Lung cancer classification

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Classification

Lung carcinomas are classified by the WHO Classification of Thoracic Tumours, 5th edition (2021).[1] The diagnostic approach proceeds from morphology to immunohistochemistry (IHC) to molecular testing. Compared with the 2015 edition, the 2021 classification adds greater emphasis on genetic testing, a dedicated framework for small biopsies, formal grading of invasive nonmucinous adenocarcinoma, recognition of spread through air spaces (STAS), reorganized squamous and neuroendocrine categories, and new entities including thoracic SMARCA4-deficient undifferentiated tumor.[1]

Anatomic extent is classified with the IASLC/AJCC/UICC TNM 9th edition, effective January 1, 2025.[2][3] The T category is unchanged from the 8th edition; N2 and M1c are now subdivided.[2][3]

The broad clinical division into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) remains useful for initial management. However, treatment selection now requires a specific histologic subtype plus a molecular profile.[4] Molecular status is recorded as a descriptor on the histologic diagnosis—for example, "invasive nonmucinous adenocarcinoma, IASLC grade 3, EGFR exon 19 deletion"—not as a separate tumor type.[4]

NSCLC Histologic Types (WHO 2021)

Entity Defining criteria Classification caveat
Adenocarcinoma in situ (AIS) ≤3 cm, pure lepidic growth, usually nonmucinous Formerly "bronchioloalveolar carcinoma" (BAC). Staged Tis(AIS). Can be multiple.[1]
Minimally invasive adenocarcinoma (MIA) ≤3 cm, lepidic-predominant, invasion ≤5 mm Staged T1mi. When multiple lepidic lesions are present, stage as one multifocal tumor using highest T plus "m" (see Multiple Pulmonary Sites).[5]
Invasive nonmucinous adenocarcinoma Glandular differentiation, mucin, or pneumocyte markers; invasive focus >5 mm Lepidic, acinar, papillary, micropapillary, and solid are growth patterns within one tumor, not separate tumor types. Graded by the IASLC system (see below).[1][6]
Adenocarcinoma variants Invasive mucinous, colloid, fetal, enteric No validated grading for invasive mucinous adenocarcinoma.[1][5]
Squamous cell carcinoma Keratinization and/or intercellular bridges, or undifferentiated NSCC with squamous IHC markers Keratinizing, nonkeratinizing, and basaloid. Lymphoepithelial carcinoma moved here in 2021.[1][7]
Adenosquamous carcinoma Each component ≥10% Definitive diagnosis requires a resection. Any adenocarcinoma component in a squamous biopsy should trigger molecular testing.[1]
Large cell carcinoma Undifferentiated NSCC, negative for TTF-1/napsin A and p40/p63 Cannot be diagnosed on biopsy or cytology.[1]
Sarcomatoid carcinoma Pleomorphic carcinoma (≥10% spindle/giant cells), carcinosarcoma, pulmonary blastoma Use the specific term. High grade by definition.[1][5]

Genetically Defined Undifferentiated Tumors ("Other Epithelial Tumors")

  • NUT carcinoma
    • Monomorphic undifferentiated cells, often with abrupt keratinization.
    • Usually p40-positive, NUT IHC-positive, with NUTM1 rearrangement.
    • Typically affects young never-smokers and presents at advanced stage.[7]
    • NCCN recommends considering NUT IHC in any poorly differentiated carcinoma without glandular differentiation, particularly in young patients or those who do not smoke (category 2A).[8]
  • Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT)
    • New WHO 2021 entity, renamed from "SMARCA4-deficient thoracic sarcoma."[9]
    • IHC: loss of BRG1, often with SMARCA2 co-loss; SOX2, SALL4, and CD34 positive; cytokeratin weak or absent.[10]
    • Differs from SMARCA4-deficient NSCLC, which is usually CK7-positive adenocarcinoma.[10]

Small Biopsy and Cytology Terminology (NCCN, category 2A)

  • Two goals: make a WHO 2021 diagnosis and preserve tissue for molecular testing.[8]
  • Preferred terms: "NSCC, favor adenocarcinoma" and "NSCC, favor squamous cell carcinoma." Use "NSCC-NOS" only when IHC is uninformative or ambiguous.[8]
  • Minimal IHC panel: one adenocarcinoma marker (TTF-1 or napsin A) plus one squamous marker (p40 or p63). TTF-1 plus p40 usually suffices.[8]
    • Tumors without squamous morphology that co-express p63 and TTF-1 are preferably classified as adenocarcinoma.[8]
  • Marker performance:
    • TTF-1 is positive in 70–90% of nonmucinous adenocarcinomas; napsin A in >80%.[8]
    • Metastatic thyroid carcinoma is TTF-1-positive. Rare gynecologic and pancreatobiliary tumors can be TTF-1-positive, depending on the antibody clone.[8]

IASLC Grading of Invasive Nonmucinous Adenocarcinoma (WHO 2021; ICCR Core Element)

Grade Criteria
1 (well differentiated) Lepidic-predominant, <20% high-grade patterns[6]
2 (moderately differentiated) Acinar- or papillary-predominant, <20% high-grade patterns[6]
3 (poorly differentiated) ≥20% high-grade patterns (solid, micropapillary, cribriform, or complex glandular), whatever the predominant pattern[6]

Grade is independently prognostic after adjustment for visceral pleural invasion and STAS.[11]

When grading applies:

  • Resection specimens only.[5]
  • Grade is reported as "not applicable" for invasive mucinous adenocarcinoma, SCC, and adenosquamous carcinoma.[5]
  • Sarcomatoid carcinomas are high grade by definition; large cell carcinoma is undifferentiated.[5]
  • In part-lepidic tumors, only the invasive size determines the T category.[1]

Neuroendocrine Neoplasms (NENs)

WHO 2021 splits lung NENs into two groups:[12][13]

  • Well-differentiated neuroendocrine tumors: typical and atypical carcinoids.
  • Poorly differentiated neuroendocrine carcinomas: large cell neuroendocrine carcinoma (LCNEC) and SCLC.

Carcinoids are not NSCLC.

WHO 2021 diagnostic criteria (NCCN NE-E-6):[12]

Tumor Mitoses per 2 mm² Necrosis
Typical carcinoid <2 None
Atypical carcinoid 2–10 +/-
LCNEC >10 +
SCLC >10 +

Mitotic counting rules (NCCN SCLC, category 2A):[14]

  • Count mitoses per 2 mm² in the most active areas, not per 10 high-power fields.
  • Near the cutoffs of 2 or 10, average at least three 2-mm² fields rather than using the single highest count.
  • Expert thoracic pathology review is strongly recommended for diagnostic dilemmas.

Adjunct stains (NCCN SCLC):[14]

  • Ki-67: typically 50–100% in SCLC. Useful in crushed or necrotic biopsies where mitoses cannot be counted.
  • RB1 and p53: carcinoids generally retain RB1 and show wild-type p53. Most neuroendocrine carcinomas show RB1 loss and/or aberrant p53.
  • TTF-1: positive in 85–90% of SCLCs.
  • Neuroendocrine markers: fewer than 5% of SCLCs are negative for all of them. POU2F3 IHC can be considered when morphology suggests SCLC but neuroendocrine markers are negative.
  • CD56: not specific on its own.[15]

Combined tumors: SCLC with any NSCLC component is combined SCLC, with no minimum percentage. The exception is combination with LCNEC, which requires at least 10% LCNEC.[14]

Small biopsies: when typical cannot be separated from atypical carcinoid, report "carcinoid tumor/NET NOS." Use "metastatic carcinoid NOS" for metastatic samples.[13]

Pre-invasive lesions retained: atypical adenomatous hyperplasia and AIS (glandular), squamous carcinoma in situ, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH).[1]

Molecular Status as Descriptor

Driver status and PD-L1 layer onto histology as therapeutic subcategories.[4] They are recorded as descriptors on the histologic diagnosis, not as separate tumor types. For the biology of individual drivers and their prevalence, see Pathophysiology. For how and when to test, see Other diagnostic studies.

TNM Staging, 9th Edition

The 9th-edition lung TNM applies to NSCLC, SCLC, and bronchopulmonary carcinoids.[2][12]

T Descriptors (Selected)

  • Tis(AIS) versus Tis(SCIS): adenocarcinoma in situ versus squamous carcinoma in situ.[8]
  • T1mi: minimally invasive adenocarcinoma.[8]
  • T1a–c: ≤1 cm, >1–2 cm, >2–3 cm.[3]
  • T2a: >3–4 cm, or invades visceral pleura, adjacent lobe, main bronchus, or associated with atelectasis/obstructive pneumonitis to hilar region.[8]
  • T2b: >4–5 cm.[3]
  • T3: >5–7 cm, or invades parietal pleura/chest wall, pericardium, phrenic nerve, azygos vein, thoracic nerve roots or stellate ganglion; separate tumor nodule(s) in same lobe.[8]
  • T4: >7 cm, or invades mediastinum, thymus, trachea, carina, recurrent laryngeal nerve, vagus nerve, esophagus, diaphragm, heart, great vessels, supra-aortic arteries, brachiocephalic veins, subclavian vessels, vertebral body, lamina, spinal canal, cervical nerve roots, or brachial plexus; separate tumor nodule(s) in a different ipsilateral lobe.[8]

N Descriptors

  • N0: no regional nodal metastasis.[8]
  • N1: ipsilateral peribronchial, hilar, or intrapulmonary nodes, including direct extension.[8]
  • N2a: metastasis in a single ipsilateral mediastinal or subcarinal nodal station.[3]
  • N2b: metastases in multiple ipsilateral mediastinal nodal stations, with or without subcarinal involvement.[3]
  • N3: contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular nodes.[8]

M Descriptors

  • M1a: pleural or pericardial nodules, malignant pleural or pericardial effusion, or separate tumor nodule(s) in a contralateral lobe.[8]
  • M1b: single extrathoracic metastasis in a single organ system (including a single non-regional node).[8]
  • M1c1: multiple extrathoracic metastases in one organ system. The skeleton counts as one organ system.[8]
  • M1c2: multiple extrathoracic metastases in multiple organ systems.[8]

Stage Groups (9th Edition)

Stage T N M
Occult carcinoma TX N0 M0
Stage 0 Tis N0 M0
Stage IA1 T1mi or T1a N0 M0
Stage IA2 T1b N0 M0
Stage IA3 T1c N0 M0
Stage IB T2a N0 M0
Stage IIA T2b N0 M0
Stage IIA T1a–c N1 M0
Stage IIB T2a–b N1 M0
Stage IIB T1a–c N2a M0
Stage IIB T3 N0 M0
Stage IIIA T3 N1 M0
Stage IIIA T1a–c N2b M0
Stage IIIA T2a–b N2a M0
Stage IIIA T3 N2a M0
Stage IIIA T4 N0–N1 M0
Stage IIIB T1a–c N3 M0
Stage IIIB T2a–b N2b M0
Stage IIIB T2a–b N3 M0
Stage IIIB T3 N2b M0
Stage IIIB T4 N2a–b M0
Stage IIIC T3–4 N3 M0
Stage IVA Any T Any N M1a–b
Stage IVB Any T Any N M1c1–c2

[8][3]

Pleural effusion: an effusion is excluded as a staging descriptor only when repeated cytology is negative, the fluid is non-bloody and not an exudate, and clinical judgment indicates the effusion is unrelated to the tumor.[8]

Pathology reporting: document the number of involved nodal stations. Direct tumor extension into a node counts as nodal involvement.[8]

STAS

STAS is a histologic descriptor recorded in the 9th edition. It does not change the T category or stage group, is not counted in invasive size, and its presence rules out a diagnosis of AIS or MIA.[5][2]

Other Histologic Descriptors Not in TNM

Lymphovascular invasion and IASLC grade are not part of TNM. Visceral pleural invasion is a T2 descriptor. Recent data suggest grade and LVI add prognostic information within 9th-edition stage groups.[5]

Staging Prefixes

Staging prefixes (c, p, yp) should be recorded. Pathologic response after neoadjuvant therapy is relevant now that perioperative chemo-immunotherapy is routine.

SCLC Staging (VALSG vs TNM)

NCCN two-stage system (still recommended alongside TNM):[14]

  • Limited stage: stage I–III disease that can be treated safely with definitive radiation doses.
  • Extensive stage: stage IV, or T3–4 disease with nodules or tumor/nodal volume too extensive for a tolerable radiation plan.

Edition mismatch:

  • NCCN SCLC still prints AJCC 8th edition TNM tables.[14]
  • AJCC version 9 explicitly covers NSCLC, SCLC, and bronchopulmonary carcinoids.[12]

State the AJCC edition used whenever reporting SCLC stage.

Multiple Pulmonary Sites of Cancer (IASLC)

Pattern TNM rule
Second primary lung cancer Separate TNM for each tumor[16]
Separate tumor nodule, same histology T3 if same lobe, T4 if different ipsilateral lobe, M1a if contralateral. Single N and M.[16]
Multifocal ground-glass/lepidic adenocarcinoma (including MIA) Highest T plus (#) or (m), e.g., T1a(3)N0M0. Single N and M.[17]
Diffuse pneumonic-type adenocarcinoma Size (or T3) if one lobe, T4 if multiple ipsilateral lobes, M1a if bilateral.[17]

Telling a separate primary from a metastasis:

  • Reliable criteria are few: different histologic type, matching DNA breakpoints, or comprehensive histologic comparison. Biomarker, imaging, and nodal features are only suggestive.[18]
  • Most second primaries share histology, so similarity does not prove the tumors are related.[18]
  • The IASLC Pathology Committee's 2025 four-step algorithm combines histology with next-generation sequencing (NGS).[19]
  • If doubt remains, the ICCR advises reporting the lower-stage option.[5]
  • When several subsolid nodules are present, biopsy the dominant lesion (AATS COR IIa, LOE C-EO).[20] For biopsy technique, see Other diagnostic studies.

Non-Carcinoma Thoracic Tumors

Papillomas, adenomas, mesenchymal, lymphohistiocytic, and ectopic tumors belong to the WHO thoracic classification but are not lung cancer.[1] They are covered in Differentiating lung cancer from other diseases. Bronchiolar adenoma/ciliated muconodular papillary tumor is a new 2021 entity.[1]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 Nicholson AG, Tsao MS, Beasley MB, et al. The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015. J Thorac Oncol. 2022;17(3):362-387. doi:10.1016/j.jtho.2021.11.003.
  2. ↑ 2.0 2.1 2.2 2.3 Fong KM, Olive G, Marshall HM, Rami-Porta R, Detterbeck F. Ninth Edition of the Tumor, Node, and Metastasis Classification of Lung Cancer. Semin Respir Crit Care Med. 2025. doi:10.1055/a-2716-4877.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Rami-Porta R, Nishimura KK, Giroux DJ, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groups in the Forthcoming (Ninth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2024;19(7):1007-1027. doi:10.1016/j.jtho.2024.02.011.
  4. ↑ 4.0 4.1 4.2 Sasaki T, Kuno H, Hiyama T, et al. 2021 WHO Classification of Lung Cancer: Molecular Biology Research and Radiologic-Pathologic Correlation. Radiographics. 2024;44(3):e230136. doi:10.1148/rg.230136.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Cooper WA, Webster F, Butnor KJ, et al. Data set for the reporting of lung cancer: recommendations from the International Collaboration on Cancer Reporting (ICCR). Histopathology. 2025;86(5):665-680. doi:10.1111/his.15313.
  6. ↑ 6.0 6.1 6.2 6.3 Moreira AL, Ocampo PSS, Xia Y, et al. A Grading System for Invasive Pulmonary Adenocarcinoma: A Proposal From the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol. 2020;15(10):1599-1610. doi:10.1016/j.jtho.2020.06.001.
  7. ↑ 7.0 7.1 Naso J, Lo YC, Sholl LM. Updates in pathology and molecular diagnostics to inform the evolving landscape of thoracic surgery and oncology. J Surg Oncol. 2023;127(2):244-257. doi:10.1002/jso.27184.
  8. ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 8.13 8.14 8.15 8.16 8.17 8.18 8.19 8.20 8.21 National Comprehensive Cancer Network. Non-Small Cell Lung Cancer. NCCN Guidelines Version 9.2026.
  9. ↑ Chatzopoulos K, Boland JM. Update on genetically defined lung neoplasms: NUT carcinoma and thoracic SMARCA4-deficient undifferentiated tumors. Virchows Arch. 2021;478(1):21-30. doi:10.1007/s00428-020-03011-3.
  10. ↑ 10.0 10.1 Wang G, Zhou G, Han W, Jiang H. The role of SMARCA4 in lung cancer. Sci Rep. 2025;15(1):28605. doi:10.1038/s41598-025-13913-4.
  11. ↑ Tan KS, Reiner A, Emoto K, et al. Novel Insights Into the International Association for the Study of Lung Cancer Grading System for Lung Adenocarcinoma. Mod Pathol. 2024;37(7):100520. doi:10.1016/j.modpat.2024.100520.
  12. ↑ 12.0 12.1 12.2 12.3 National Comprehensive Cancer Network. Neuroendocrine and Adrenal Tumors. NCCN Guidelines Version 1.2026.
  13. ↑ 13.0 13.1 Pelosi G, Travis WD. Head-to-head: Should Ki67 proliferation index be included in the formal classification of pulmonary neuroendocrine neoplasms? Histopathology. 2024;85(4):535-548. doi:10.1111/his.15206.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 National Comprehensive Cancer Network. Small Cell Lung Cancer. NCCN Guidelines Version 1.2027.
  15. ↑ Kawasaki K, Rekhtman N, Quintanal-Villalonga Á, Rudin CM. Neuroendocrine neoplasms of the lung and gastrointestinal system: convergent biology and a path to better therapies. Nat Rev Clin Oncol. 2023;20(1):16-32. doi:10.1038/s41571-022-00696-0.
  16. ↑ 16.0 16.1 Detterbeck FC, Nicholson AG, Franklin WA, et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers With Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016;11(5):639-650. doi:10.1016/j.jtho.2016.01.024.
  17. ↑ 17.0 17.1 Detterbeck FC, Marom EM, Arenberg DA, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules With Ground Glass or Lepidic Features or a Pneumonic Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016;11(5):666-680. doi:10.1016/j.jtho.2015.12.113.
  18. ↑ 18.0 18.1 Detterbeck FC, Franklin WA, Nicholson AG, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers From Metastatic Foci in Patients With Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11(5):651-665. doi:10.1016/j.jtho.2016.01.025.
  19. ↑ Chou TY, Dacic S, Wistuba I, et al. Differentiating Separate Primary Lung Adenocarcinomas From Intrapulmonary Metastases With Emphasis on Pathological and Molecular Considerations: Recommendations From the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol. 2025;20(3):311-330. doi:10.1016/j.jtho.2024.11.016.
  20. ↑ Chen H, Kim AW, Hsin M, et al. The 2023 American Association for Thoracic Surgery (AATS) Expert Consensus Document: Management of Subsolid Lung Nodules. J Thorac Cardiovasc Surg. 2024;168(3):631-647.e11. doi:10.1016/j.jtcvs.2024.02.026.
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