Adenocarcinoma in situ

Editorial Board Member: Jefree J. Schulte, M.D.
Deputy Editor-in-Chief: Andrey Bychkov, M.D., Ph.D.
Atreyee Basu, M.D.
Fang Zhou, M.D.

Last author update: 15 December 2022
Last staff update: 15 December 2022

Copyright: 2022,, Inc.

PubMed Search: Adenocarcinoma in situ

Atreyee Basu, M.D.
Fang Zhou, M.D.
Page views in 2022: 7,440
Page views in 2023 to date: 8,415
Cite this page: Basu A, Zhou F. Adenocarcinoma in situ. website. Accessed October 4th, 2023.
Definition / general
  • Preinvasive lung adenocarcinoma
  • Size: ≤ 30.0 mm
  • Pure lepidic growth pattern with no invasion (neoplastic cells along pre-existing alveolar structures)
  • Diagnosed only when all tumor has been sampled
  • Diagnosis cannot be made in small biopsy or cytology specimen
Essential features
  • Lepidic growth with no stromal, vascular or pleural invasion
  • Size: ≤ 30.0 mm
  • Diagnosed only after complete sampling of a resected lesion
  • Bronchioloalveolar carcinoma (historical term, obsolete)
ICD coding
  • ICD-O:
    • 8250/2 - adenocarcinoma in situ, nonmucinous
    • 8253/2 - adenocarcinoma in situ, mucinous
  • Multistep progression model (Ann Oncol 2015;26:156, Int J Mol Sci 2018;19:1259)
    • Adenocarcinoma in situ (AIS) is the step between atypical adenomatous hyperplasia (AAH) and minimally invasive carcinoma (MIA)
    • Incidence of EGFR mutations increases from atypical adenomatous hyperplasia → adenocarcinoma in situ → minimally invasive carcinoma
    • KRAS and BRAF mutations do not show same progression, suggesting other molecular alterations are also involved in tumor evolution
  • EPPK1, KMT2C, KMT2D, NOTCH3 and NF1 mutations may present as early events in the progression of lung adenocarcinoma (Am J Respir Crit Care Med 2020;201:697)
  • Same as invasive lung adenocarcinoma
    • #1 risk factor is tobacco smoking
    • Possible risk factors in never smokers: secondhand smoke, radon, occupational exposures, air pollution
    • Most cases of lung cancer in never smokers are idiopathic, with different mutational profile than smoking related lung cancer
  • Reference: J Thorac Oncol 2012;7:1352
Clinical features
  • Often incidental
  • May occur alone or along with invasive adenocarcinoma as a separate focus
  • Slow growing
  • May or may not be seen on CT or MRI, depending on size and association with scar
  • Radiologic features that suggest indolence (Ann Am Thorac Soc 2015;12:1193):
    • Small size
    • Longer volumetric doubling time (> 400 days)
    • Maximum standardized uptake value (SUV) < 1
  • Definitive diagnosis requires excision and histopathologic evaluation
Radiology description
Radiology images

Images hosted on other servers:

AIS as ground glass lesion

Prognostic factors
Case reports
Gross description
Gross images

Contributed by Atreyee Basu, M.D. and Fang Zhou, M.D.

Firm, tan, ill defined lesion

Frozen section description
  • Lepidic pattern adenocarcinoma with mild to moderate cytologic atypia
  • Do not diagnose as adenocarcinoma in situ on frozen section; invasion may be present on deeper levels or in the remainder of the tumor that was not submitted for frozen section
  • If no invasion is seen on frozen, one may call it adenocarcinoma with the lepidic pattern on 1 representative section, pending evaluation of permanent sections (or the remainder of the tumor)
  • Reference: J Clin Pathol 2016;69:1076
Frozen section images

Contributed by Atreyee Basu, M.D. and Fang Zhou, M.D.

Neoplastic cells, lepidic pattern

Microscopic (histologic) description
  • Lepidic growth pattern only: back to back neoplastic cells growing along pre-existing alveolar structures only
  • No stromal, vascular or pleural invasion; no necrosis
  • Diagnosed only in resections after complete sampling
  • Cannot be diagnosed in small biopsies, cytology or frozen sections (differential diagnosis minimally invasive carcinoma and invasive adenocarcinoma)
  • Size: ≤ 30.0 mm
  • Nonmucinous adenocarcinoma in situ = mild to moderate cytologic atypia, consisting of various combinations of the following features: nuclear membrane irregularity, intranuclear pseudoinclusions, nuclear grooves, hyperchromasia, anisocytosis, small nucleoli, increased nuclear to cytoplasmic ratio, hobnailing
    • Not all features may be present
  • Mucinous type adenocarcinoma in situ = extremely rare; mucinous tumors are usually associated with invasion
    • Mucinous cells show minimal atypia with abundant intracellular mucin and basally oriented nuclei
  • References: J Thorac Oncol 2016;11:1204, Int J Mol Sci 2018;19:1259
Microscopic (histologic) images

Contributed by Atreyee Basu, M.D. and Fang Zhou, M.D.

Neoplastic cells, lepidic pattern

Neoplastic cells, nuclear atypia

Cytology description
  • Mild to moderate cytologic atypia
  • Nuclear membrane irregularity, nuclear grooves and intranuclear pseudoinclusions (resembles papillary thyroid carcinoma cytology)
  • Definitive diagnosis requires excision
Cytology images

Contributed by Atreyee Basu, M.D. and Fang Zhou, M.D.

Nuclear irregularities and anisocytosis

Nuclear pseudoinclusions and grooves

Nuclear atypia

TTF1 immunostain

Positive stains
Negative stains
Molecular / cytogenetics description

Adenocarcinoma in situ
by Dr. Thomas Colby

Sample pathology report
  • Lung, middle lobe, right, lobectomy:
    • Adenocarcinoma in situ (pTis) (see synoptic report)
    • Tumor size: 25.0 mm
    • Bronchial and vascular margins are negative for carcinoma

  • Lung, right upper lobe; biopsy:
    • Adenocarcinoma with lepidic pattern
  • Note: Adenocarcinoma in situ cannot be definitely diagnosed until the entire tumor is examined and invasive adenocarcinoma ruled out. Thus, on small biopsy specimens, potential cases of adenocarcinoma in situ are signed out as above.
Differential diagnosis

Table 1: Differential diagnosis of lepidic predominant lung tumors
Overall size ≤ 30.0 mm Overall size > 30.0 mm

Lepidic pattern only

Adenocarcinoma in situ
Adenocarcinoma, lepidic predominant
(stage as pT1a)
Invasion ≤ 5.0 mm Minimally invasive adenocarcinoma Adenocarcinoma, lepidic predominant
Invasion > 5.0 mm Adenocarcinoma, lepidic predominant Adenocarcinoma, lepidic predominant
Board review style question #1

What is the most commonly mutated gene associated with adenocarcinoma in situ?

  1. ALK
  2. BRCA
  3. EGFR
  4. PIK3CA
Board review style answer #1
Board review style question #2
On a resection specimen in which the tumor is entirely submitted, there is a 28.0 mm tumor with 2.0 mm of stromal invasion (acinar pattern). What is the diagnosis?

  1. Acinar predominant with lepidic adenocarcinoma
  2. Adenocarcinoma in situ
  3. Lepidic predominant with acinar adenocarcinoma
  4. Minimally invasive carcinoma
Board review style answer #2
D. Minimally invasive carcinoma

Comment Here

Reference: Adenocarcinoma in situ
Back to top
Image 01 Image 02