Adenocarcinoma of the lung

Adenocarcinoma of the lung, also lung adenocarcinoma, is common malignant lung tumour.

Adenocarcinoma of the lung
Diagnosis in short
Invasive adenocarcinoma, acinar pattern (right of image) and benign lung (left of image). H&E stain.
LM	+/-nuclear atypia (may be absent in mucinous tumours), eccentrically placed nuclei, usu. abundant cytoplasm (classically with mucin vacuoles), often conspicuous nucleoli, +/-nuclear pseudoinclusions
LM DDx	atypical adenomatous hyperplasia of the lung, adenocarcinoma in situ, squamous cell carcinoma of the lung, small cell carcinoma of the lung, non-small cell lung carcinoma, malignant mesothelioma, metastatic adenocarcinoma (esp. colorectal adenocarcinoma, breast adenocarcinoma (invasive ductal carcinoma of the breast, invasive lobular carcinoma))
IHC	CK7 +ve, TTF-1 +ve, CK20 -ve, p40 -ve, p63 -ve (usually)
Molecular	+/-KRAS mutations, +/-EGFR mutations, +/-ALK chromosomal translocation (inv(2)(p21p23) -- EML4-ALK fusion), +/-ROS1 rearrangements, +/-RET rearrangements
Staging	lung cancer staging
Site	lung - see lung tumours
Prevalence	most common primary lung tumour
Radiology	lung mass - typically peripheral lesion (distant from large airways), may be multifocal
Prognosis	dependent on stage (minimally invasive and noninvasive: very good; invasive: moderate)
Clin. DDx	other lung tumours - primary and metastatic
Treatment	surgical resection if feasible

General

• Adenocarcinoma is the most common (primary lung cancer).
• Adenocarcinoma is the non-smoker tumour - SCLC and squamous are more strongly associated with smoking.
• Lung adenocarcinoma is the most common brain metastasis.

Treatment:

• Lung adenocarcinoma may be treated with EGFR inhibitors (e.g. gefitinib (Iressa), erlotinib (Tarceva)).

Patients that receive EGFR inhibitors classically are:

• Non-smokers.
• Female.
• Asian.
  • Caucasians also benefit.

Gross

• Classically peripheral lesions.
• May be multifocal.

Image

• 

  Lung adenocarcinoma. (WC/Rosen)

Microscopic

Features:

• +/-Nuclear atypia - important.
  • May be absent in mucinous tumours - may look similar to foveolar epithelium.
• Eccentrically placed nuclei.
• Abundant cytoplasm - classically with mucin vacuoles.
• Often conspicuous nucleoli.
• +/-Nuclear pseudoinclusions.

Negatives:

• Lack of intercellular bridges.

Patterns:

• Lepidic - tumour grows long the alveolar wall; means scaly covering. At lower power, the shapes should still resemble lung acini.
• Acinar - berry-shaped glands, smaller than lung acini.
• Papillary - fibrovascular cores.
• Micropapillary - nipple shaped projections without fibrovascular cores.
• Solid - sheet of cells.

Notes:

• Lymphovascular invasion is common.
• Micropapillary predominant pattern and tumours with any amount of the lepidic pattern are associated with EGFR mutations.

DDx:

• Atypical adenomatous hyperplasia of the lung - spaced hobnail cells, mild-to-moderate nuclear atypia, small lesion (must be <5 mm).
• Adenocarcinoma in situ.
• Papillary carcinoma of thyroid.
• Squamous cell carcinoma of the lung.
• Small cell carcinoma of the lung.
• Adenoid Cystic Carcinoma.
• Non-small cell lung carcinoma - diagnosis should be avoided if possible.
• Malignant mesothelioma.
• Metastatic adenocarcinoma.
  • Colorectal adenocarcinoma.
  • Breast adenocarcinoma.
    • Invasive ductal carcinoma of the breast.
    • Invasive lobular carcinoma.
    • Bronchiolar metaplasia.
  • Other carcinomas.
• Carcinomas of the bronchial glands, e.g. adenoid cystic carcinoma.

Images

Acinar adenocarcinoma

• 

  Acinar LA - low mag.

• 

  Acinar LA - intermed. mag.

• 

  Acinar LA - high mag.

• 

  Acinar LA - very high mag.

• 

  Acinar LA - very high mag.

• 

  Acinar adenocarcinoma. (WC/Yale Rosen)

• 

  Acinar adenocarcinoma. (WC/Yale Rosen)

Mucinous adenocarcinoma

• 

  MAL - low mag.

• 

  MAL - intermed. mag.

• 

  MAL - high mag.

• 

  MAL - very high mag.

• 

  MAL - low mag.

• 

  MAL - intermed. mag.

• 

  MAL - high mag.

• 

  MAL - intermed. mag.

• 

  MAL - high mag.

• 

  MAL - high mag.

• 

  BAC - mucinous type - low mag. (WC/Yale Rosen)

• 

  BAC - mucinous type - high mag. (WC/Yale Rosen)

Papillary adenocarcinoma

• 

  PAL - very low mag. (WC/Nephron)

• 

  PAL - low mag. (WC/Nephron)

• 

  PAL - intermed. mag. (WC/Nephron)

• 

  PAL - high mag. (WC/Nephron)

Fetal adenocarcinoma

• 

  FAL - very low mag. (WC)

• 

  FAL - very low mag. (WC)

• 

  FAL - low mag. (WC)

• 

  FAL - intermed. mag. (WC)

• 

  FAL - high mag. (WC)

www

• BAC mucinous type adjacent to benign (pathpedia.com).
• BAC mucinous and nonmucinous (cancergrace.org).
• Lepidic adenocarcinoma with invasive (flickr.com/Yale Rosen).
• Lepidic adenocarcinoma (flickr.com/Yale Rosen).
• Lepidic adenocarcinoma (rosaicollection.org/index.cfm).
• Mucinous adenocarcinoma (pathlabmed.typepad.com).
• Non-mucinous adenocarcinoma in situ (flickr.com/Yale Rosen).
• Non-mucinous adenocarcinoma in situ (flickr.com/Yale Rosen).
• Acinar adenocarcinoma (flickr.com/Yale Rosen).
• Acinar adenocarcinoma (flickr.com/Yale Rosen).

Classification

Classification based on extent:

1. Adenocarcinoma in situ (AIS) - previously known as bronchioloalveolar carcinoma (abbreviated BAC).
   • Subtypes: nonmucinous, mucinous, mixed mucinous/nonmucinous.
   • Definition: lack of invasion into the stroma, vascular spaces and pleura.
   • Must have a lepidic growth pattern.
2. Minimally invasive adenocarcinoma (MIA).
   • Lepidic growth with up to 5 mm of invasion.
   • Subtypes: nonmucinous (most common), mucinous (uncommon), mixed (mucinous/nonmucinous).
   • Should not have lymphovascular invasion.^{[citation needed]}
3. Invasive adenocarcinoma:
   • Subtypes: micropapillary, mucinous (previously mucinous BAC), colloid, fetal, enteric.

Grading

Graded G1-G4 - as per CAP protocol (version 3.4.0.0):

• G1 = lepidic.
• G2 = acinar, papillary, cribriform.
• G3 = micropapillary, solid, mucinous, colloid.
• G4 = undifferentiated - not used for lung adenocarcinoma; it used for small cell carcinoma and large cell carcinoma.

Note:

• There is no consensus currently on grading - as per the international consensus guidelines of 2011.

Special stains

• Mucicarmine +ve, cytoplasmic.
• PAS-diastase +ve, cytoplasmic.

IHC

Primary versus metastatic:

• TTF-1 +ve.
• CK7 +ve.
• CK20 -ve.

Panel for adenocarcinoma versus SCC:

• TTF-1 +ve.
• Napsin A +ve.
• p40 -ve.
• CK5/6 -ve.

Others:

• p63 -ve -- occasionally +ve.
• Vimentin -ve/+ve (+ve relatively common).
  • Poor prognosticator.

Note:

• In mucinous adenocarcinoma of the lung TTF-1 is usu. -ve (46% +ve) and napsin is usu. -ve (36% +ve).
  • Positive staining is unusual but useful if present, as metastatic disease is uniformily negative for both.

Molecular

• EGFR mutations (typically assessed by PCR) - respond to TKIs (e.g. gefitinib, erlotinib) if:
  • Exon 19 deletion.
  • Exon 21 L858R.
    • Natural history of mutation is suspected to have a better prognosis vs. wild-type.
  • KRAS mutations are absent, i.e. wild-type KRAS.

• ALK chromosomal translocation (inv(2)(p21p23) -- EML4-ALK fusion).
  • Associated with a poor prognosis.
  • Amenable to treatment with TKI.
  • See lung carcinoma with ALK rearrangement.
  • Do not occur with EGRF mutations or KRAS mutations.

• ROS1 - good response to crizotinib.
  • Approximately 1% of NSCLC.

Sign out

Biopsy

Consensus recommendations:

• Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma should not be used in the reporting of small biopsies and cytology.
  • Tumours with a non-invasive pattern are referred to by their pattern, e.g. lepidic growth, not as AIS.

Lung, Right Upper Lobe, Core Biopsy:
- INVASIVE ADENOCARCINOMA, NON-MUCINOUS.

Comment:
The adenocarcinoma is positive for TTF-1 and napsin. EGFR/ALK testing was ordered.

Lepidic pattern on biopsy

Important note: lesion must be >=5 mm and <=30 mm.

Lung, Left Upper Lobe, Core Biopsy:
     - ADENOCARCINOMA, lepidic pattern.

Comment:
The tumour is stains as follows:
POSITIVE: TTF-1, napsin A, CK7. 
NEGATIVE: p40.

The findings are in keeping with lepidic pattern adenocarcinoma.  The differential diagnosis includes: (1) adenocarcinoma in situ, (2) lepidic pattern adenocarcinoma, and (3) invasive adenocarcinoma.

Lung biomarkers (EGFR, ALK, PDL1, ROS1) have been ordered.

Mucinous adenocarcinoma with noncontributory stains

Lung, Right Upper Lobe, Core Biopsy:
- ADENOCARCINOMA, MUCINOUS, see comment.

Comment:
The adenocarcinoma is negative for both napsin and TTF-1. EGFR/ALK testing was ordered.

The findings are compatible with a primary or secondary adenocarcinoma; clinical and 
radiologic correlation is required.

Block letters

LUNG, LEFT, BIOPSY:
- ADENOCARCINOMA, LEPIDIC GROWTH; INVASION CANNOT BE EXCLUDED IN THIS SMALL SPECIMEN.

LUNG, RIGHT UPPER LOBE, NEEDLE BIOPSY:
- INVASIVE ADENOCARCINOMA, NON-MUCINOUS.

COMMENT:
The tumour stains as follows:
POSITIVE: TTF-1.
NEGATIVE: p40.

The immunoprofile is compatible with lung adenocarcinoma.

MASS, LEFT LOWER LOBE OF LUNG, BIOPSY:
- INVASIVE ADENOCARCINOMA.

COMMENT:
The tumour is positive for TTF-1.

Tissue will be sent for molecular testing and the results reported as an addendum.

Resection

LUNG, LEFT UPPER LOBE, LOBECTOMY:
- ADENOCARCINOMA WITH AN ACINAR PATTERN, SOLID PATTERN, MICROPAPILLARY PATTERN 
  AND LEPIDIC PATTERN -- PATTERNS IN ORDER OF PREVALENCE.
- MARGINS NEGATIVE FOR MALIGNANCY.
- THREE LYMPH NODES NEGATIVE FOR MALIGNANCY (0 POSITIVE/3).
- PLEASE SEE TUMOUR SUMMARY.

LUNG, RIGHT UPPER LOBE, LOBECTOMY:
- MULTIPLE ADENOCARCINOMAS (x2) WITH AN ACINAR PATTERN, SOLID PATTERN, MICROPAPILLARY PATTERN 
  AND LEPIDIC PATTERN -- PATTERNS IN ORDER OF PREVALENCE.
- MARGINS NEGATIVE FOR MALIGNANCY.
- FOUR LYMPH NODES NEGATIVE FOR MALIGNANCY (0 POSITIVE/4).
- LYMPHOVASCULAR INVASION PRESENT.
- PLEASE SEE TUMOUR SUMMARY AND COMMENT.

COMMENT:
The histology of the two adenocarcinomas resemble one another and lymphovascular
invasion is present.  These findings favour that the smaller tumor is a metastasis, rather
than a synchronous primary.

Micro

Size (tissue): scant tissue (<0.5 cm).
Gland formation: focal, poorly formed.
Cell size: large.
Cytoplasm: moderate-to-abundant, grey-eosinophilic.
Nucleus location: eccentric.
Nuclear pleomorphism: moderate.
Nuclear moulding: absent.
Nucleoli: present, prominent.
Nuclear pseudoinclusions: present.

Number of cores: 3.
Length of cores (total): 2.0 cm.

Gland formation: present.
Cell size: large.
Cytoplasm: moderate, grey-eosinophilic.
Necrosis: none apparent.
Mucin: none.

Nucleus location: eccentric.
Nuclear pleomorphism: moderate.
Nuclear moulding: absent.
Nuclear pseudoinclusions: absent.
Nuclear shape/arrangment: cigar-like/pseudostratified.
Nucleoli: present.

Mucinous

The sections show cores with well-formed glands composed of foveolar-like columnar cells with a relatively bland cytomorphology. Mitotic activity is not readily apparent. A small amount of non-lesional lung parenchyma is present.

Lung cancer staging

Main article: Lung cancer staging

See also

• Lung tumours.
• Adenocarcinoma.
• Metastasis.
• Lung carcinoma with ALK rearrangement.
• SMARCA4-deficient adenocarcinoma of the lung.

External links

• Lung cancer staging (cancer.org).
• Thoracic lymph node stations (nucmedresource.com).