement of bronchiolar or bronchial epithelium with squamous epithelium
• Squamous metaplasia of the alveolar epithelium is characterized by replacement of type I and type II pneumocytes with squamous epithelium.
• Mild, moderate, severe
Squamous cell carcinoma in situ
• Asymptomatic
• Not detectable at imaging
• Atypical cells at cytology (sputum, BAL)
• Eventually followed by invasive carcinoma
Epithelial cytological atypia is severe with mitoses seen at all
levels. Cell maturation is absent.
Squamous cell carcinomaGross pathology
• Different growth patterns
1.Exophytic
– Into the bronchial lumen
– Distal atelectasia
– Infections
2.Infiltrating peribronchial tissues
3.Dislocating lung tissue forming large, caulilflower like masses
Squamous cell carcinomaHistology
• SqCC is characterized by:
1.Keratinization
– Squamous pearls
– Individual cells with markedly eosinophilic dense cytoplasm
2.Intercellular bridges
• Well, moderately, and scarcely differentiated became keratinizing and nonkeratinizing
keratinizing
nonkeratinizing
Basaloid SqCC
• Uncommon histological variant composed of cells exhibiting cytological and tissue architectural features of both squamous cell lung carcinoma and basal cell carcinoma
TTF-1 positiveCD56 positiveChromogranin positiveSynaptophysin positive
CK5/6 positiveCK7 negative
Large cell carcinoma
Large cell carcinoma
• Indifferentiated large cell tumor (anaplastic)
• No glandular/squamous differentiation
• Aboundant cytoplasm
• Vescicular chromatin
• Evident nucleulus
Other types of epithelial tumors
Salivary gland-type tumors
• Rare
• All ages, no gender preference
• More often endoluminal
• Morphologically analogue to those arising in salivary glands
• Origin: bronchial, submucosal glands
• DD vs. metastasis from salivary glands
• Overall indolent behavior
– Adenoid cystic carcinoma: poor response to radiotherapy and chemotherapy
Adenosquamous carcinoma• Association of the two histological variants
• At leat 10% constituted by each type
• Sual overlap between the histological types
• Possibly more aggressive
Adenosquamous
carcinoma
Sarcomatoid carcinoma
• Morphologically simulating a sarcoma
• Fusated cells
• Vorticoid/spindle cell appearnce
• IHC necessary for diagnosis
Neuroendocrine tumors
Neuroendocrine cells in the lung
• Kultscitsky cells (Feyrter cells/APUD ssystem)
– Basal layer bronchial epithelium
– Sub-bronchial glands
• Single elemnts or groups (neuroepithelial bodies)
• Increasing from bronchus to bronchioles
– Rare in terminal bronchioles and alveoli
neuroepithelial body
Diffuse, Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH)
• Currently considered a possible pre- invasive lesion
• Generalizedproliferation of scattered single neuroendocrine cells, forming small nodules or linear proliferations
Neuroendocrine tumors
Generally characterized by:
• Organoid growth pattern
• Presence of neurosecretory
granules
• Positive staining for
neuroendocrine markers
Carcinoid tumors
• 5-10% of lung tumors
• Low grade malignancies
• Age often <40 y
• M=F
• Mostly 3-4 cm in the main bronchi
– Peripheral as solid nodules
– Infiltrating the brnchial wall
Carcinoid tumorsHistology
• Organoid
• Trabecular
• Palisanding
• Ribbon
• Rosette like
• Cells separated by thin fibrovascular stroma
• Uniform rounded shape
• Eosinophilic cytoplasm
Typical vs. atypical carcinoid
• Mitosis 2-10/10 HPF
• Spotss of necrosis
• Increased pleomorphism
• More prominent nucleoli
• More likely to have
– Disorganized growth
– Lymphoatic invasion
• Mitosis <2 /10 HPF
• Lack of necrosis
Carcinoid tumorsClinical features
Depends on:• Intraluminal growth (obstruction)• Capacity to give metastasis• Production and secretion of
vasoactive amines (carcinoid syndrome)(10%)– Diarrhea– Flushing– Cianosis
• 95% OS at 5y for typical vs. 70% for atypical
Lerge cell neuroendocrine carcinoma (LCNEC)
• Anaplastic
• Large cells
• Prominent nucleoli
• The differentiation between LCNEC and SCLC can be difficult in some cases
• 30% survival at 5y
Transl Lung Cancer Res. 2017 Oct; 6(5): 530–539.
Small cell lung carcinoma
Small cell lung carcinoma (SCLC)
• Most aggressive lung cancer
• 5y survival 5%
• Early metastasis
• Age: 50-70 years
• >98% in smokers
• Central or peripheral
Small cell carcinomaHistology
• Relatevily small cells with scant cytoplasm
• Ill-defined cell borders
• Granular chromatin
• No nucleoli
• Cells can be:
– Round
– Oval
– Spindle
• High mitotic rate
Small cell lung carcinomaHistology
• Cell growth in clusters
• Extensive necrosis
• Neurosecretory granules
• Neuroendocrine markers
• Hormone secretion (PTH)
• BCL2 expression (90%)
Immunophenotype of Lung Cancers
Immunohistochemistry 1
• Adenocarcinoma vs. Squamous cell carcinoma
– Adenocarcinoma: TTF-1 (NKX2-1)* and/or Napsin A
– Squamous cell carcinoma: p40, CK5/6, and TP63*
• * not very specific!
TTF1
NAP1
KRTSA
TP63
Immunohistochemistry 2
• Neuroendocrine markers: CHGA (chromogranin A), SYP (synaptophysin), NCAM1 (CD56), or INSM1.
INSM1
Immunohistochemistry 3
Carcinoid, Chromogranin A
Immunohistochemistry 4
ALK
ROS1
RET
EGFR
Markers of genetic lesions/therapeutic targets
PD1-PDL1 axis inhibitors
PD-L1 (CD274) is an immune modulator that promotes immunosuppression by
binding to PD-1 (PDCD1). PD-L1 on the surface of tumor cells inhibits an immune-
mediated attack by binding to PD-1 on cytotoxic T-cells
Genetics of lung cancer
Clinical relevance of genetic lesions
10-15%
Targeting EGF/EGFR-Erlotinib
- Gefitinib
Cell proliferation
Cell survival
Molecular subsets of lung adenocarcinoma
2%
ALK translocations in lung cancer
Prognosis and outcome
Extension/spread
• Extension to pleural surface and pericardium
• Bronchial, tracheal and mediastanil nodes most often involved
• Metastasis
– Lymphoatic
– Ematogenous
– Brain (20%), bone/bone marrow (20%), liver (30-50%), adrenal glands (>50%)…
– Early event (but not in SqCC)
Survival rates by stage and by hostology
http://dx.doi.org/10.1136/thoraxjnl-2013-203884
February 2015Oncology letters 9(2):563-568
Thank you
Q&A