Histology and staging of lung cancer & metastatic

HISTOLOGY AND STAGING OF LUNG CANCER &
METASTATIC AND NON METASTATIC
COMPLICATION OF LUNG CANCER
Dr Nikhil Kumar Tailor
Moderator – Dr Suresh Koolwal Sir

HISTOLOGY AND STATING OF LUNG CANCER
 Lung cancer is the most frequently diagnosed
cancer worldwide, with approx. 1.2 millions new
cases reported in 2002,and it is the most
common cause of cancer mortality in males.
 According to 2004 WHO classification lung
cancer were broadly divided into Non Small
Cell cancer lung (NSCLC) and Small Cell lung
cancer (SCLC) for treatment purposes.
 NSCLCs traditionally includes squamous cell
ca, adenocaecinoma and large call carcinoma
but in the broadest sense may include any
epithelial tumor that lacks a small cell
component ,as surgery is the primary treatment
modality for all of these tumors.

WHO CLASSIFICATION OF LUNG TUMORS,2015
WHTAS NEW??????
The most significant changes in this edition involve:-
(1) Use of immunohistochemistry throughout the
classification
(2) A new emphasis on genetic studies, in particular,
integration of molecular testing to help personalize
treatment strategies for advanced lung cancer patients
(3)A new classification for small biopsies and cytology

DIAGNOSTIC LUNG IMMUNOHISTOCHEMISTRY

2015 WHO CLASSIFICATION OF LUNG TUMORS
 1)Epithelial tumors
i) Adenocarcinoma
ii)Squamous cell carcinoma
 2)Neuroendocrine tumors
i) Small cell carcinoma
ii) Large cell neuroendocrine carcinoma
iii) Carcinoid tumors
iv) Preinvasive lesion (Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia)
v) Large cell carcinoma
vi) Adenosquamous carcinoma
vii) Sarcomatoid carcinomas
viii)Other and Unclassified carcinomas (Lymphoepithelioma-like carcinoma and NUT
carcinoma)
ix) Salivary gland-type tumors
x) Papillomas
xi) Adenomas

2015 WHO CLASSIFICATION OF LUNG
TUMORS
 3)Mesenchymal tumors
i. Pulmonary hamartoma
ii. Chondroma
iii. PEComatous tumors
iv. Congenital peribronchial myofibroblastic tumor
v. Diffuse pulmonary lymphangiomatosis
vi. Inflammatory myofibroblastic tumor
vii. Epithelioid hemangioendothelioma
viii. Pleuropulmonary blastoma
ix. Myoepithelial tumors
x. Synovial sarcoma
xi. Pulmonary artery intimal sarcoma
xii. Pulmonary myxoid sarcoma with EWSR1–CREB1 translocation
 4)Lymphohistiocytic tumors
i)Extranodal marginal zone lymphomas of mucosa-associated Lymphoid tissue (MALT lymphoma)
ii)Diffuse large cell lymphoma
iii)Lymphomatoid granulomatosis
iv)Intravascular large B cell lymphomae 9712/3
v)Pulmonary Langerhans cell histiocytosis

5)Tumors of ectopic origin
 i)Germ cell tumors (Teratoma-mature and
Teratoma-immature)
 ii)Intrapulmonary thymoma
 iii)Melanoma
 iv)Meningioma
6)Metastatic tumors

ADENOCARCINOMA
1. Acinar adenocarcinoma
2. Papillary adenocarcinoma
3. Micropapillary adenocarcinoma
4. Solid adenocarcinoma
5. Lepidic adenocarcinoma
6. Invasive mucinous adenocarcinoma A)Mixed
invasive mucinous B) Nonmucinous adenocarcinoma
7. Colloid adenocarcinoma
8. Fetal adenocarcinoma
9. Enteric adenocarcinoma
10. Minimally invasive adenocarcinoma
A)Nonmucinous B) Mucinous
11. Preinvasive lesions
A)Atypical adenomatous hyperplasia
B)Adenocarcinoma in situ i)Nonmucinous ii)Mucinous

SQUAMOUS CELL CARCINOMA
1. Keratinizing squamous cell carcinoma
2. Nonkeratinizing squamous cell carcinoma
3. Basaloid squamous cell carcinoma
4. Preinvasive lesion
A)Squamous cell carcinoma in situ

HISTOLOGY AND STAGING OF LUNG CANCER
2004 WORLD HEALTH ORGANIZATION CLASSIFICATION OF
MALIGNANT EPITHELIAL TUMORS
(A)Squamous cell carcinoma
i) Papillary
ii) Clear cell
iii) Small cell
iv) Basaloid
(B)Small cell carcinoma
Combined small cell carcinoma
(C)Adenocarcinoma
i) Mixed pattern
ii) Acinar
iii) Papillary
iv) Bronchioloalveolar
v) Mucinous
vi)Nonmucinous

 Mixed
 Solid with mucin production
 Fetal adenocarcinoma
 Mucinous (colloid) carcinoma
 Mucinous cystadenocarcinoma
 Signet ring
 Clear cell
 Large cell carcinoma
i) Large cell neuroendocrine carcinoma
ii) Basaloid carcinoma
iii) Lymphoepithelioma-like carcinoma
iv)Clear cell carcinoma
v) Large cell carcinoma, rhabdoid phenotype

 Adenosquamous carcinoma
 Sarcomatoid carcinoma
i)Pleomorphic carcinoma
ii) Spindle cell carcinoma
iii)Giant cell carcinoma
iv)Carcinosarcoma
v)Pulmonary blastoma
 Carcinoid tumor
i) Typical carcinoid tumor
ii)Atypical carcinoid tumor
 Salivary gland tumors
i) Mucoepidermoid carcinoma
ii) Adenoid cystic carcinoma
iii)Epithelial-myoepithelial carcinoma

HISTOLOGY AND STAGING OF LUNG
CANCER
 These four histologies account for approximately 90% of
all epithelial lung cancers.
1.Small Cell Lung Cancer (SCLC)
2.Adenocarcinoma Non Small Cell
lung
carcinoma (NSCLC)
3.Squamous Cell Carcinoma
4.Large Cell Carcinoma

EPITHELIAL CELL LUNG CANCERS
 WESTERN COUNTRIES INDIA-1986-2001
Squamous
Others
Large
Adeno
Adeno
Squamo
us
Large
Small

 Q.Most common form of lung cancer among
women and young adults (<60 years) tends to
??????
ANS :- ADENOCARCINOMA
 In lifetime of never smokers, all histologic forms of
lung cancer can be found, although
adenocarcinoma tends to be predominate.
 The incidence of small cell carcinoma is also on the
decline.

LUNG CANCER IN INDIA
 Non-small-cell lung cancer constitutes 75 - 80% of lung
cancers.
 More than 70 % of them are in Stages III and IV, thus
 curative surgery can not be done in these cases.
 Small-cell lung carcinoma constitute 20% of all lung
cancers .
 Extensive stage in 70% of patients at the time of diagnosis.
 While in many Western countries adenocarcinoma has
become the commonest lung cancer.
 In India it is still squamous cell carcinoma in both
males and females

 There are three histologic degrees of differentiation:
1) well differentiated,
2) moderately differentiated and
3) poorly differentiated.
 If a tumor is largely undifferentiated but contains recognizable
foci of squamous cell carcinoma or adenocarcinoma, it is
classified as a poorly differentiated squamous cell carcinoma
or adenocarcinoma, respectively.
 Some tumors, such as small-cell carcinoma or sarcomatoid
carcinoma are, by definition, poorly differentiated.

Small cell carcinoma
 Poorly differentiated neuroendocrine tumor.
 Highly prevalent in smokers.
 Incidence rates are higher among men than
women.
 Central mass with endobronchial growth.

 May produce specific peptide hormones such as
 - adrenocorticotrophic hormone (ACTH),
 - arginine vasopressin (AVP),
 -atrial natriuretic factor (ANF), and
 -gastrin-releasing peptide (GRP).

 These hormones may be associated with
distinctive
 paraneoplastic syndromes

HISTOLOGY AND STAGING OF LUNG
CANCER
 Differential diagnosis :
 -poorly differentiated non small cell carcinomas
 -neuro endocrine carcinomas,
 -poorly differentiated squamous cell carcinoma
 -nonepithelial tumors
 lymphoma,
 small round blue cell tumors,
 sarcomas (e.g., synovial sarcoma).
: Abeloff's Clinical Oncology, 4th ed
.

SMALL-CELL CARCINOMA. CLASSIC TUMOR CELL
APPEARANCE WITH SCANT AMOUNTS OF CYTOPLASM,
HYPERCHROMATIC NUCLEI, NUCLEAR MOLDING, CRUSH
ARTIFACT, AND NECROSIS.

SMALL DEEPLY BASOPHILIC CELLS AND AREAS
OF NECROSIS

SHOWS CLUSTERS OF TUMOR CELLS FROM A SMALL CELL
CARCINOMA, WITH MOLDING AND NUCLEAR ATYPIA
CHARACTERISTIC OF THIS TUMOR

 Squamous cell carcinomas
 Identical to extrapulmonary (i.e., head and
neck)
 squamous cell carcinomas .
 Occur centrally .
 Classically associated with a history of
smoking.
 Pattern is that of an infiltrating nest of tumor
cells with
 central necrosis , resulting in cavitation.

 Keratin can usually be seen when present.
 Important variants-
 -papillary pattern
 -basaloid variant

 Differential diagnosis
 -reactive processes that may result in
squamous
 metaplasia with reactive atypia such as that
 observed with infection or radiation-induced
injury.

WELL-DIFFERENTIATED SQUAMOUS CELL
CARCINOMA SHOWING KERATINIZATION

A. DESMOPLASTIC RESPONSE WITH NESTS OF INFILTRATING SQUAMOUS CELL CARCINOMA.
B. SQUAMOUS CELL CARCINOMA WITH KERATINIZATION AND INTRACELLULAR BRIDGES.
C.HIGH POWER VIEW OF KERATINIZATION AND INTERCELLULAR BRIDGES.
D. TUMOR CELLS WITH CLEAR CYTOPLASM FROM A SQUAMOUS CELL CARCINOMA

.
:Fishman’s Pulmonary Diseases and Disorders 4th Edition
Histology and Staging of lung cancer

A sputum specimen shows an orange-staining, keratinized squamous
carcinoma cell with a prominent hyperchromatic
nucleus (arrow)
:ROBBINS AND COTRAN PATHOLOGIC BASIS OF DISEASE, 7/E

ADENOCARCINOMAS
 - Peripheral lung locations.
 - It is the most common type of lung cancer
occurring in
 never smokers.
 - Histologically, the tissue may contain :

 glands,
 papillary structure,
 bronchioloalveolar pattern,
 cellular mucin, or
 solid pattern if poorly differentiated.


- Solid and micropapillary patterns in
adenocarcinomas may predict a worse prognosis.
- Variants of adenocarcinomas include
-signet-ring,
-clear cell,
-mucinous,
-fetal adenocarcinomas.
Primarily descriptive
Distinct
Rare
Young smokers
Better Prognosis
: Abeloff's Clinical Oncology, 4th ed

Fetal Adenocarcinoma
Adult tumors consisting entirely of malignant primitive glandular
epithelium have also been described and are termed fetal
adenocarcinomas, now classified as a variant of adenocarcinoma.
This have a histologically distinct, malignant glandular component that
resembles the developing fetal lung at an early gestational age and
malignant cellular stroma with an embryonic appearance.

Adenocarcinoma in situ, nonmucinous. Uniform proliferation of
atypical nonciliated columnar cells with apical nuclei. The tumor
cells are growing along the alveolar septa without invasion.

Invasive mucinous adenocarcinoma-
A. Tall columnar cells with abundant mucinous cytoplasm line the
alveolar septa (former mucinous bronchiolalveolar carcinoma)
B. Invasive pattern in same tumor.

The IASLC/ATS/ERS consensus panel further proposed that invasive
adenocarcinomas be characterized by a predominant subtype and
recognized five patterns:
1)Lepidic predominant,
2)acinar predominant,
3)papillary predominant,
4)micropapillary predominant, and
5)solid predominant with mucin production.
The introduction of a “predominant” pattern was intended as a practical
way to evaluate the characteristic heterogeneity of many adenocarcinomas
and to allow for better stratification than the “mixed subtype.”
The recommendation was based on studies in stage I tumors that had
suggested that these different histologic patterns had prognostic value in a
grading system and that these different patterns can be reproducibly
recognized.

Gland-forming adenocarcinoma
:ROBBINS AND COTRAN PATHOLOGIC BASIS OF
DISEASE, 7/E

Peripheral adenocarcinoma of the lung with pleural puckering.

Bronchioloalveolar carcinoma (BAC)
 subtype of adenocarcinoma
 grows along the alveoli without invasion.
 present radiographically as a single mass, as a
diffuse multinodular lesion, as a fluffy infiltrate.
 on CT scans as a "ground-glass" opacity (GGO).
:Harrison's Principles of Internal Medicine, 18e

Bronchioloalveolar carcinoma, mucinous type. Tall columnar ce
abundant mucinous cytoplasm line the alveolar septa

Large cell carcinomas
 fewer than 10% of lung cancer.
 occur peripherally.
 poorly differentiated carcinomas
 sheets of large malignant cells,
 often with associated necrosis.
 Cytologically, the tumor is also arranged in
syncytial groups and single cells.

Variants of large cell carcinoma:
- basaloid carcinoma- present as an endobronchial
lesion and may resemble a high-grade
neuroendocrine tumor,
- lymphoepithelioma-like carcinoma- similar to the
same-named tumor of other sites and is Epstein-
Barr virus–related.

Large-cell carcinoma of the lung. There is no obvious squamous
differentiation in the form of keratinization or intercellular
bridges and a mucin stain was negative

Basaloid carcinoma of the lung. The tumor cells are relatively
small with hyperchromatic nuclei and scant cytoplasm. The
tendency of the tumor cells to palisade at the periphery of the
tumor nest.

Lymphoepithelioma-like carcinoma. Large malignant cells with
prominent nucleoli are arranged in nests within a lymphoid-rich
stroma

Large cell carcinoma, featuring pleomorphic, anaplastic tumor cells and
absence of squamous or glandular differentiation.
:ROBBINS AND COTRAN PATHOLOGIC BASIS
OF DISEASE, 7/E

T – Primary Tumour (8th Edition)
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 3 cm or less in greatest diameter
surrounded by lung or visceral pleura, without
evidence of main bronchus
T1a(
mi)
Mininally invasive adenocarcinoma
T1a Tumour 1 cm or less in greatest diameter
T1b Tumour more than 1 cm but not more than 2 cm
T1c Tumour more than 2 cm but not more than 3 cm
T2 Tumour more than 3 cm but not more than 5
cm; or tumour with any of the following
features: Involves main bronchus (without
involving the carina), invades visceral pleura,
associated with atelectasis or obstructive
pneumonitis that extends to the hilar region
T2a Tumour more than 3 cm but not more than 4 cm
T2b Tumour more than 4 cm but not more than 5 cm
T3 Tumour more than 5 cm but not more than 7
cm or one tha directly invades any of the
following: chest wall, phrenic nerve, parietal
pericardium, or associated separate tumour
nodule(s) in the same lobe as the primary
T4 Tumours more than 7 cm or one that invades
any of the following: diaphragm, mediastinum,
heart, great vessels, trachea, recurrent
7th TNM Edition

T-descriptor
Every cm counts…
Proposed (TNM 8th)
Up to 1 cm: T1a
>1-2 cm: T1b
>2-3 cm: T1c
>3-4 cm: T2a
>4-5 cm: T2b
>5-7 cm: T3
>7 cm: T4
Previous (TNM 7th)
T1a
T1a
T1b
T2a
T2a
T2b
T3
Rami-Porta R, J Thoracic Oncol, 2015
International Association for the Study of Lung Cancer, 2015

N – Regional Lymph Nodes (8th Edition)
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and
intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or
contralateral scalene or supraclavicular lymph node(s)
M – Distant Metastasis(8th Edition)
M
0
No distant metastasis
M
1
Distant metastasis
M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleaural or
pericardial nodules or malignant pleural or pericardial effusion
M1b Single extrathoracic metastasis in a single organ
M1c Multiple extrathoracic metastases in one or several organs
International Association for the Study of Lung CanceHistology and Staging of lung cancer

7th TNM Edition

N-descriptor
No changes in the TNM 8th Edition…
Exploratory subgrouping (for future validation)
- N1a: Single N1
- N1b: Multiple N1
- N2a1: Single N2 (skip metastasis)
- N2a2: Single N2 + N1
- N2b: Multiple N2
Asamura H et al. J Thoracic Oncol, 2015, in press

M-descriptor (TNM 8th Edition)
Eberhardt W et al. J Thoracic Oncol, 2015, in press
 M1a: as it is
 M1b: single metastasis in a single
organ
 M1c: multiple metastases in a single
organ or in several organs

STAGE T N M
Occult TX N0 M0
0 Tis N0 M0
IA1 T1a(mi)/T1a N0 M0
IA2 T1b N0 M0
IA3 T1c N0 M0
IB T2a N0 M0
IIA T2b N0 M0
IIB T1a-T2b N1 M0
T3 N0 M0
IIIA T1a-T2b N2 M0
T3 N1 M0
T4 N0/N1 M0
IIIB T1a-T2b N3 M0
T3/T4 N2 M0
IIIC T3/T4 N3 M0
IVA Any T Any N M1a/M1b
IVB Any T Any N M1c

STAGE T N M
Occult TX N0 M0
0 Tis N0 M0
IA1 T1a(mi)/T1a N0 M0
IA2 T1b N0 M0
IA3 T1c N0 M0
IB T2a N0 M0
IIA T2b N0 M0
IIB T1a-T2b N1 M0
T3 N0 M0
IIIA T1a-T2b N2 M0
T3 N1 M0
T4 N0/N1 M0
IIIB T1a-T2b N3 M0
T3/T4 N2 M0
IIIC T3/T4 N3 M0
IVA Any T Any N M1a/M1b
IVB Any T Any N M1c
NEW

N0 N1 N2 N3 M1
a
M1
b
M1
c
T1
a
IA1 IIB IIIA IIIB IVA IVA IVB
T1
b
T1
c
T2
a
IB IIB IIIA IIIB IVA IVA IVB
T2
b
IIA IIB IIIA IIIB IVA IVA IVB
T3 IIB IIIA IIIB IIIC IVA IVA IVB
TNM Classification for Lung Cancer
8th Edition 7th Edition
Histology and Staging
of lung cancer

CLINICAL MANIFESTATIONS
 In newly presenting patients 80% are inoperable at
presentation and only 20% may proceed to curative
resection.(much less in india)
 Lung cancer produces more symptoms in adults
than any other cancer(respiratory and constitutional
symptoms)
 There is no clear demarcation between the clinical
pictures of SCLC and NSCLC, however due to
rapid dissemination, the duration of symptoms of
SCLC tends to be shorter.

The spectrum of clinical presentation of lung cancer
can be divided into:
(A)Local manifestations,
(B)Metastatic manifestations and
(C)Non metastatic systemic manifestations (also
called paraneoplastic syndromes).

A)LOCAL MANIFESTATIONS
1.HEMOPTYSIS
 Cardinal symptom of lung cancer (particularly in
an elderly smoker)
 BUT hemoptysis, is neither the most common nor
diagnostic of cancer.
CAUSE :- If scanty - bronchial mucosal ulceration
If massive - when tumor erodes the
bronchial or pulmonary artery
 Chest Xray is usually abnormal in patients with
hemoptysis, but in a small % of patients it may be
normal.
D/D in India????????????

1.HEMOPTYSIS
 Cardinal symptom of lung cancer (particularly in
an elderly smoker)
 BUT hemoptysis, is neither the most common nor
diagnostic of cancer.
CAUSE :- If scanty - bronchial mucosal ulceration
If massive - when tumor erodes the
bronchial or pulmonary artery
 Chest Xray is usually abnormal in patients with
hemoptysis, but in a small % of patients it may be
normal.
D/D in India=>tuberculosis

2.COUGH
 It is the most common presenting symptom of
Ca lung.
 Cough is present in more than 65% patients and
productive cough in more than 25% of patients.
Q.WHEN YOU SUSPECT THE LUNG CANCER??

2.COUGH
 It is the most common presenting symptom of Ca lung.
 Cough is present in more than 65% patients and productive
cough in more than 25% of patients.
Q.WHEN YOU SUSPECT THE LUNG CANCER??
ANS:- 1.The development of new cough
2.A recent increase in the preexisting chronic productive
cough (in a middle aged smoker)
3.Any new cough that persists for more than 2 weeks (in
chronic smoker of more then 35yrs of age)
4.A change in the character of an established cough . In
patients with chronic lung disease)
5.Bronchorrhea- expectoration of large amounts of
mucoid sputum occurs in 10% of patients with
bronchoalveolar carcinoma.

 CAUSE:-a) Endobronchial tumors
i]airway obstruction
ii]postobstructive pneumonia
iii)bronchial mucosal ulceration
b)peripheral tumors
i]by pleural involvement.

3.BREATHLESSNESS
 Like cough, dyspnea is the most commonly reported
symptom in lung cancer
 15% of patients having dyspnea at diagnosis and 65% at
some point during the course of their illness
 CAUSES :- a)Direct involvement of the respiratory
system by the tumor (major airway obstruction,
consolidation,carcinomatous lymphangitis)
b)Indirect respiratory complications of lung
cancer(postobstructive pneumonia, pleural effusion, phrenic
nerve paralysis)
 c) Treatment related (anemia or radiation and
chemotherapy induced lung toxicity) respiratory due to
pulmonary embolism and lung infections.
 d) Comorbid conditions (COPD, asthma, heart
failure,prior lung resection, pericardial effusion and
malnutrition).

4.CHEST PAIN
1)An ill-defined chest discomfort
-> intermittent bronchogenic carcinoma
->aching in quality
2)Definite pleuritic pain
->direct spread of the tumor to the pleural surface
In peripheral neoplasms (adenocarcinoma or large-cell
carcinoma)
( It is the invasion of pain receptors in the parietal pleura by the tumor that
produces typical pleuritic pain which frequently disappears with accumulation of pleural
fluid.)
3)continuous pain -> malignancy spreads beyond the pleura into the chest wall.
4)Shoulder pain -> radiates along the ulnar distribution of arm
-> may originate from local extension of tumor growing in the
apex of the lung involving 8th cervical, and 1st and 2nd thoracic nerves (Pancoast’s or
superior sulcus tumor).

B)METASTATIC MANIFESTATIONS
1.INTRA THORASIC METASTASIS
2.EXTRA THORASIC METASTASIS
A.)SUPERIOR VENA CAVA SYNDROME
 Bronchogenic carcinoma (46 to 75% of all cases of SVC
obstruction)
 The most common histological subtype a/w SVCS is small
cell carcinoma (10% cases) {only 1.7% cases of non small cell
carcinoma}
 Malignancies other then lung cancer includes 20% cases ( like
lymphoma, mesothelioma and metastatic mediastinal
 Lymphadenopathy)
 The remaining 20% patients can have benign etiologies (like
granulomatous mediastinitis,mediastinal fibrosis, intrathoracic
goiter or aneurysm, placement of pacemakers or thrombosis
complicating central venous catheterization.
 Various mechanisms that lead to SVC obstruction include
direct compression by the primary tumor, compression by
enlarged right paratracheal metastatic lymph nodes or
intraluminal thrombosis

CECT SCAN CHEST OF A PATIENT OF SMALL CELL CARCINOMA
SHOWING A THROMBUS IN SUPERIOR VENA CAVA (SHORT ARROW). ENLARGEMENT OF
RIGHT HILAR, SUB-CARINAL AND AZYGOESOPHAGEAL RECESS LYMPH NODES IS ALSO
SEEN.
NOTE PLEURAL EFFUSION ON RIGHT SIDE AND DILATED AZYGOUS
VEIN (LONG ARROW) DUE TO BLOOD DIVERSION.

B)MALIGNANT PLEURAL EFFUSION
 It occur due to direct pleural involvement by
bronchogenic carcinoma occur in 7-15% of lung cancer
patients
 Paramalignant effusions are not the direct result of
malignant involvement of the pleura but are still related
to the primary lung tumor.
It may be due to postobstructive pneumonia
complicated by parapneumonic effusion,pul. embolism
and infarction, chylothorax due to obstruction of the
thoracic duct, radiation therapy and chemotherapy.
 Dyspnea, the most common presenting symptom of
malignant pleural effusion is reported by more than 50%
of patients.

C)RECURRENT LARYNGEAL NERVE PALSY Patients of Lung
cancer may develop hoarseness of voice because of vocal
cord paralysis due to recurrent laryngeal nerve (RLN)
involvement.
It produces cough that lacks explosive quality of a normal
cough resulting in ineffectual expiratory noise (bovine cough).
RLN involvement seen in 2 to 18% of lung cancer patients
D)PHRENIC NERVE PARALYSIS
Diaphragmatic paralysis may complicate lung cancer due to
phrenic nerve entrapment by the tumor in the mediastinum.
In bilateral phrenic nerve paralysis patients have orthopnea and a
downhill disease course. (Asymptomatic in Unilateral Paralysis)

E) Pancoast’s Syndrome
 Pancoast tumor (also known as thoracic inlet or
superior sulcus tumor) is a complication of local
extension of an Apical lung cancer.
 It is usually associated with squamous cell lung
cancer, comprise less than 5% of all lung cancers
 The syndrome results from the involvement of lower
part of brachial plexus by the tumor producing pain
in the lower part of shoulder and inner aspect of
arm along C8, T1 and T2 distribution that may be
associated with sensory loss, weakness and
wasting of the small muscles of hand.

F)HORNER’S SYNDROME
 Horner’s syndrome is a consequence of invasion by the
apical lung cancer of the C7 & T1 ganglion (stellate
ganglion)
 It may be observed in 20 to 50% of bronchogenic
carcinoma.
 Its clinical components include
 Ipsilateral ptosis, miosis, enopthalmos and lack of facial
sweating (anhidrosis).
 It is usually a complication of Pancoast Tumor, but may
very rarely complicate spontaneous pneumothorax
that produces mediastinal shift and consequent
mechanical traction of the sympathetic ganglion.

G) Involvement of Heart and Pericardium
 Cardiac and pericardial metastases from bronchogenic
Ca usually occur by direct lymphatic spread.
 In lung cancer, cardiac involvement is reported in 15%
of cases (Pericardium is the most common site)
 Some patients may even develop cardiac tamponade
H) Involvement of Esophagus
 Dysphagia due to esophageal compression by
massively enlarged metastatic hilar and mediastinal
nodes is an unusual clinical feature of lung cancer and
is generally a late symptom.

 Metastases from lung cancer may occur in virtually
every organ system but are more commonly in
brain, bones,liver, adrenal glands and lymph
nodes.
 Extrathoracic spread of bronchogenic carcinoma
makes a patient clearly inoperable.
 Metastatic disease in general, is more common
with small cell than with non-small cell lung
cancer.

A)BRAIN METASTASIS
 Intracranial metastases constitute the first clinical
problem in 10% of SCLC patients the cumulative
incidence at 2 years is more than 50%.(33% of
patients in NSCLC)
 Squamous cell lung cancer >adenocarcinoma and
large cell carcinomas.
 It usually presents with headache, nausea and
vomiting, rarely with impaired intellectual function or
personality changes.
 Seizures and motor or sensory neurological deficits
may occur.

B)SKELETAL METASTASIS
 Bronchogenic carcinoma frequently metastasizes to
vertebrae and ribs however, any bone in the body
may be involved.
 Most Common symptom is pain which is invariably
progressive.
 There is higher incidence of skeletal metastases
with SCLC than with NSCLC.
C)SPINAL CORD COMPRESSION
 Due to epidural or vertebral metastases may
complicate lung cancer producing an oncologic
emergency.Such patients need immediate
assessment by a neurologist.

D)ADRENAL METASTASIS
 It is common with small cell carcinoma, but rarely
produces adrenal insufficiency.
 Solitary adrenal metastasis if resected along with
primary lung tumor has a better prognosis with a 3-
year survival rate of 38%.
 Surgical resection for solitary adrenal metastases,
in comparison to chemotherapy alone for usual
disseminated metastatic disease, prolongs the
median survival, resulting in survival rate of 17% at
15 years.

CORONAL CONTRAST CT SCAN REVEALING A RIGHT HILAR
BRONCHOGENIC CARCINOMA (SHORT THICK ARROW) WITH
METASTASIS IN THE LEFT
ADRENAL GLAND (LONG THIN ARROW)

E)HEPATIC METASTASIS
 Liver metastases occur commonly with lung cancer their
presence carries a very poor prognosis.
 Patient usually complains of fatigue and weight loss;
 On physical examination the liver is hard and irregularly
enlarged.
 However, liver function test results are seldom
abnormal until the metastases are numerous and large.
 Both USG and CT scan are equally good in picking
up hepatic metastases, a finding that makes the
patient inoperable.

C.NON METASTATIC SYSTEMIC MANIFESTATIONS
PARANEOPLASTIC SYNDROME
 A group of clinical disorders that are associated with
malignant diseases, not directly related to the physical
effects of primary or metastatic tumors are known as
paraneoplastic syndromes.
 These syndromes occur in 10% of patients with lung
cancer.
 The pathogenetic mechanisms by which paraneoplastic
syndromes occur are not fully understood in all cases,
but in many it appears to relate with either the
production of biologically active substances by the
tumor itself (e.g. polypeptide hormones or
cytokines) or in response to the tumor (e.g.
antibodies).

C.NON METASTATIC SYSTEMIC MANIFESTATIONS
 The size of the primary tumor has no impact on
the extent of paraneoplastic symptoms.
 The most common tumors producing
paraneoplastic syndromes in humans are lung
cancers.
 These are more frequently associated with
small cell cancer but can be seen with any
histological type.
 With successful treatment of lung cancer, the
paraneoplastic phenomena usually resolve.

C)NON METASTATIC SYSTEMIC MANIFESTATIONS
1.ENDROCRINE SYNDROMES
a)Cushing Syndrome
 Lung cancer is the most common source of ectopic
secretion of ACTH) among nonpituitary neoplasms,usually produced by small cell
carcinoma (85%), uncommonly by carcinoid tumors (10%) and adenocarcinoma (5%) of
the lung.
 MECHANISM – 1)Lung cancer cells express precursor gene, Pro-opiomelanocortin
(POMC) from which ACTH is derived. Increased serum ACTH level seen up to 50% of
patients with bronchogenic carcinoma.
2)Cushing syndrome has been described in 1 to 5% of patients with
SCLC.
3)It may rarely be caused by ectopic production of Corticotropin
Releasing Hormone (CRH) which leads to excessive ACTH secretion from the pituitary
gland.
 These patients usually do not develop the classical features of Cushing’s syndrome ,
Diagnosis is usually suggested by features of acute hypercortisolism such as
hypertension, hyperglycemia and hypokalemic alkalosis.Muscle weakness associated
with hypokalemia, may be profound. Proximal myopathy and edema are commonly found
on physical examination
 TREATMENT -Chemotherapy with or without irradiation for small cell carcinoma and
surgical resection for carcinoid tumors should be offered to the patient as early as
possible.
When the tumor cannot be resected or ectopic ACTH secretion cannot be controlled,
bilateral adrenalectomy may be effective in some patients.
Ketoconazole, metapyrone, aminoglutethimide or octreotide may be used to induce
effective steroid synthesis inhibition.
Ectopic ACTH production by small cell carcinoma of lung is associated with aggressive
tumor behavior, hence poor prognosis.

b)Hypercalcemia
 Overall, 10% patients of lung cancer have hypercalcemia,which
usually complicates SCC that secretes parathyroid hormone-
related peptide (PTH-rP). (Hypercalcemia may also be seen with
adenocarcinoma, but it is extremely rare in patients with small cell carcinoma of
lung.)
 MECHANISM- 1) Primarily by ectopic production of parathyroid hormone-
related peptide (PTH-rP),
2)uncommonly by osteolytic metastatic deposits
3)very rarely by ectopic secretion of Parathyroid Hormone (PTH).
 The diagnosis of PTH-rP associated paraneoplastic syndrome is
considered if serum calcium level exceeds 10.5 mg/dl.
 An elevated PTH-rP level confirms the diagnosis in the absence of bone
metastases.
 D/D - sarcoidosis,hyperthyroidism and drugs like thiazides, lithium and
vitamin D.
 Primary hyperparathyroidism should be excluded by PTH
radioimmunoassay.
 TREATMENT - Control or treatment of underlying lung cancer constitutes
the most effective method of managing hypercalcemia.

c)Syndrome of Inappropriate Antidiuretic
Hormone (SIADH)
 Elevated Antidiuretic Hormone (ADH) levels and impaired water
handling are found in 30 to 70% of patients with lung cancer, but the
production of excess ADH does not always produce symptoms.
 The SIADH production is mainly A/W small cell lung cancer.
 MECHANISM – 1)Ectopic production by lung cancer cells
2) Inappropriate peripheral baroreceptor
stimulation of ADH release from the hypothalamus.
TREATMENT – 1) Strict fluid restriction (i.e. 500 ml / day)
2) demeclocycline (600 to 1200 mg)
3) Severe symptomatic hyponatremia is treated with
hypertonic saline (3%) along with intravenous loop diuretic that
enhance net free-water clearance.

3.NEUROLOGICAL SYNDROMES
 It affect 5% of lung cancer patients,
associated almost exclusively with small cell
carcinoma.
 The severity of neurologic symptoms is unrelated to
the tumor bulk; more often seen in patients with
limited disease.
 The syndromes develop through autoimmune
mechanisms as nearly all are associated with the
presence of type 1 antineuronal nuclear antibodies
(also known as anti-Hu antibodies).

a)Eaton-Lambert Syndrome
 It affects up to 5% of patients with Small cell lung cancer
uncommonly complicates non-small cell lung cancer.
MECHANISM -It is caused by the formation of IgG
autoantibodies directed at voltage gated P/Q
calcium channels involved in the release of
acetylcholine at nerve terminals thereby producing
a functional blockade at neuromuscular junction.
Diagnosis -Demonstration of IgG autoantibodies in
the serum of patients with small cell lung cancer
confirms the diagnosis.
 TREATMENT – It usually resolves with chemotherapy of small
cell carcinoma.

b)Encephalomyelitis and Sensory neuropathy
 This syndrome is a/w small cell lung cancer
MECHANISM - The neuronal damage is mediated by IgG anti-
Hu antibody, also known as Anti-Neuronal Nuclear Antibody
(ANNA-1).
Diagnosis- MRI images which show increased T2 signal in the
affected areas of the brain and is confirmed by demonstration
of anti-Hu antibody in the serum.
TREATMENT - Removal of culprit IgG by plasmapheresis and
corticosteroids administration is effective in only 15% of these
patients.

C)NON METASTATIC SYSTEMIC
MANIFESTATIONS
c)Paraneoplastic cerebellar degeneration
 Seen in patients of small cell lung cancer
MECHANISM – Cerebellar degeneration leading to nystagmus,
impaired coordination and ataxia.
These patients have anti-Hu antibodies in
serum and frequently tend to develop encephalitis or sensory
neuropathy.
d)Cancer Associated Retinopathy
 It occurs as the first sign of occult small cell carcinoma of lung.
MECHANISM – Ganglion cells of retina are characteristically
damaged by binding of auto-antibodies to recoverin, a
photoreceptor-specific protein.
Diagnosis - demonstration of anti-recoverin antibody.
 TREATMENT - Systemic steroids but not to the chemotherapy
for primary tumor.

MANIFESTATIONS
e) Opsoclonus and Myoclonus
 This rare paraneoplastic syndrome is associated with both
small cell and non-small cell lung cancers.
 The patient shows rapid involuntary conjugate eye
movements in both the horizontal and the vertical directions.
 Some SCLC patients with this syndrome have anti-Hu
antibody in serum.

MANIFESTATIONS
4.HEMATOLOGICAL SYNDROMES
a) Granulocytosis
 Granulocytosis with absolute white cell count of 10,000 to
25,000 occurs in 20% patients of non-small cell lung cancer.
 MECHANISM – Not known although some non-small cell tumors
may produce various cytokines like Interleukin-6 (IL-
6),granulocyte colony-stimulating factor (G-CSF) or
granulocytemonocyte colony-stimulating factor (GM-CSF).
(neutrophilia and eosinophilia also seen)
 Bone marrow biopsy is usually normal.
Diagnosis is made on exclusion.
b) Thrombocytosis
It is common phenomenon observed in 40% patients of both small
cell and non-small cell carcinomas.
MECHANSIM - Not known, it is most likely linked to a
megakaryocyte cytokine, i.e IL-6.
Diagnosis - if bone marrow biopsy is normal and platelet count
exceeds 500,000/mm.2

MANIFESTATIONS
4.HEMATOLOGICAL SYNDROMES
c) Thromboembolism
MECHANISM - Not known, no proteins or cytokines
have been linked to it.
It can complicate both non-small cell and small cell
cancers of lung.
Trousseau’s syndrome or recurrent migratory
venous thrombophlebitis is more commonly
associated with bronchogenic carcinoma than
pancreatic or other gastrointestinal cancers.
TREATMENT - Isolated venous thrombosis is treated
with oral warfarin, but long term heparin is more
effective than warfarin in recurrent thrombosis
(Trousseau’s syndrome).

MANIFESTATIONS
5.SKELETAL SYNDROMES
a)Digital Clubbing And Hypertrophic Osteoarthropathy
 Digital clubbing which is, more common among wowen than man (40 vs
19%), is observed in more than 30% patients and Hypertrophic Pulmonary
Osteoarthropathy (HPOA) in up to 10% patients of nonsmall cell lung cancer.
 MECHANISM - 1)Neurogenic, hormonal and vascular
mechanisms.
2)Overexpression of Vascular Endothelial
Growth Factor (VEGF) has been implicated in the pathogenesis.
Bone scans show active deposition of new bone along the inner
aspect of periostium.
TREATMENT – 1) HPOA responds well to surgical resection of the
primary lung tumor.
2) In unresectable tumors, corticosteroids and
NSAIDs drugs are used for symptomatic relief.
3)Vagotomy can also be done, if thoracotomy is
undertaken with an attempt to cure.

MANIFESTATIONS
5.MISCELLANEOUS
1)Renal - glomerulonephritis, nephrotic Syndrome
2)Vasculitic - systemic lupus erythematosus
3)Systemic - fever, anorexia, cachexia
4)Metabolic - hypouricemia, lactic acidosis
5)Cutaneous manifestations - dermatomyositis-
polymyositis, scleroderma, acanthosis nigricans,
papillary dermatosis, erythema gyratum repens,
erythema multiforme, exfoliative dermatitis, Sweet
syndrome, pruritus and urticaria.
6) Gynecomastia - Seen in Adenocarcinoma and
large cell bronchogenic carcinoma (tumor cell
production of HCG, which results in overproduction
of testicular estrogen.

Histology and staging of lung cancer & metastatic

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