International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma

Abstract

Introduction: Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies.

Methods: An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach.

Results: The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤ 5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized.

Conclusions: This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.

Conflict of interest statement

Disclosure: The other authors declare no conflicts of interest.

Figures

Figure 1

Atypical adenomatous hyperplasia. A, This 3-mm nodular lesion consists of atypical pneumocytes proliferating along preexisting alveolar walls. There is no invasive component. B, The slightly atypical pneumocytes are cuboidal and show gaps between the cells. Nuclei are hyperchromatic, and a few show nuclear enlargement and multinucleation.

Figure 2

Nonmucinous adenocarcinoma in situ. A, This circumscribed nonmucinous tumor grows purely with a lepidic pattern. No foci of invasion or scarring are seen. B, The tumor shows atypical pneumocytes proliferating along the slightly thickened, but preserved, alveolar walls.

Figure 3

Mucinous adenocarcinoma in situ. A, This mucinous AIS consists of a nodular proliferation of mucinous columnar cells growing in a purely lepidic pattern. Although there is a small central scar, no stromal or vascular invasion is seen. B, The tumor cells consist of cuboidal to columnar cells with abundant apical mucin and small basally oriented nuclei. AIS, adenocarcinoma in situ.

Figure 4

Nonmucinous minimally invasive adenocarcinoma. A, This subpleural adenocarcinoma tumor consists primarily of lepidic growth with a small (<0.5 cm) central area of invasion. B, To the left is the lepidic pattern and on the right is an area of acinar invasion. C, These acinar glands are invading in the fibrous stroma.

Figure 5

Mucinous minimally invasive adenocarcinoma. A, This mucinous MIA consists of a tumor showing lepidic growth and a small (<0.5 cm) area of invasion. B, The tumor cells consist of mucinous columnar cells growing mostly in a lepidic pattern along the surface of alveolar walls. The tumor invades the areas of stromal fibrosis in an acinar pattern. MIA, minimally invasive adenocarcinoma.

Figure 6

Major histologic patterns of invasive adenocarcinoma. A, Lepidic predominant pattern with mostly lepidic growth (right) and a smaller area of invasive acinar adenocarcinoma (left). B, Lepidic pattern consists of a proliferation type II pneumocytes and Clara cells along the surface alveolar walls. C, Area of invasive acinar adenocarcinoma (same tumor as in A and B). D, Acinar adenocarcinoma consists of round to oval-shaped malignant glands invading a fibrous stroma. E, Papillary adenocarcinoma consists of malignant cuboidal to columnar tumor cells growing on the surface of fibrovascular cores. F, Micropapillary adenocarcinoma consists of small papillary clusters of glandular cells growing within this airspace, most of which do not show fibrovascular cores. G, Solid adenocarcinoma with mucin consisting of sheets of tumor cells with abundant cytoplasm and mostly vesicular nuclei with several conspicuous nucleoli. No acinar, papillary, or lepidic patterns are seen, but multiple cells have intracytoplasmic basophilic globules that suggest intracytoplasmic mucin. H, Solid adenocarcinoma with mucin. Numerous intracytoplasmic droplets of mucin are highlighted with this DPAS stain. DPAS, diastase-periodic acid Schiff.

Figure 7

Invasive mucinous adenocarcinoma. A, This area of invasive mucinous adenocarcinoma demonstrates a pure lepidic growth. The tumor consists of columnar cells filled with abundant mucin in the apical cytoplasm and shows small basal oriented nuclei. B, Nevertheless, elsewhere this tumor demonstrated invasion associated with desmoplastic stroma and an acinar pattern.

Figure 8

Adenocarcinoma, variants. A, Colloid adenocarcinoma consists of abundant pools of mucin growing within and distending airspaces. Focally well-differentiated mucinous glandular epithelium grows along the surface of fibrous septa and within the pools of mucin. Tumor cells may be very inconspicuous. B, This colloid adenocarcinoma contains a cystic component surrounded by a fibrous wall that is filled with pools of mucin; such a pattern was previously called mucinous cystadenocarcinoma. The surface of the fibrous wall is lined by well-differentiated cuboidal or columnar mucinous epithelium. C, Fetal adenocarcinoma consists of malignant glandular cells growing in tubules and papillary structures. These tumor cells have prominent clear cytoplasm, and squamoid morules are present. D, Enteric adenocarcinoma consists of an adenocarcinoma that morphologically resembles colonic adenocarcinoma with back-to-back angulated acinar structures. The tumor cells are cuboidal to columnar with nuclear pseudostratification.

Figure 9

Algorithm for adenocarcinoma diagnosis in small biopsies and/or cytology. Step 1: When positive biopsies (fiberoptic bronchoscopy [FOB], transbronchial [TBBx], core, or surgical lung biopsy [SLBx]) or cytology (effusion, aspirate, washings, and brushings) show clear adenocarcinoma (ADC) or squamous cell carcinoma (SQCC) morphology, the diagnosis can be firmly established. If there is neuroendocrine morphology, the tumor may be classified as small cell carcinoma (SCLC) or non-small cell lung carcinoma (NSCLC), probably large cell neuroendocrine carcinoma (LCNEC) according to standard criteria (+ = positive, − = negative, and ± = positive or negative). If there is no clear ADC or SQCC morphology, the tumor is regarded as NSCLC-not otherwise specified (NOS). Step 2: NSCLC-NOS can be further classified based on (a) immunohistochemical stains (b) mucin (DPAS or mucicarmine) stains, or (c) molecular data. If the stains all favor ADC: positive ADC marker(s) (i.e., TTF-1 and/or mucin positive) with negative SQCC markers, then the tumor is classified as NSCLC, favor ADC. If SQCC markers (i.e., p63 and/or CK5/6) are positive with negative ADC markers, the tumor is classified as NSCLC, favor SQCC. If the ADC and SQCC markers are both strongly positive in different populations of tumor cells, the tumor is classified as NSCLC-NOS, with a comment it may represent adenosquamous carcinoma. If all markers are negative, the tumor is classified as NSCLC-NOS. See text for recommendations on NSCLCs with marked pleomorphic and overlapping ADC/SQCC morphology. †EGFR mutation testing should be performed in (1) classic ADC, (2) NSCLC, favor ADC, (3) NSCLC-NOS, and (4) NSCLC-NOS, possible adenosquamous carcinoma. In a NSCLC-NOS, if EGFR mutation is positive, the tumor is more likely to be ADC than SQCC. Step 3: If clinical management requires a more specific diagnosis than NSCLC-NOS, additional biopsies may be indicated (−ve = negative; +ive = positive; TTF-1: thyroid transcription factor-1; DPAS +ve: periodic-acid-Schiff with diastase; +ve: positive; e.g., IHC, immunohistochemistry; NE, neuroendocrine; CD, cluster designation; CK, cytokeratin; NB, of note). EGFR, epidermal growth factor receptor; DPAS, diastase-periodic acid Schiff.

Figure 10

Adenocarcinoma in small biopsy and cytology. Poorly differentiated non-small cell carcinoma, favor adenocarcinoma. A, This core biopsy shows a solid pattern of growth, and morphologically, it lacks any acinar, papillary, or lepidic patterns. The mucin stain was also negative. B, The TTF-1 stain is strongly positive. C, The p63 stain is very focally positive. The strongly and diffusely positive TTF-1 and only focal p63 staining favor adenocarcinoma. In this case, EGFR mutation was positive. D, Cytology from different adenocarcinoma shows large malignant cells with abundant cytoplasm and prominent nuclei growing in an acinar structure. EGFR, epidermal growth factor receptor; TTF, thyroid transcription factor.

Figure 11

CT of preinvasive lesion (AAH or AIS). Axial 2-mm image through the left upper lobe shows a 5 mm pure ground-glass nodule (GGN), which has remained stable for 8 years (arrow). AAH and AIS can be single or multiple. AIS, adenocarcinoma in situ; CT, computed tomography.

Figure 12

CT of a peripheral 2 cm nonmucinous AIS. A, Axial CT section. B, Coronal maximal intensity projection (MIP) image shows a pure GGN in the left lower lobe. Vessels and lung architecture are seen through the nodule. AIS, adenocarcinoma in situ; CT, computed tomography; GGN, ground-glass nodule.

Figure 13

CT of mucinous adenocarcinoma in situ; 2 cm predominantly solid nodule with air bronchogram (arrow) is noted in the left upper lobe. CT, computed tomography.

Figure 14

CT of nonmucinous minimally invasive adenocarcinoma. Axial 2-mm CT section shows a peripheral, predominantly ground-glass, part-solid nodule in the right upper lobe that includes a 4 × 3 mm solid component (arrow), which corresponded to invasion by pathology. CT, computed tomography.

Figure 15

CT and FDG-PET of invasive adenocarcinoma. A, Axial CT image and (B) FDG-PET images show a 2-cm spiculated hypermetabolic solid nodule in the left lower lobe. CT, computed tomography; FDG-PET, fluorodeoxyglucose positron emission tomography.

Figure 16

Invasive adenocarcinoma. A, Axial CT image shows a part-solid nodule in the left upper lobe. B, Corresponding sagittal CT images show automated estimation of the volume of (B) the solid component (1.188 cm3) and (C) the entire lesion (8.312 cm3). In this case, if tumor size were measured only by the invasive component, the size T factor would change from T2a (3.2 cm) to T1a (1.8 cm). Recording of total and invasive sizes are suggested until it is known whether invasive size predicts prognosis better than total size. CT, computed tomography.

Figure 17

CT of nonmucinous lepidic predominant adenocarcinoma. CT images show (A) predominantly GGO in the right upper lobe and (B) multiple GGN in the right lower lobe. CT, computed tomography; GGN, ground-glass nodule.

Figure 18

CT of invasive mucinous adenocarcinoma. A, Axial and (B) coronal CT images show multilobar consolidation and nodules mixed with GGO. Air bronchograms are present. CT, computed tomography; GGO, ground-glass opacity.

Figure 19

CT and FDG PET of invasive mucinous adenocarcinoma. A, Coronal CT and (B) FDG-PET images show a hypermetabolic hypodense solid 4 cm mass in the right lower lobe. CT, computed tomography; FDG-PET, fluorodeoxyglucose positron emission tomography.

Figure 20

CT of multicentric GGNs of AIS/AAH. A and B, Multiple subsolid nodules (arrows) on axial 3-mm CT images show differing sizes and attenuation. These were presumed to represent preinvasive lesions (AAH and AIS). Because the dominant nodule in the right upper lobe posteriorly near the fissure in part A (large arrowhead) appears somewhat dense, it was excised surgically and found to be nonmucinous AIS. AAH, atypical adenomatous hyperplasia; AIS, adenocarcinoma in situ; CT, computed tomography; GGN, ground-glass nodule.