1. Update in Lung Cancer pathology
Dr. Yasser Mohamed El-Dowik
Lecturer of pathology- Al-Azhar University 

2. General and Clinical Features

3. Lung cancer is the second most common cancer in both men and women.
The American Cancer Society reported that in 2015 there were 221,200 new cases and 158,040 deaths from lung cancer in the United States
Lung cancer mainly occurs in older people more than 98% of patient above 45 years of age or older

4. In Egypt, lung cancer is one of the most common cancers, 5. 0%-7
In Egypt, lung cancer is one of the most common cancers, 5.0%-7.0% of all cancers .
It's incidence increased during [5], from 11.9 to 63.3/ populations for men and from 3.7 to 13.8/ populations for women

5. Risk factors
-Many risk factors but The cigarette smoking is the main risk factors for lung cancer.
linear correlation between the severity of the changes and the amount of cigarette consumption
-Approximately 10%–15% of cases of lung carcinoma occur in non-smokers. three-fourths are women, and a high proportion of cases show an adenocarcinoma histology
-Another factor thought to be related to the development of carcinoma is pulmonary fibrosis.

6. Symptoms and signs
Most lung cancers are in a relatively advanced stage by the time of diagnosis.
About 60% are inoperable
Symptoms and signs develop relatively late , related to partial or complete bronchial obstruction, and may lead to confusion with a primary inflammatory process.
Lung neoplasms are sometimes associated with extrapulmonary manifestations (paraneoplastic syndromes) remote from the sites of primary or metastatic tumor.

7. Pathology of lung cancer

8. Pathology of lung cancer has expanded to cover both tissue diagnosis and selection of specific subtypes of lung cancers for further molecular testing.

9. Confirmatory histologic diagnosis directs surgical resection of early-stage disease,
whereas pathologic classification and molecular testing enable selection of tumor type–tailored adjvuant therapy and genotype-based treatment regimen to improve the survivals of advanced-stage patients.

10. significant update in lung cancer classification has occurred for lung adenocarcinomas based on better understanding of tumor biology.
This update is manifested by streamlined classification for small biopsies and cytology specimens, with special emphasis on separating adenocarcinomas from the rest of the lung cancers in order to effectively screen cases responsive to current mutation-driven therapeutic paradigms.

11. 2004>HE, mucin and IHC and Genitics for resection
WHO classifications
1967 >HE
1981>HE &mucin.
1999>HE, mucin and IHC
2004>HE, mucin and IHC and Genitics for resection
2015>HE, mucin and IHC and Genitics and radiology (included small specimens)

12. The most significant changes in WHO Classification of Tumours of the Lung,fourth edition,2015
(1) adoption of the adenocarcinoma carcinoma classification proposed by the panel of the International Association for the Study of Lung Cancer/ATS/European Respiratory Society;
(2) reclassifying squamous carcinoma into keratinizing, nonkeratinizing, and basaloid subtypes;
(3) grouping neuroendocrine tumors (small cell, carcinoid, and large cell neuroendocrine carcinoma) together into one category;
(4) restricting the diagnosis of large cell carcinoma only to resected tumors that lack any clear differentiation by morphology or immunohistochemistry;
(5) new classification for small biopsies and cytology specimens.

14. ADENOCARCINOMA

15. most common type of lung cancer about 40% of lung cancers, 60% of the NSCC , more than 70% of surgically resected cases
Common ,peripherally located mass with central fibrosis and pleural puckering,
may be centrally located mass, diffuse lobar consolidation, bilateral multinodular distribution, and pleural thickening
Multiple gene alterations can occur in adenocarcinomas, with approved molecular targeted therapy available to improve patient survival
There has been significant refinement in adenocarcinoma classification in recent years based on close pathologic and clinical correlation

16. AIS(Adenocacinoma insitu)
less than 3 cm with neoplastic cells growing along preexisting alveolar structures (lepidic growth pattern) , without evidence of stromal, vascular, or pleural invasion.
(Lepidic is a descriptive term for rind or membranous growth pattern and is now specifically used to describe tumor cells proliferating along the surface of intact alveolar walls)
Most AISs are the nonmucinous type, with mild to moderate pleomorphic cuboidal to columnar tumor cells linearly lining alveolar walls

18. the tumor contains a small focus (<5 mm) of invasive growth,
Minimally Invasive Adenocarcinoma
the tumor contains a small focus (<5 mm) of invasive growth,
can manifest as nonlepidic growth, such as acinar, papillary, micropapillary, or solid patterns.
lack of more advanced invasive pattern, such as tumor necrosis, lymphovascular invasion, and pleural invasion.
Both types of tumor are low grade and have 100% 5-year survival rate

20. Invasive Adenocarcinoma
more than 5 mm of invasion (presence of desmoplastic or myofibroblastic stroma); spread through air spaces; lymphatic or vascular invasion; pleural invasion; tumor necrosis.
Mostly mixed morphological subtypes , classified according to the predominant architectural structures
(lepidic, acinar common type of adenocarcinoma with tumor cells arranged in classic glandular structure on a fibroelastic stroma , papillary, micropapillary, and solid patterns patternless sheets

21. This architectural-driven classification has prognostic significance,
most favorable prognosis for lepidic-predominant adenocarcinomas,
intermediate survival rate for acinar and papillary predominant adenocarcinomas,
poor prognosis for solid and micropapillary predominant adenocarcinomas

22. colloid and fetal adenocarcinoma
Rare Variants of Invasive Adenocarcinoma
invasive mucinous adenocarcinoma ,Frequently multicentric and the tumor cells lack expression of TTF-1
colloid and fetal adenocarcinoma
enteric adenocarcinoma, should be distinguished from metastatic colorectal adenocarcinoma

25. Histologic subtyping for surgeonResected lung nodules that are diagnosed as adenocarcinoma are first classified based on the degree of lepidic growth pattern. Tumors with lepidic predominant growth are composed of 3 groups: adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LEP). AIS is defined as a ≤3 cm tumor with a pure lepidic pattern (no invasion). MIA is defined as a ≤3 cm tumor with ≤5 mm stromal invasion. LEP is defined as a tumor that is >3 cm in total size and/or >5 mm in invasive size with a non-mucinous lepidic predominant pattern. Each histologic pattern % is recorded in 5% increments. When showing conventional lung adenocarcinoma morphology, non-lepidic predominant invasive adenocarcinomas are classified into acinar (ACI), papillary (PAP), micropapillary (MIP), or solid subtype (SOL) on the basis of predominant histologic pattern. Variant histologies included invasive mucinous, colloid, fetal and enteric subtype.

26. SQUAMOUS CELL CARCINOMA

27. About 20% of lung cancers
SCC usually occurs in the central portion of the lung, along major airways
On microscopic examination, SCC characteristically shows keratinization and intercellular bridges and exhibits a solid nested growth pattern

28. There can be individual tumor cell keratinization or groups of keratinizing squamous cells forming keratin pearls centrally placed within solid tumor nests
SCCs are further divided into: keratinizing, nonkeratinizing, and basaloid subtypes.
No apparent prognostic utility except for basaloid SCCs intrinsic resistance to cytotoxic chemotherapy.
Survival rate for SCC is significantly better than adenocarcinoma.

29. Large Cell Carcinoma

30. minority of NSCC cases less than 3% of the lung cancers , devoid of lineage-specific differentiation, and lack morphologic and immunohistochemical evidence of adenocarcinoma, SCC, or neuroendocrine carcinoma (null immunophenotype)
LCC is usually peripherally located, bulky, and necrotic in appearance.
the tumor cells are large and polygonal in shape with pleomorphic and vesicular nuclei. The tumor cells form patternless solid sheet or nests.

31. “NSCC, not otherwise specified (NOS)” in a small biopsy or cytology material, not LCC
It is important to apply ancillary tests such as IHC to avoid inclusion of poorly differentiated NSCC, such as solid adenocarcinoma and nonkeratinizing SCC
Metastatic tumors should be excluded

33. OTHER NON–SMALL CELL CARCINOMA TYPES

34. Adenosquamous carcinoma is a rare type of NSCC, accounting for less than 5% of all lung cancers.
Pleomorphic, spindle cell, and giant cell carcinomas are rare types of NSCC, accounting for less than 3% of lung cancers. reported as “NSCC with spindle and/or giant cell carcinoma , Expression of cytokeratin is important in this setting to exclude a primary pulmonary sarcoma.

36. Carcinosarcoma is composed of NSCC and sarcomatous elements such as rhabdomyosarcoma, chondrosarcoma, and osteosarcoma.

38. NEUROENDOCRINE TUMORS

39. common lung tumors, accounting for about 20% to 25% of lung cancers.
These features include organoid growth pattern, finely granular or “salt-and-pepper” chromatin pattern, and
Expression of several hallmark neuroendocrine markers as chromogranin A, synaptophysin, and CD56

40. NETs have heterogeneous degree of differentiation, correlates with tumor aggressiveness and prognosis
In 2015 WHO classification separates this group of tumors into 4 major categories, including typical carcinoid, atypical carcinoid, small cell carcinoma (or SCLC), and LCNEC according to presence of necrosis, No. of mitosis /10HPF, KI67 index .

42. Typical carcinoids
at relatively younger age (mean age range at presentation 45–55 years) , good prognosis (more than 90% 5-year survival rate , no direct association with smoking

43. Atypical carcinoids
cytomorphological features similar to typical carcinoids, although tumor cells in atypical carcinoids tend to display more cytologic atypia

44. (A) Typical carcinoid with organoid cell nests
(A) Typical carcinoid with organoid cell nests. (B) positive staining for synaptophysin (C) less than 4% Ki67 labeling (D) Atypical carcinoid with organoid cell nests(E) Atypical carcinoid with positive staining for synaptophysin (F) Atypical carcinoid with greater than 4% Ki67 labeling index

45. Small Cell Carcinoma more than 10% of all lung cancers
Smoking history is present in virtually all cases of SCLC
SCLC is commonly centrally located in the major airway
SCLC is a highly aggressive malignancy.
Patients usually have metastatic disease at the time of presentation.
Most patients relapse within the first 2 years after treatment and the 2-year survival rate is less than 10% in metastatic patients.

46. ME :/ The diagnosis is based on light microscopy and IHC can be very helpful in establishing the diagnosis and in excluding other morphologic mimics
SCLC has distinct morphologic features ,form organoid nests or diffuse sheets.
The tumor cells are small in size compared with other types of lung cancers, usually less than the diameter of 3 mature lymphocytes. The chromatin is finely granular without prominent nucleoli. The cytoplasm is scanty, and the cellular borders are inconspicuous
high mitotic rate more than 10 mitoses per 10 HPF
extensive tumor necrosis
IHC : pankeratin and neuroendocrine markers (CD56, chromogranin, synaptophysin) TTF-1 90% of SCLC , High Ki67 (MIB-1) labeling index (>50%

47. Large Cell Neuroendocrine Carcinoma

48. Large Cell Neuroendocrine Carcinoma
LCNEC, highly aggressive neuroendocrine carcinoma , like SCLC, is associated with heavy smoking history
5-year survival rate is reported close to 30%
usually peripherally located in the lung.
the tumor cells are larger than SCLCs and they have abundant cytoplasm with prominenet nucleoli, and low nuclear-cytoplasmic (N:C) ratio.
neuroendocrine architecture, including organoid arrangement, trabecular growth, and rosettelike structures
Immunohistochemical stains play an important ancillary role With positive neuroendocrine marker

49. A) Small cell carcinoma (SCLC) with small-sized nuclei and scanty cytoplasm (H&E) (B) positive staining for synaptophysin (C) SCLC with greater than 80% Ki67 labeling (D) LCNEC with large- sized cells and tumor necrosis (E) LCNEC with positive staining for synaptophysin. (F) LCNEC with greater than 40% Ki67 labeling index

50. The role of PATHOLOGY DIAGNOSIS OF LUNG CANCER treatment

51. Lung cancer diagnosis and classification provide pivotal information for prognosis and guide selection of therapeutic regimens
The purpose of tissue biopsy includes establishment of malignancy diagnosis based on histomorphological findings, classification of tumor type and grade aided by IHC staining, and obtaining cellular material for targeted therapy- driven molecular testing.

52. The diagnosis and the treatment of lung cancer is multidisciplinary approach with input from pathology, radiology, pulmonology, surgery, and oncology teams is warranted
ROSE (rapid on site evolution) To avoid nondiagnostic or repeat biopsies, with effective tissue sampling strategy
three key steps of analysis:
-The first step is morphologic evaluation using H&E-stained slides differentiated NSCC and SCLC
-second step : IHC confirmation
-third step : molecular biomarker testing

53. IMMUNOHISTOCHEMISTRY for diagnostic classification
The most important ancillary method in lung cancer diagnosis and classification is IHC

54. The role of IHC in lung cancer therapy

55. ALK / ROS1 • PD-L1 • BRAF • EGFR.
Molecular detection of driver mutations in specific histologic types of lung cancer can predict favorable response to targeted therapy.
ALK / ROS1 • PD-L1 • BRAF • EGFR.

56. ALK-1 Anaplastic lymphoma kinase gene, CD246
Interpretation: usually cytoplasmic and nuclear staining
Predictive marker for therapy in non small cell lung cancer with specific tyrosine kinase inhibitors. 

58. Epidermal Growth Factor Receptor
Epidermal Growth Factor Receptor Also called HER1
Lung: mutations are associated with terminal respiratory unit type adenocarcinoma of lung EGRF tyrosine kinase inhibitors (gefitinib) show rapid clinical response in 10% of lung cancer patients

60. Programmed Cell Death Protein 1(pdl-1)
PDL1 expression is detected in most human cancers, including bladder, breast, cervical, esophageal, gastric, kidney, lung, ovary and pancreatic cancers
High expression of PDL1 is associated with reduced numbers of tumor infiltrating lymphocytes and poor prognosis
second or third line treatment of non small cell lung cancer,
The recommended cutoff for positive staining is >50% at any intensity

62. TAKE HOME MASSAGE

63. Significant progress has been made in the understanding of lung cancer biology. in large part to advancement in the understanding of tumor biology and pathogenesis.
Therefore, characterization of histologic type of lung cancer plays an increasingly pivotal role in the multidisciplinary approach in the diagnosis and management of lung cancer.
comprehensive and accurate tumor classification has been developed, which is important for treatment and prognosis.