KEY TOPICS IN LUNG
PATHOLOGY
FOR THE FRCPath PART 1 EXAM
Part 1 FRCPath (Histopathology)
Simple advice from personal experience that may be helpful to consider:
• Follow the instructions.
• Look through the whole paper v. quickly before starting – confirm how many questions, lay-out, idea of future questions may aid recall.
• Keep an eye on time and be aware of approximate time per question.
• answer each question and immediately complete the answer sheet.
• do not put answers on separate paper and transcribe at the end.
• complete the answer sheet very carefully.
• check answers at the end if time and complete any omitted.
• be very cautious changing answers at the end – if you are not sure, your 1st impression may be correct.
Adenocarcinoma
Epithelial lung tumours
Small cell carcinoma
Squamous cell carcinoma
Large cell carcinoma
Adenosquamous carcinoma
Sarcomatoid carcinoma
Carcinoid tumours
Q. 73F. Pleural effusion. ?mass on CXR. Pleural fluid cell block performed. Cells positive for D2-40 and calretinin; negative for MOC31. Possible diagnoses based on IHC include:
A. Adenocarcinoma T/F
B. Squamous cell carcinoma T/F
C. Small cell carcinoma T/F
D. Reactive mesothelial cells T/F
E. Malignant mesothelioma T/F
F. Malignant melanoma T/F
Q. 73F. Pleural effusion. ?mass on CXR. Pleural fluid cell block performed. Cells positive for D2-40 and calretinin; negative for MOC31. Possible diagnoses based on IHC include:
A. Adenocarcinoma F
B. Squamous cell carcinoma F
C. Small cell carcinoma F
D. Reactive mesothelial cells
E. Malignant mesothelioma
F. Malignant melanoma
Q. Primary lung adenocarcinoma is positive for which of the following markers? T/F
A. CDX2
B. CK7
C. CK20
D. MOC31
E. TTF1
F. Napsin A
G. P63
H. AE1/AE3
Q. Primary lung adenocarcinoma is positive for which of the following markers? T/F
A. CDX2
B. CK7
C. CK20
D. MOC31
E. TTF1
G. P63
F. Napsin A T
H. AE1/AE3
Q. Which of the following are epithelial markers that could be used for IHC in a pleural fluid sample in parallel with mesothelial markers? T/F
A. CDX2
B. AE1/AE3
C. Calretinin
D. CK5/6
E. CK7
F. CAM5.2
G. BerEP4
H. CK20
I. MOC31
K. TTF1
J. MNF 116
L. 34betaE12
Q. Which of the following are epithelial markers that could be used for IHC in a pleural fluid sample in parallel with mesothelial markers? T/F
A. CDX2
B. AE1/AE3
C. Calretinin
D. CK5/6
E. CK7
F. CAM5.2
H. CK20
G. BerEP4 TRUE
J. MNF 116
K. TTF1
L. 34betaE12
I. MOC31 TRUE
Q. Which of the following are cytokeratins? T/F
A. CDX2
B. AE1/AE3
C. Calretinin
D. CK5/6
E. CK7
F. CAM5.2
G. BerEP4
H. CK20
I. MOC31
K. TTF1
J. MNF 116
L. 34betaE12
Q. Which of the following are cytokeratins? T/F
A. CDX2
C. Calretinin
D. CK5/6
B. AE1/AE3 T
E. CK7 T
G. BerEP4
F. CAM5.2 T
I. MOC31
H. CK20 T
K. TTF1
J. MNF 116 T
L. 34betaE12
Q. The following are useful markers to distinguish malignant mesothelioma from adenocarcinoma:
A. WT 1
B. AE1/AE3
C. Calretinin
D. CK5/6
E. CK7
F. CAM5.2
G. BerEP4
H. CK20
I. MOC31
J. MNF 116
K. Thrombomodulin
L. cadherin
M. CEA
N. EMA
Q. The following are useful markers to distinguish malignant mesothelioma from adenocarcinoma:
B. AE1/AE3
A. WT T
E. CK7
C. Calretinin T
F. CAM5.2
D. CK5/6 T
G. BerEP4
H. CK20
J. MNF 116
I. MOC31 T
K. Thrombomodulin
L. cadherin
M. CEA
N. EMA
Q. Which one of the following markers can help to distinguish between malignant mesothelioma and adenocarcinoma by differential subcellular staining:
A. WT
B. AE1/AE3
C. Calretinin
D. CK5/6
E. CK7
F. CAM5.2
G. BerEP4
H. CK20
I. MOC31
J. MNF 116
K. Thrombomodulin
L. cadherin
M. CEA
N. EMA
Q. Which one of the following markers can help to distinguish between malignant mesothelioma from adenocarcinoma by differential subcellular staining:
EMA
BerEP4
MOC31
Epithelial marker
Epithelial marker
Calretinin Mesothelial marker
CK5/6 Mesothelial marker
WT1 Mesothelial marker
Thrombomodulin Mesothelial marker
D2-40 Mesothelial marker
Adenocarcinoma Mesothelioma
BerEP4 +MOC31 +Calretinin - + CK5/6 - +
- + Thrombomodulin - + D2-40 - + CEA +CD15 +/-E-cadherin +EMA + cytoplasmic + membranous
Q. Which of the following markers may be useful to distinguish reactive mesothelial cells from malignant mesothelioma? T/F
A. Calretinin
B. MOC31
C. AE1/AE3
D. Desmin
E. p53
F. CEA
G. D2 40
H. EMA
I. CK7
J. p63
K. SMA
L. vimentin
M. BAP1
N. GATA3
Q. Which of the following markers may be useful to distinguish reactive mesothelial cells from malignant mesothelioma? T/F
A. Calretinin
B. MOC31
C. AE1/AE3
D. Desmin T
F. CEA
E. p53 T
G. D2 40
I. CK7
H. EMA T
J. p63
K. SMA
L. vimentin
M. BAP1 T
N.GATA3
Reactive mesothelial cells Mesothelioma
Desmin + (83%) - (28%)
EMA - (15%) + (75%) p53 - (9%) + (59%)
BAP1 immunohistochemistry and p16 fluorescence in situ hybridization (FISH) have recently been reported as reliable markers of malignancy in biopsies of mesothelioma.
Combined use of BAP1 IHC and p16 FISH is expected to increase the accuracy of MPM diagnosis
• BAP1
• For differentiation of mesothelioma from benign mesothelial proliferation:
• in biopsies initially interpreted as reactive mesothelial proliferation- Loss of nuclear expression of BAP1 loss was 100% predictive of malignancy
• BAP1 is encoded by the BAP1 gene located on the short arm of chromosome 3 (3p21)
p16 FISH
• Homozygous deletion (HD) of p16 (CDKN2A) is one of the common gene alterations associated with MPM(malignant pleural mesothelioma)
Q.?metastasis in lung or primary. CK7-, CK20- : which primary tumours typically have this immunoprofile?
A. Lung adenocarcinoma
B. Colon adenocarcinoma
C. Mesothelioma
D. Pancreatic adenocarcinoma
E. Small intestine adenocarcinoma
F. Breast adenocarcinoma
G. Prostate adenocarcinoma
H. Ovarian mucinous adenocarcinoma
I. Ovarian serous / endometrioid adenocarcinoma
J. Bladder transitional cell carcinoma
K. Endometrial adenocarcinoma
Q.?metastasis in lung or primary. CK7+, CK20- : which primary tumours typically have this immunoprofile?
A. Lung adenocarcinoma
B. Colon adenocarcinoma
C. Mesothelioma
D. Pancreatic adenocarcinoma
E. Small intestine adenocarcinoma
F. Breast adenocarcinoma
G. Prostate adenocarcinoma
H. Ovarian mucinous adenocarcinoma
I. Ovarian serous / endometrioid adenocarcinoma
J. Bladder transitional cell carcinoma
K. Endometrial adenocarcinoma
Q.?metastasis in lung or primary. CK7+, CK20+ : which primary tumours typically have this immunoprofile?
A. Lung adenocarcinoma
B. Colon adenocarcinoma
C. Mesothelioma
D. Pancreatic adenocarcinoma
E. Small intestine adenocarcinoma
F. Breast adenocarcinoma
G. Prostate adenocarcinoma
H. Ovarian mucinous adenocarcinoma
I. Ovarian serous / endometrioid adenocarcinoma
J. Bladder transitional cell carcinoma
K. Endometrial adenocarcinoma
Q.?metastasis in lung or primary. CK7-, CK20+ : which primary tumours typically have this immunoprofile?
A. Lung adenocarcinoma
B. Colon adenocarcinoma
C. Mesothelioma
D. Pancreatic adenocarcinoma
E. Small intestine adenocarcinoma
F. Breast adenocarcinoma
G. Prostate adenocarcinoma
H. Ovarian mucinous adenocarcinoma
I. Ovarian serous / endometrioid adenocarcinoma
J. Bladder transitional cell carcinoma
K. Endometrial adenocarcinoma
CK7+/CK20- CK7+/CK20+ CK7- / CK20+ CK7-/CK20Lung Ovary (mucinous) colorectal prostate
Breast Small intestine RCC
mesothelioma Bladder - TCC HCC
Ovary (serous, endometrioid) Pancreas
Endometrial
Thyroid
Q. In the subtyping of metastatic lung tumours, please match the tumours with the antigen that could aid diagnosis by IHC. Each tumour can have no antigen, one or more than one corresponding positive antigens. Each antigen can be used once, more than once or not at all.
A. Prostate adenocarcinoma
B. Breast adenocarcinoma
C. Endometrial adenocarcinoma
D. Renal cell carcinoma
E. Gastric adenocarcinoma
F. Colorectal adenocarcinoma
G. Pancreatic adenocarcinoma
H. Seminoma
Q. In the subtyping of metastatic lung tumours, please match the tumours with the antigen that could aid diagnosis by IHC. Each tumour can have no antigen, one or more than one corresponding positive antigens. Each antigen can be used once, more than once or not at all.
A. Prostate adenocarcinoma
B. Breast adenocarcinoma
C. Endometrial adenocarcinoma
D. Renal cell carcinoma
E. Gastric adenocarcinoma
F. Colorectal adenocarcinoma
G. Pancreatic adenocarcinoma
H. Seminoma
10) AR 13)PSA 11)PSAP
1) ER 7) PR
8) PAX8 1) ER 7) PR
8) PAX8 5) Vimentin
3) CDX2
3) CDX2
6) SMAD4
9) PLAP 2)
Q. Which of the following conditions in the lung have a tendency to cavitate?
A. Lung adenocarcinoma
B. Tuberculosis
C. Sarcoidosis
D. Lung squamous cell carcinoma
E. Lung small cell carcinoma
Q. Which of the following conditions in the lung have a tendency to cavitate?
A. Lung adenocarcinoma
C. Sarcoidosis
B. Tuberculosis T
E. Lung small cell carcinoma
D. Lung squamous cell carcinoma T
Q: A 78 year old man is found to have a 4.2 cm left upper lobe mass with central cavitation.
Histology of the mass is shown above. What is the expected staining pattern of this mass?
1.TTF1+, napsin A+, p40-
2.TTF1+, napsin A-, p40+
3.TTF1-, napsin A-, p40+
4.TTF1-, napsin A+, p40+
Answer C
TTF1-, napsin A-, p40+.
• The radiographic description and cytology specimen is consistent with squamous cell carcinoma, which typically stains positive for p40.
• Answers A, B and D are incorrect because TTF1 and napsin A are typically positive in adenocarcinomas.
• Of note, TTF1 can also positive in tumors of neuroendocrine lineage and may also stain background benign bronchial cells.
Q.Which of the following markers help to distinguish between lung adenocarcinoma and lung squamous cell carcinoma?
A. TTF1
C. CK5/6
B. MNF 116
D. Calretinin
E. p63
F. p16
G. p40
H. CK14
I. CK8
Q.Which of the following markers help to distinguish between lung adenocarcinoma and lung squamous cell carcinoma?
B. MNF 116
A. TTF1 T
D. Calretinin
C. CK5/6 T
F. p16
E. p63 T
G. p40 T
I. CK8
H. CK14 T
• p63
• p40
• CK5/6
• CK14
Squamous markers
Bishop JA, Teruya-Feldstein J, Westra WH, Pelosi G, Travis WD, Rekhtman
N. p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol. 2012 Mar;25(3):405-15.
Lung squamous cell carcinoma
• c. 45% primary lung tumours in men. c.25% in women.
• >90% in cigarette smokers
• may cavitate
• histological criteria
• keratinisation
• intercellular bridging
• +/- dysplasia / CIS
• variants – small cell, basaloid, papillary, clear cell, alveolar spacefilling peripheral variant
Lung Adenocarcinoma
Adenocarcinoma in situ
Minimally invasive adenocarcinoma
Invasive adenocarcinoma
Non mucinous (describe predominant pattern)
Lepidic (formerly bronchioloalveolar)
Acinar
Papillary
Micropapillary
Solid
Mucinous adenocarcinoma (describe predominant pattern)
Mucinous (colloid)
Fetal
Enteric
Signet ring
Clear cell
Lung adenocarcinoma
• c.28% of primary lung tumours in men and c.42% in women.
• most occur in smokers but the most common type of lung cancer in non-smokers.
• identification of:
• lepidic pattern (previously bronchioloalveolar pattern), acinar pattern (definite gland formation), papillary pattern, papillary nodules without stromal cores (micropapillary pattern) or intracellular mucin-containing vacuoles in more than five cells in two consecutive high power fields of an otherwise undifferentiated carcinoma (solid pattern).
• Recording of the predominant pattern of tumour is now recommended.
• identification of minimally invasive tumours (area of invasion less than or equal to 5 mm)
• identification of adenocarcinoma-in-situ when the tumour is wholly lepidic (previously termed ‘bronchioloalveolar’) in pattern.
• CK7+, CK20-, TTF1+, NapsinA +
Napsin A, a New Marker for Lung Adenocarcinoma, Is Complementary and More Sensitive and Specific Than Thyroid Transcription Factor 1 in the Differential Diagnosis of Primary Pulmonary Carcinoma: Evaluation of 1674 Cases by Tissue Microarray
Bradley M. Turner, Philip T. Cagle, Irma M. Sainz, Junya Fukuoka, Steven S. Shen and Jaishree Jagirdar
Archives of Pathology & Laboratory Medicine Feb 2012, Vol. 136, No. 2 (February 2012) pp. 163-171
doi: http://dx.doi.org/10.5858/arpa.2011-0320-OA
• lung adenocarcinoma – peripheral tumour
• arises in terminal bronchioles
Lung Adenocarcinoma
1. Lepidic (formerly bronchioloalveolar)
2. Mucinous Ca
Adenocarcinoma
3. Papillary adenocarcinoma
4. Papillary adenocarcinoma
Lung Adenocarcinoma
5. Signet ring adenocarcinoma
Pulmonary Adenocarcinoma: The Expanding Spectrum of Histologic Variants
Cesar A. Moran Archives of Pathology & Laboratory Medicine Jul 2006, Vol. 130, No. 7 (July 2006) pp. 958-962
Q:A 65 year old woman with an extensive smoking history is found to have a 4.2 cm right lower lobe lung mass. Histology of the mass is shown above. What set of genes should always be interrogated for mutations or rearrangements in this type of tumor in order to guide treatment?
1.EGFR, ALK, ROS1, BRAF
2.EGFR, MET, ALK, ASCL1
3.ERBB2 (HER2), KRAS, NEUROD1, BRAF
4.MET, RET, ERBB2 (HER2), YAP1
Answer
1. EGFR, ALK, ROS1, BRAF.
• This is an adenocarcinoma and all adenocarcinomas should be tested for mutations or rearrangements in EGFR, ALK, ROS1 and BRAF to predict response to treatment with tyrosine kinase and BRAF inhibitors (although it may be reasonable to perform sequential testing on EGFR and ALK, followed by ROS1 testing).
• Additionally, IHC for PDL1 is standard of care in NSCLC to evaluate potential treatment with immune checkpoint inhibitors.
• ASCL1, NEUROD1, POU2F3 and YAP1 are genes involved in SCLC subtyping
(J Thorac Oncol 2018;13:323, Drugs Context 2023;12:2022, J Thorac Oncol 2020;15:1823).
Q :Lung adenocarcinoma -the following statements are true except
1.invasive mucinous-ADC (IMA), invasive non-mucinous-ADC, fetal carcinoma, colloid carcinoma, and enteric type carcinoma are all subtypes of Lung Adenocarcinomas
2.most prevalent subtype of lung cancer is invasive nonmucinous-ADC.
3.most prevalent subtype of lung cancer is invasive mucinous-ADC.
4.lepidic predominant tumors have a better prognosis.
5. high-grade patterns of lung adenocarcinomas are solid, complex glandular, micropapillary, and cribriform
Answer :3
• The most prevalent subtype of lung cancer is invasive nonmucinous-ADC, consisting of malignant epithelial tumors with immunohistochemical or morphological evidence of glandular differentiation.
Lung adenocarcinomas (ADC)
• current update has classified ADC as invasive mucinousADC (IMA), invasive non-mucinous-ADC, fetal carcinoma, colloid carcinoma, and enteric type carcinoma.
• The most prevalent subtype of lung cancer is invasive nonmucinous-ADC, consisting of malignant epithelial tumors with immunohistochemical or morphological evidence of glandular differentiation.
• staging and grading system based on the measurement of invasion, specifically for nonmucinous-part lepidic-ADC.
Lung Adenocarcinomas
• Determine the tumor grade and define the major histologic pattern (subtype), the percentage of each pattern is recorded in 5%–10% increments.
• lepidic predominant tumors have a better prognosis.
• KRAS mutations are common in solid-predominant ADC and IMA.
• EGFR mutations are more common in ADC with a nonmucinous lepidic and papillary pattern, as well as in those that are TTF-1 positive. ALK, ROS1, and RET50,51 translocations are found with signet ring patterns and cribriform/solid patterns.
Invasive mucinous adenocarcinomas
• IMA with its columnar or goblet cell morphology can be characterized by TTF1, CDX2 focal, CK7+, CK20 focal.
• IMA is distinguished by multilobar, multifocal, and bilateral presentation rather than intrapulmonary spread
• IMA accounts for 3%–10% of invasive ADC, with nonmucinous types accounting for the remainder.
Q. Characteristics of small cell lung carcinoma: T/F
A. Finely granular chromatin
B. Cytoplasmic vacuolation
C. Dense cytoplasm on Pap staining
D. Positive staining for synaptophysin
E. Is generally treated by surgery
F. Nuclear moulding
G. Accounts for 45% of primary lung cancers
H. Is distinguished from primary lung adenocarcinoma by its lack of staining for TTF1
I. Is a small round blue cell tumour
J. Is strongly related to cigarette smoking
K. Azzopardi effect
Q. Characteristics of small cell lung carcinoma: T/F
A. Finely granular chromatin
B. Cytoplasmic vacuolation
C. Dense cytoplasm on Pap staining
D. Positive staining for synaptophysin
E. Is generally treated by surgery
F. Nuclear moulding
G. Accounts for 45% of primary lung cancers
H. Is distinguished from primary lung adenocarcinoma by its lack of staining for TTF1
I. Is a small round blue cell tumour
J. Is strongly related to cigarette smoking
K. Azzopardi effect
Lung small cell carcinoma
• c. 20% primary lung tumours.
• strong association with cigarette smoking, usually central/hilar
•Cells “small” with scant cytoplasm, round to spindled nuclei, fine chromatin. No conspicuous nucleoli.
• Nuclear moulding common.
• Crush artefact.
• High mitotic count - usually > 60 /10 HPF.
• The Azzopardi effect: encrustation of blood vessels with nuclear basophilic material.
• +ve for NE markers – synaptophysin, chromogranin, CD56
• +ve for TTF1; dot-like pan-CK staining.
• EM – dense core neurosecretory granules 100-200nm
• Associated with paraneoplastic syndromes.
• Df Dx – lymphoid infiltrates, lymphoma, other small round blue cell tumours (e.g. metastatic small cell ca / Merkel cell carcinoma CK20+, TTF1-; small cell variants of other tumours e.g. SCC, MM; etc), large cell neuroendocrine carcinoma,
• Tx – chemotherapy (except few v. early stage tumours)
Small cell carcinoma – central tumour
Q: A patient undergoes a biopsy of a lung mass with the histology shown in the image. Which of the following immunohistochemical results would be most typical of the lesion?
1.INSM1+, chromogranin+, Cam5.2+ diffuse, p40+, Ki67 low
2.INSM1+, chromogranin-, Cam5.2 + diffuse, p40+, Ki67 high
3.INSM1-, chromogranin+, Cam5.2 punctate, p40+, Ki67 high
4.INSM1+, chromogranin+, Cam5.2 punctate, p40-, Ki67 high
5.INSM1-, chromogranin-, Cam5.2 punctate, p40-, Ki67 low
Answer
• D. INSM1+, chromogranin+, Cam5.2punctate, p40-, Ki67 high.
• The tumor shown is small cell carcinoma of the lung.
• Of the choices listed, INSM1+, chromogranin+, Cam5.2- punctate, p40-, Ki67 high (answer D) is the most likely immunoprofile.
INSM1
• Nuclear marker of neuroendocrine differentiation with equivalent or better sensitivity and specificity compared to synaptophysin, chromogranin and CD56.
• Expressed in a broad spectrum of neuroendocrine tumors (including small cell carcinoma, large cell neuroendocrine carcinoma and well differentiated neuroendocrine tumor / carcinoid tumor of various sites, paraganglioma / pheochromocytoma, Merkel cell carcinoma, olfactory neuroblastoma and medullary thyroid carcinoma)
• Also expressed in normal adult neuroendocrine tissues (adrenal medulla, pineal gland, pituitary gland, gastrointestinal enterochromaffin cells, pancreatic islet cells, thyroid C cells) and developing neurons
Small cell Carcinoma lung Paraneoplastic syndromes
• Small cell lung cancer is associated with paraneoplastic syndromes
• one of the most common is Cushing syndrome, caused by increased production of adrenocorticotropic hormone by the small cell tumor. Symptoms include weight gain, fatigue, glucose intolerance, moon face, buffalo hump, muscular weakness, skin manifestations (thinning, acne, abdominal striae), psychological symptoms (depression, anxiety, decreased libido), hypertension, increased risk of bone fracture and reproductive symptoms (irregular or absent menstruation in females and erectile dysfunction in males).
• Other paraneoplastic syndromes associated with small cell lung carcinoma include syndrome of inappropriate antidiuretic hormone secretion and Lambert-Eaton.
Q. Which one of the following lung tumours are associated with haemorrhage including potentially fatal haemoptysis when treated with monoclonal antibody therapy (bevacizumab) : T/F
A. Squamous cell carcinoma
B. Adenocarcinoma
C. Small cell carcinoma
D. Large cell neuroendocrine carcinoma
E. Atypical carcinoid tumours
Q. Which one of the following lung tumours are associated with haemorrhage including potentially fatal haemoptysis when treated with monoclonal antibody therapy (bevacizumab) : T/F
B. Adenocarcinoma
C. Small cell carcinoma
A. Squamous cell carcinoma T
D. Large cell neuroendocrine carcinoma
E. Atypical carcinoid tumours
• Bevacizumab is not licenced for SCC
• SCC arises from large bronchi whereas adenocarcinomas are usually peripheral
• Central tumours may invade major vessels
Q. Molecular pathology of lung tumours: Which one technique is favoured / forecasted in pathology to be the principal instrumental technique that will lead lung cancer molecular diagnostics in the future : T/F
A. miRNA analysis
B. Genomic DNA sequencing
C. Whole human genome expression arrays
D. High throughput proteomics by MALDI mass spectometry
E. Gene expression by multiplex qPCR
F. Mitochondrial DNA mutation analysis
G. Raman spectroscopy
Q. Molecular pathology of lung tumours: Which one technique is favoured / forecasted in pathology to be the principal instrumental technique that will lead lung cancer molecular diagnostics in the future : T/F
A. miRNA analysis
B. Genomic DNA sequencing
C. Whole human genome expression arrays
D. High throughput proteomics by MALDI mass spectometry
E. Gene expression by multiplex qPCR Mitochondrial DNA mutation analysis
F. Raman spectroscopy
Lorito A, Schmitt FC. (Cyto)Pathology and sequencing: next (or last) generation? Diagnostic Cytopathology 2011;40:459 61.
DNA sequencing for mutation analysis
•can be used for high-throughput DNA sequencing and mutation analysis
Q: Which of the following are important genes in lung cancer molecular testing? T/F
A. MIB1
B. p63
C. EGFR
D. TTF1
E. EML7 ALK
F. EML3 ALK
G. EML4 ALK
I. KRAS
H. KRAS ALK
J. MYC
K. MYBL1
L. BRAF
M. p40
Q: Which of the following are important genes in lung cancer molecular testing? T/F
A. MIB1
B. p63
D. TTF1
C. EGFR T
E. EML7 ALK
F. EML3 ALK
H. KRAS ALK
G. EML4 ALK T
J. MYC
K. MYBL1
I. KRAS T
M. P40
L. BRAF T
NSLC –Non small cell lung carcinoma
Molecular screening is mandatory in patients with nonsquamous cell carcinoma and those with squamous cell carcinoma (SCC) who are never- or light smokers. (NCCNGuidelinesInsights:Non–SmallCellLungCancer, Version2.2021) Histological phenotype of NSCLC can guide molecular testing.
Molecular profiling in lung cancer
Molecularprofilingisusedtopredicttherapeutic efficaciesinNSCLCs
Typicallyincludes EGFR, KRAS, ROS1, ALK, MET, BRAF, RET, ERBB2 (HER2),and NTRK .
PD-L1(programmedcelldeathligand-1)by immunohistochemistry(IHC)topredictresponseto immunecheckpointinhibitors.
EGFR mutation testing in lung cancer
• Epidermal growth factor receptor
• small molecular inhibitors of the tyrosine kinase domain of EGFR (ergotinib, gefitinib) are particularly effective in patients with specific EGFR mutations:
• c. 85% of these are deletions in exon 19 or the L858R substitution mutation in exon 21
• most EGFR mutations occur in adenocarcinoma
• EGFR mutations reported at 10-15% of cases in European / Caucasian studies (40-60% in East Asia).
Molecular proiling in lung cancer
EGFR mutations involve10%-35%oflung adenocarcinomainWesternpopulations(andashigh as50%inAsianpopulations)and3%oflungsquamous cellcarcinoma(SqCC).
• MutationscanpredicttherapeuticresponsetoEGFRspecifictyrosinekinaseinhibitors(TKIs).
KRAS mutations aredetectablein25%-35%oflung adenocarcinoma,and5%ofSqCC.
• AKRASinhibitordrugthatspecificallytargetsthe G12Cmissensemutation(seenin~13%ofNSCLCs) isavailable.
• The most common cause of acquired resistance to EGFR TKIs is a second-site EGFR T790M mutation that negates their inhibitory action.
• Osimertinib is a third-generation oral EGFR TKI that targets the EGFR T790M mutation while leaving the wild-type EGFR intact.
Molecular profiling in lung cancer
• ALK activating rearrangements occur in ~5% of lung adenocarcinoma, particularly in young non-smokers.
• ROS1 genefusion(1%-2%ofNSCLCs)signifies responsetocertainALKinhibitorsduetohomology betweentherearranged ROS1 and ALK genes.
• MET exon14skippingmutations, BRAF V600E mutation, RET genefusionand NTRK genefusioncan predicttherapeuticresponsetotheirrespective inhibitors.
Immunotherapy in lung cancer(IO)
• Immunotherapy agents improve the immune system's capacity to recognize and delete tumors, including lung cancer.
• The use of IO, such as anti-programmed cell death protein ligand 1 (anti-PDL1), anti-programmed cell death protein 1 (anti-PD-1), and anti-cytotoxic Tlymphocyte-associated protein 4 (anti-CTLA-4) monoclonal antibody (mAbs), with or without chemotherapy, has become the gold-standard treatment in non–oncogene-addicted NSCLC.
• PD-L1proteinexpressiondetectedbyIHCanalysishasbeenthemain predictivebiomarkerexploredforresponsetoanti–PD-1/PD-L1 immunotherapy.
• Testing is significant for the first-line use of ICIs, which is precluded by EGFR mutations. EGFR mutations and ALK translocations prevent ICIs from being used as a first-line treat
Lung carcinoid tumours
• Histologic subtypes of pulmonary neuroendocrine tumours: typical carcinoids, atypical carcinoids, small cell carcinoma, and large cell neuroendocrine carcinoma
TYPICAL CARCINOID TUMOUR
• <5% of primary lung tumors
● Locally invasive
● Usually 40 years or below
● No gender predilection, not related to smoking
● May infiltrate or spread to local lymph nodes, but doesn’t affect prognosis
● Rarely produces carcinoid syndrome (flushing, diarrhoea, cyanosis)
● Nests or trabeculae of medium sized polygonal cells of low nuclear grade, round to oval finely granular nuclei and lightly eosinophilic cytoplasm. Nucleoli inconspicuous.
● No/minimal mitotic activity <2/10hpf or necrosis
Lung carcinoid tumours
ATYPICAL CARCINOID TUMOUR
• 2-10 mitoses/10HPF or necrosis
• both TC and AC are + for CK and NE markers.
• TTF1 + in c. 1/3 TC and up to ½ of AC (if +ve supports lung primary site)
Beasley MB. Diagnostic Histopathology. 2008; 14:10: 465
Q. Which of the following is classical of bronchiolitis obliterans organising pneumonia?
A. Fibrosis
B. Asbestos fibres
C. Macrophages within alveoli
D. Intrabronchiolar fibroblastic plugs
E. Granulomas
F. Hyaline membranes
Q. Which of the following is classical of bronchiolitis obliterans organising pneumonia?
D. Intrabronchiolar fibroblastic
plugs
Bronchiolitis obliterans organising pneumonia
Common response to infectious or inflammatory injury to lungs
• Requires Clinicopathological correlation
• A clinicopathological syndrome that can be caused by various agents including drugs, infections, toxic inhalants and immune disorders.
• Histology – intrabronchioloar fibroblastic plugs (Masson plugs), interstitial inflammatory cells, lumenal macrophages.
Q. Aspergillus has the following features:
A. 45% branching of hyphae
B. Non-septate
C. Invasion of blood vessels
D. Infection in immunocompetent patients
Q. Aspergillus has the following features:
A. 45% branching of hyphae T
B. Non-septate F
C. Invasion of blood vessels T
D. Infection in immunocompetent patients F
Q. Pneumocystis pneumonia:
A. jirovecii is the species that causes lung infection
B. carinii is the species that causes lung infection
C. motoso is the species that causes lung infection
D. Is an opportunistic infection
E. Histologically - alveolar spaces filled with eosinophilic foamy material containing fungi.
F. Is characteristed by non-branching septate hyphae
G. Is characteristed by 4-6micron diameter cup-shaped cysts
Q. Pneumocystis pneumonia:
A. jirovecii is the species that causes lung infection
B. carinii is the species that causes lung infection
C. motoso is the species that causes lung infection
D. Is an opportunistic infection
E. Histologically - alveolar spaces filled with eosinophilic foamy material containing fungi.
F. Is characteristed by non-branching septate hyphae
G. Is characteristed by 4-6micron diameter cup-shaped cysts
Formerly known as P. carinii, a pneumocystis variant that occurs in animals; P. jiroveci is specific to humans
● Opportunistic yeast-like fungus present in bronchoalveolar lavage (BAL), sputum or biopsy
● Classical pneumonia in AIDS patients
● May also occur in otherwise immunocompetent patients with protein-calorie malnutrition, haematologic malignancies or undergoing chemotherapy or chronic corticosteroid treatment.
Q. In routine diagnostic practice, asbestos fibres can be counted using:
A. H&E sections
B. Electron microscopy
C. Perls staining
D. Nitric acid digest and light microscopy
E. Autofluorescence
F. Unstained FFPE sections
Q. In routine diagnostic practice, asbestos fibres can be counted using:
A. H&E sections T
B. Electron microscopy
C. Perls staining
D. Nitric acid digest and light microscopy T
E. Autofluorescence
F. Unstained FFPE sections T
Q. Abestos bodies:
A. Are synonomous with feruginous bodies
B. Are diagnostic of asbestosis
C. The asbestos fibre count decreases over time in living patients lung tissue
D. Are not found in hilar lymph nodes
E. Are usually found in mesothelioma tissue
F. Amphiboles are associated more than crysotiles with mesothelioma
Q. Abestos bodies:
A. Are synonomous with feruginous bodies F
B. Are diagnostic of asbestosis F
C. The asbestos fibre count decreases over time in living patients lung tissue T
D. Are not found in hilar lymph nodes F
E. Are usually found in mesothelioma tissue F
F. Amphiboles are associated more than crysotiles with mesothelioma T
Q. 36F. Heavy smoker. Progressive SOB. CXR – bilateral ground glass appearance. Lung biopsy – alveoli filled with histiocytes, hyperplasia or type 2 pneumocytes, lymphoplasmacytic infiltrate. Diagnosis:
A. Bronchiolitis obliterans organising pneumonia
B. Usual interstitial pneumonia
C. Desquamative interstitial pneumonia
D. Extrinsic allergic alveolitis
E. Non-specific interstitial pnemonia
Q. 36F. Heavy smoker. Progressive SOB. CXR – bilateral ground glass appearance. Lung biopsy – alveoli filled with histiocytes, hyperplasia or type 2 pneumocytes, lymphoplasmacytic infiltrate. Diagnosis:
A. Bronchiolitis obliterans organising pneumonia
B. Usual interstitial pneumonia
C. Desquamative interstitial pneumonia
D. Extrinsic allergic alveolitis
E. Non-specific interstitial pnemonia
Desquamative interstitial pneumonia
Usually adults
• insidious onset of shortness of breath
• M:F = 1:2
• usually one decade younger that UIP patients
• 90% are current or past cigarette smokers
• associated with collagen vascular disease
• Patients who stop smoking +/- steroid therapy have good prognosis
• Mean survival of 12 years, mortality 28%
• Histology – accumulation of macrophages and type 2 pneumocyte hyperplasia.
• Diffuse collections of intraalveolar macrophages containing lipid and PAS+ granules (originally considered to be desquamated pneumocytes)
Further reading for the part 1
Robbins pathology and MCQ book
RCPath datasets and documents
Check for screening programmes (NHS screening website) immunohistochemistry vade mecum (Dr Paul Bishop) http://e-immunohistochemistry.info/web/histopathology_help.htm
