Researchers have identified markers that can distinguish between major subtypes of lung cancer

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Example Images of squamous cell carcinoma (Left) and adenocarcinoma (Right). Notice: 1. Elongated or spindle cells are more abundant in squamous; 2. Squamous has more clear cell boarders; 3. Squamous usually are more pink while Adeno are more purple or blue.

By examining both blood samples and tumor tissues from patients with non-small-cell lung cancer (NSCLC), investigators at Massachusetts General Hospital (MGH) have identified markers that can distinguish between major subtypes of lung cancer and can accurately identify lung cancer stage.

Their proof-of-concept test accurately predicted whether the blood samples they examined came from patients with shorter or longer survival following lung cancer surgery, including patients with early-stage disease.

Their findings could eventually help physicians decide whether an individual patient with lung cancer can benefit from standard treatment or may need more aggressive therapy.

The study is published in the open-access journal Scientific Reports.

The US Preventive Services Task Force currently recommends that middle-age and older persons with a history of heavy smoking be screened annually for lung cancer with low-dose CT (computed tomography).

Low-dose CT is effective at detecting small lung tumors, but the cost of CT screening and risks of repeated radiation exposure prevent its use for screening of the general population.

This points to a need for a low cost, minimally invasive method for identifying people who may require further CT screening to catch the disease at earlier, more readily treatable stages, says co-principal investigator Leo L. Cheng, Ph.D., an associate biophysicist in the departments of Pathology and Radiology at MGH.

“You cannot use CT as a screening tool for every patient or even for every at-risk patient every year, so what we’re trying to do is to develop biomarkers from blood samples that could be incorporated into physical exams, and if there is any suspicion of lung cancer, then we would put the patient through CT,” Cheng says.

Along with co-principal investigator David C. Christiani, MD, MPH, a physician in the Department of Medicine at MGH, Cheng and other colleagues studied paired blood samples and tumor tissues taken at the time of surgery and looked for unique metabolomic markers using high-resolution magnetic resonance spectroscopy (MRS), a sensitive technique for characterizing the chemical composition of tissues.

Cheng says that although other research groups have used MRS to identify potential biomarkers of lung cancer in serum, “the uniqueness of our study is that we have paired samples from patients obtained at the same time as surgery.”

The paired specimens came from 42 patients with squamous cell carcinomas (SCC) of the lung, and 51 patients with adenocarcinomas of the lung.

The investigators also examined blood samples from 29 healthy volunteers who served as controls.

The patients included 58 with early (Stage I) lung cancer, and 35 with more advanced disease (Stage II, III, or IV).

The experiments were designed to see whether blood samples and tumor tissue samples from the same patient had common features that would identify the presence or absence of lung cancer, discriminate between cancer subtypes, and confirm the diagnostic accuracy of a simple blood test.

The investigators identified specific profiles of metabolites common to both types of samples and showed the differences between the profiles could signal whether a patient had SCC or adenocarcinoma, which require different treatments.

They also found that the profiles could distinguish between early-stage disease, which is often highly treatable, and later disease stages which require more aggressive or experimental treatments.

Importantly, the tests also identified whether the samples came from patients who lived an average of 41 months after surgery, or from those patients who lived longer than 41 months.

This finding, if validated in further studies, could identify early on those patients at especially high risk for early death, who might benefit from clinical trials of new drugs.

The ultimate goal of the study is to develop a blood test that could be included as part of a standard physical and could indicate whether a specific patient has suspicious signs pointing to lung cancer. Patients identified by the blood screen would then be referred for CT.


Lung cancer is the leading cause of cancer-related deaths worldwide in both men and women (1). It is categorized into two main histological groups: small cell lung carcinoma (SCLC, 15% of all lung cancers) and non-SCLC (NSCLC, 85% of all lung cancers). NSCLCs are generally subcategorized into adenocarcinoma, squamous cell carcinoma (SqCC), and large cell carcinoma. Accumulating evidence suggests that lung cancer represents a group of histologically and molecularly heterogeneous diseases even within the same histological subtype (226).

The histopathological classification of lung cancer has recently been revised and published as the 2015 WHO classification (2). Several major revisions were made in this classification to reflect recent discoveries related to the molecular pathology of lung cancer.

Human comprehensive molecular characterization projects have resulted in the identification of novel molecular characteristics of lung cancer and the different subtypes at levels of DNA alteration, DNA methylation, mRNA expression, microRNA expression, and protein expression. This review introduces and briefly summarizes recent studies on the molecular pathology of lung cancer with a focus on the association between molecular profiles and morphology (2).Go to:

The 2015 Who Classification

The WHO classification was updated based on newly identified molecular profiles and targetable genetic alterations in lung cancer.

For lung adenocarcinoma, the 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society classification (27) was mostly adopted in the 2015 WHO classification.

Table ​Table 1 shows the WHO classification of lung tumors (epithelial tumors) (2).

The major revisions to the WHO classification are described below.

Table 1

WHO classification of tumors of the lung (epithelial tumors) (2).

AdenocarcinomaLarge cell carcinoma
 Lepidic adenocarcinomaAdenosquamous carcinoma
 Acinar adenocarcinomaPleomorphic carcinoma
 Papillary adenocarcinomaSpindle cell carcinoma
 Micropapillary adenocarcinomaGiant cell carcinoma
 Solid adenocarcinomaCarcinosarcoma
 Variants of adenocarcinomaPulmonary blastoma
 Invasive mucinous adenocarcinomaOther and unclassified carcinomas
 Mixed invasive mucinous and non-mucinous adenocarcinomaLymphoepithelioma-like carcinoma
 Colloid adenocarcinomaNUT carcinoma
 Fetal adenocarcinomaSalivary gland-type tumors
 Enteric adenocarcinomaMucoepidermoid carcinoma
 Minimally invasive adenocarcinomaAdenoid cystic carcinoma
 Non-mucinousEpithelial–myoepithelial carcinoma
 MucinousPleomorphic adenoma
 Preinvasive lesionsPapillomas
 Atypical adenomatous hyperplasiaSquamous cell papilloma
 Adenocarcinoma in situExophytic
 Non-mucinousInverted
 MucinousGlandular papilloma
Squamous cell carcinoma (SqCC)Mixed squamous cell and glandular papilloma
 Keratinizing SqCCAdenomas
 Non-keratinizing SqCCSclerosing pneumocytoma
 Basaloid SqCCAlveolar adenoma
 Preinvasive lesionPapillary adenoma
 SqCC in situMucinous cystadenoma
Neuroendocrine tumorsMucous gland adenoma
 Small cell carcinoma
 Combined small cell carcinoma
 Large cell neuroendocrine carcinoma (LCNEC)
 Combined LCNEC
 Carcinoid tumors
 Typical carcinoid
 Atypical carcinoid
 Preinvasive lesion
 Diffuse idiopathic pulmonary neuroendocrine cell
 Hyperplasia

Definition of Adenocarcinoma and SqCC

Pathologists are required to categorize lung cancer into adenocarcinoma and SqCC due to the targetable driver genetic alterations identified in lung adenocarcinoma and inappropriate drugs for SqCCs due to side effects in patients with SqCC.

Before the 2015 WHO classification, adenocarcinoma was defined as carcinoma with an acinar/tubular structure or mucin production, whereas SqCC was defined as carcinoma with keratinization or intercellular bridges.

If poorly differentiated carcinoma lacking light microscopic evidence of glandular differentiation (Figure ​(Figure1A)1A)

is proven by immunohistochemistry to express “adenocarcinoma markers,” such as TTF-1 (Figure ​(Figure1B)1B) and/or Napsin A (Figure ​(Figure1C),1C), it is diagnosed as a solid adenocarcinoma.

If poorly differentiated carcinoma lacking light microscopic evidence of squamous differentiation (Figure ​(Figure1D)1D) is proven by immunohistochemistry to express “SqCC markers,” (28) such as p40 (Figure ​(Figure1E),1E), CK5/6 (Figure ​(Figure1F),1F), and p63, it is diagnosed as non-keratinizing SqCC. Because of this classification, the proportion of large cell carcinoma has been markedly reduced.

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Figure 1
Solid adenocarcinoma (A–C) and non-keratinizing squamous cell carcinoma (SqCC) (D–F). Solid adenocarcinoma [(A) HE staining] is immunohistochemically positive for TTF-1 (B) and Napsin A (C). Non-keratinizing SqCC [(D) HE staining] is immunohistochemically positive for p40 (E) and CK5/6 (F).

Adenocarcinoma

Classification according to the Extent of Invasiveness

The 2015 WHO classification divides adenocarcinomas into adenocarcinoma in situ (AIS, preinvasive lesion), minimally invasive adenocarcinoma (MIA), or (overt) invasive adenocarcinoma based on the extent of invasiveness.

The disease-free survival rate of AIS and MIA when completely resected is 100% (29).

Adenocarcinoma in situ is defined as an adenocarcinoma comprising a lepidic pattern with a diameter of ≤3 cm.

If the tumor diameter exceeds 3 cm, it is defined as “lepidic predominant adenocarcinoma, suspect AIS” because these tumors are rare and lack adequate characterization.

Minimally invasive adenocarcinoma is defined as an adenocarcinoma with a diameter of ≤3 cm and an invasion size of ≤5 mm.

Even if the tumor size and invasion size comply with the definition of MIA, the presence of lymphovascular invasion, pleural invasion, or tumor necrosis can be an exclusion factor for an MIA diagnosis.

If the tumor size exceeds 3 cm with an invasion size of ≤5 mm, it is defined as “lepidic predominant adenocarcinoma, suspect MIA” because these tumors are rare and lack adequate characterization.

The term “invasive adenocarcinoma, mixed subtype” for invasive adenocarcinoma is no longer used. Invasive adenocarcinoma is now classified using five predominant patterns: lepidic, papillary, acinar, micropapillary, and solid adenocarcinoma.

Variants of Invasive Adenocarcinoma

The term “mucinous bronchioloalveolar carcinoma (BAC)” is no longer used because most mucinous BACs included invasive components.

Therefore, the term “invasive mucinous adenocarcinoma (IMA)” replaced mucinous BAC. IMA and mucinous AIS are accurately classified based on invasiveness.

Besides IMA, variants of invasive adenocarcinoma comprise enteric, colloid, and fetal adenocarcinoma. Enteric adenocarcinoma is defined as adenocarcinoma with a predominant component that resembles adenocarcinoma arising in the colorectum and often shows CDX2 immunoreactivity (30).

Squamous Cell Carcinoma

In the 2015 WHO classification, SqCCs are classified into keratinizing SqCC, non-keratinizing SqCC, and basaloid SqCC.

Before this classification, basaloid SqCC was categorized as a variant of large cell carcinoma. However, basaloid SqCC immunohistochemically shows “SqCC markers” (e.g., p40, CK5/6, and p63) and is therefore categorized as SqCC.

Neuroendocrine Tumors

In the 2015 WHO classification, a new category of “neuroendocrine tumors” was established.

Invasive neuroendocrine tumors comprise three subtypes: SCLC, large cell neuroendocrine carcinoma (LCNEC), and carcinoid tumor (typical/atypical).

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is extremely rare and non-invasive; therefore, its clinical importance is low.

On the other hand, the distinction between a high-grade neuroendocrine tumor (HGNET), comprising SCLC and LCNEC, and a carcinoid tumor is very important in both pathological and clinical practice.

HGNET is one of the most aggressive subtypes and characterized by a history of heavy smoking in the patient, whereas carcinoid tumors usually carry a benign prognosis and frequently occur in patients with no history of smoking.


More information:Scientific Reports (2019). DOI: 10.1038/s41598-019-46643-5

Journal information: Scientific Reports
Provided by Massachusetts General Hospital

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