Pathobiology and staging of small cell carcinoma of the lung

INTRODUCTION — Small cell lung cancer (SCLC) is distinguished from non-small cell lung cancer (NSCLC) by its rapid doubling time, high growth fraction, and the early development of widespread metastases. Although the cancer is initially highly responsive to chemotherapy, with or without immunotherapy, and radiotherapy, the majority of patients will relapse with broadly resistant disease within a few months to a year from initial therapy.

The epidemiology, pathology, clinical presentation, staging, and prognostic factors of SCLC will be reviewed here. The treatment of SCLC is discussed separately. (See "Extensive-stage small cell lung cancer: Initial management" and "Limited-stage small cell lung cancer: Initial management" and "Prophylactic cranial irradiation for patients with small cell lung cancer".)

EPIDEMIOLOGY — SCLC occurs almost exclusively in smokers and appears to be most common in heavy smokers [1]. Historically, SCLC has been rare in never smokers, representing just 2.0 percent of the lung cancer cases in multiple case series [2].

The proportion of lung cancer in the United States that is classified as SCLC is approximately 14 percent [3]. The percentage of cases of SCLC arising in women is 50 percent.

PATHOLOGY

Classification of SCLC — SCLC is a high-grade neuroendocrine carcinoma, grouped with other tumors of neuroendocrine origin including (table 1) [4]:

●Combined SCLC, consisting predominantly of SCLC with some areas of non-small cell lung cancer (NSCLC)

●Large cell neuroendocrine carcinoma of the lung (LCNEC)

●Carcinoid tumors, typical and atypical

SCLC and LCNEC are both high-grade neuroendocrine tumors, as compared with atypical carcinoid and typical carcinoid, which are intermediate-grade and low-grade tumors, respectively. Many large cell neuroendocrine cancers appear to have a biologic behavior that is similar to SCLC, which is supported by frequently shared gene expression and proteomic profiles. (See "Pathology of lung malignancies", section on 'Large cell neuroendocrine carcinoma' and "Large cell neuroendocrine carcinoma of the lung".)

A diagnosis of SCLC is based primarily upon light microscopy. Small cell carcinoma is characterized by small "blue" malignant cells about twice the size of lymphocytes. The cytoplasm is sparse, and nuclear features include finely dispersed chromatin without distinct nucleoli. In contrast, the cells of LCNEC are distinguished by the presence of prominent nucleoli, a more granular chromatin pattern, and variable amounts of cytoplasm. Mitotic rates are high, and necrosis of individual tumor cells is common. Nuclear molding is considered characteristic in well-preserved specimens, although a nondiagnostic "crush" artifact is more frequently observed. The neoplastic cells are typically arranged in clusters, sheets, or trabeculae, separated by a delicate fibrovascular stroma.

In the combined cell subtype, SCLC coexists with squamous cell carcinoma, adenocarcinoma, LCC, or, rarely, spindle cell carcinoma. If SCLC coexists with large cell components, at least 10 percent of each component should be present. For other non-small cell elements, the presence of any amount indicates classification as "combined." While coexistence with another cell type of carcinoma is rarely detected in untreated specimens, up to 30 percent of autopsies with SCLC demonstrate areas of differentiation into non-small cell carcinoma.

These findings have led to the hypothesis that pulmonary carcinogenesis occurs in a pluripotent stem cell capable of differentiation along several pathways. Further supporting this is the observation that approximately 14 percent of NSCLC tumors with epidermal growth factor receptor (EGFR) mutations acquire SCLC morphology and expression of neuroendocrine markers as EGFR-inhibitor resistance evolves, and that these tumors are sensitive to standard SCLC regimens [5].

In the combined cell subtype, metastatic disease usually contains predominantly SCLC even if the SCLC element is low. Therefore, standard SCLC treatment for patients with the combined subtype is appropriate.

Tumor markers — For SCLC and LCNEC, there are standard immunohistochemical markers for lung origin and/or neuroendocrine features which are useful for establishing the diagnosis. Additionally, some molecular biomarkers, especially those that are potentially targetable, may be useful for guiding treatment in the future. However, unlike NSCLC where biomarkers such as EGFR mutations (for targeted therapies) and programmed cell death ligand 1 (PD-L1; for immunotherapies) have been incorporated into standard clinical practice, there are no molecular markers that are recommended for treatment selection for SCLC outside of clinical trials.

●Virtually all SCLCs are immunoreactive for keratin and epithelial membrane antigen because of their epithelial cellular origin. A majority will also express thyroid transcription factor-1 (TTF1), which can help distinguish SCLC from neuroendocrine cancers originating in an organ other than the lung.

●One or more markers of neuroendocrine differentiation can be found in approximately 75 percent of SCLCs [6]. In contrast to LCNEC, the immunohistochemical demonstration of neuroendocrine differentiation is not a prerequisite for the diagnosis of small cell carcinoma [7]. Markers reflecting neuroendocrine and neural differentiation commonly used in the diagnostic setting include synaptophysin, chromogranin, and CD56 (neural cell adhesion molecule [NCAM]). Expression of neuron-specific enolase (NSE), dopa decarboxylase, calcitonin, gastrin-releasing peptide (GRP), and insulin-like growth factor-I (IGF-1) is also commonly observed.

A subset of patients produce autoantibodies that crossreact with both SCLC cells and the central nervous system or the neuromuscular junction. These autoantibodies can cause cerebellar degenerative syndromes or the Lambert Eaton myasthenic syndrome. SCLC is the most common malignancy associated with neurologic paraneoplastic syndromes. (See "Overview of paraneoplastic syndromes of the nervous system" and "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis", section on 'Pathophysiology' and "Lambert-Eaton myasthenic syndrome: Treatment and prognosis", section on 'Evaluation for malignancy'.)

SCLC cells can also produce a number of polypeptide hormones, including ACTH and vasopressin (antidiuretic hormone), resulting in various paraneoplastic endocrinologic syndromes. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)" and "Establishing the cause of Cushing syndrome".)

Genetic abnormalities — The development of both SCLC and NSCLC occurs through stimulation of proliferation and mutagenesis occurring over years, most commonly resulting from exposure to tobacco and other carcinogens. Multiple genetic defects have been detected; some are characteristic and perhaps involved with oncogenesis, whereas others are probably random or secondary events. A detailed discussion of the molecular genetic changes associated with neuroendocrine tumors is beyond the scope of this review. The most common characteristics of SCLC are summarized below and were recently reviewed [8-10]:

●p53 mutations are detected in nearly all SCLC tumors (75 to 98 percent based on previous reports) [11-14].

●Loss of the retinoblastoma gene (RB1) function at 13q14 is nearly ubiquitous in SCLC [15,16]. As an example, approximately 60 percent of SCLC cell lines have undetectable transcripts, while the remaining 40 percent have an abnormal gene product.

●MYC family members (MYC, MYCL1, and MYCN) are amplified in approximately 20 percent of SCLCs, are mutually exclusive of each other, and may contribute to the SCLC variant neuroendocrine subtype and long-term tumor-propagating cells in SCLC [17,18].

●MYC-amplified tumors may be more sensitive to targeted therapy with Aurora kinase inhibitors, based on preclinical data and retrospective analysis of clinical data [19-23].

●Other genes commonly altered in a subset of SCLC include phosphatase and tensin homolog (PTEN), NOTCH receptors, chromatin regulator CREB-binding protein (CREBBP), and the histone lysine methyltransferase (KMT2D) [14,23]. A recent, single-center study suggests that certain germline genotypes (especially alterations in DNA repair genes) may also contribute to SCLC in some patients, in addition to tobacco exposure [24].

●Haploinsufficiency due to loss of material on chromosome 3p at multiple break sites leads to absent or lower expression of many putative tumor-suppressor genes in the majority of SCLCs [25].

●In contrast to NSCLC, mutations in the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogenes and p16 abnormalities are rare, except in occasional cases of SCLC transformation of EGFR-mutated lung adenocarcinomas [26]. Related to this, patients with EGFR-mutated NSCLC and loss of tumor protein p53 (TP53) and RB1 are at higher risk for SCLC transformation [27]. However, the presence of alterations in EGFR, TP53, and RB1 (eg, by liquid biopsy [circulating tumor DNA (ctDNA)] or next-generation sequencing of tumor tissue) is not sufficient to make a diagnosis of transformation to SCLC, which needs to be confirmed with a tissue biopsy showing histologic features of SCLC.

SCLC expression profiles — While ubiquitous loss of TP53 and RB1 have limited efforts to identify therapeutic targets via genomic profiling of SCLC, diverse features of SCLC biology and potential therapeutic biomarkers and vulnerabilities have been revealed by extensive transcriptomic and proteomic characterization of SCLC tumors.

●Recognition of diverse phenotypes among SCLC models dates back more than three decades to descriptions of classic and variant SCLC [28]. Advanced molecular profiling has revealed that expression of the transcription factor achaete-scute homolog 1 (ASCL1) and its targets underlie much of so-called classic (neuroendocrine-high) SCLC, now termed SCLC-A [22,29]. Variant (neuroendocrine-low) SCLC, on the other hand, is composed of several unique subtypes, including a neuronal differentiation 1 (NEUROD1)-regulated subtype (SCLC-N) and a novel POU domain, class 2, transcription factor 3 (POU2F3)-regulated subtype (SCLC-P) that originates in the pulmonary tuft cells, both of which are associated with increased expression of MYC [22,29,30]. Importantly, each of these subtypes is enriched for unique, putative therapeutic targets and predictive biomarkers with plans for future trials to integrate SCLC subtyping into predictive and prognostic analyses [31,32].

While the nomenclature varies for the remaining subset of SCLC tumors that lack a single, dominant transcriptional driver, multiple groups agree that these tumors are unified by mesenchymal differentiation and inflamed biology [31,33,34]. Retrospective analyses found that this fourth subset, termed SCLC-inflamed (SCLC-I) in this context, predicted those patients that received the most benefit from front-line immune checkpoint blockade In the Impower133 study [33].

Whereas other biomarkers for benefit from immune checkpoint blockade have shown only limited potential in SCLC (eg, tumor mutational burden and PD-L1 expression), the SCLC-I signature may be able to better select patients for immune checkpoint blockade. (See "Extensive-stage small cell lung cancer: Initial management".)

●Proteomic profiling has identified major differences in protein expression between SCLC or LCNEC and other NSCLC cancers. These include higher expression of poly(ADP-ribose) polymerase 1 (PARP1) and other DNA repair proteins, and of enhancer of zeste homolog 2 (EZH2) [35]. Clinical trials investigating the use of PARP1, checkpoint kinase 1 (CHEK1), WEE1, ataxia telangiectasia and Rad3-related protein (ATR), and other DNA repair inhibitors (alone or in combination) in SCLC patients have been initiated [36]. Promising clinical data for the PARP1 inhibitors (veliparib, olaparib) in combination with temozolomide in patients with relapsed/refractory SCLC suggest that expression of schlafen family member 11 (SLFN11) detected by immunohistochemistry (for veliparib plus temozolomide) and/or high expression of inflammatory-response genes (for olaparib plus temozolomide) may predict benefit to PARP inhibitors [37,38]. SLFN11 expression by immunohistochemistry is being assessed as prospective patient selection criteria in a trial combining a PARP inhibitor and immune checkpoint blockade in front-line maintenance setting (NCT04334941).  

Delta-like ligand 3 (DLL3), an inhibitory NOTCH ligand, is commonly expressed at the surface of SCLC tumor cells and is under investigation as a therapeutic target, including a chimeric antigen receptor T-cell (CAR T-cell, AMG119) and bispecific T-cell engager (bispecific antibodies, AMG757), the latter of which has shown preliminary signs of efficacy [39].

INITIAL EVALUATION — A tissue diagnosis is required to confirm the diagnosis of SCLC and to distinguish this from non-small cell lung cancer and from other neuroendocrine cancers. The initial evaluation of a patient with suspected lung cancer is discussed separately. (See "Overview of the initial treatment and prognosis of lung cancer".)

CLINICAL PRESENTATION — SCLC typically arises in the central airways, infiltrating the submucosa, and gradually narrowing the bronchial lumen through extrinsic or endobronchial spread. The most common presentation is that of a large hilar mass with bulky mediastinal adenopathy (image 1). Potential clinical consequences include cough, dyspnea, weight loss, and debility. Hemoptysis and postobstructive pneumonia are less common than with squamous cancers, for example, due to the diffuse submucosal, as opposed to intraluminal, growth pattern. Approximately 70 percent of patients present with overt metastatic disease; SCLC has a particular propensity to spread to liver, adrenals, bone, bone marrow, and brain.

SCLC can occasionally present as a peripheral nodule without central adenopathy. However, this presentation of SCLC is uncommon and a cytologic diagnosis alone (eg, from a fine needle aspirate) cannot be trusted to differentiate SCLC from other neuroendocrine cancers such as typical or atypical carcinoid, for which surgery should be strongly considered. In this situation, mediastinal staging followed by surgical resection is recommended. Histopathologic evaluation of the resected tumor frequently fails to confirm SCLC. (See "Limited-stage small cell lung cancer: Initial management", section on 'Surgery'.)

Less commonly, SCLC can present with an endocrinologic or neurologic paraneoplastic syndrome. (See "Overview of paraneoplastic syndromes of the nervous system" and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)" and "Establishing the cause of Cushing syndrome".)

STAGING

Limited- versus extensive-stage disease — A modification of the two-stage system originally introduced by the Veterans' Affairs Lung Study Group (VALSG) for use in clinical trials in the late 1950’s continues to be widely utilized in staging patients with SCLC because of its simplicity and clinical utility:

●Limited stage – Tumor confined to the ipsilateral hemithorax and regional nodes able to be included in a single tolerable radiotherapy port (corresponding to Tumor, Node, Metastasis [TNM] stages I through IIIB (table 2)).

●Extensive stage – Tumor beyond the boundaries of limited disease including distant metastases, malignant pericardial, or pleural effusions, and contralateral supraclavicular and contralateral hilar involvement.

Compared with TNM staging, which has historically depended upon pathologic staging and, thus, surgical resection for confirmation, the simplified system above is quite functional, given that approximately 90 percent of patients with SCLC present with either locally advanced (35 to 40 percent) or metastatic disease (60 to 65 percent), and thus are not amenable to resection. This simple, two-stage system carries both prognostic importance and implications for treatment that are similar to the value of TNM staging since patients with limited-stage disease are candidates for curative-intent chemoradiation and chemotherapy, while those with extensive-stage disease are treated with chemoimmunotherapy and consolidative or palliative radiation as clinically indicated.

TNM staging system — In 2007, the International Association for the Study of Lung Cancer (IASLC) proposed changes to the Tumor, Node, Metastasis (TNM) non-small cell lung cancer (NSCLC) staging system, mainly in T and M descriptors and subsequent stage groupings [40]. These changes in the lung cancer TNM system were incorporated into the AJCC seventh edition (2010), and again in the eighth edition (2017), which recommends TNM staging for SCLC as well as NSCLC (table 2).

The applicability of the proposed changes to SCLC was validated in a study comparing the new system with the Union for International Cancer Control (UICC) 6^th edition criteria using 8088 clinically staged cases in the IASLC database diagnosed between 1990 and 2000 [40]. This study demonstrated the applicability and improved prognostication of the proposed system compared with the UICC 6^th edition, with both T and N descriptors, and overall stage groupings prognostic for survival with the exception of overlap in stage IA and II A, and IB and IIB [40]. The prognostic import of the stage groupings was confirmed in a separate cohort of 4884 patients in the Surveillance, Epidemiology, and End Results (SEER) database. The two systems were further compared in 349 patients staged surgically, confirming trends toward decreasing survival with increased T, N, and overall stage classification [41].

The specific prognosis of patients with stage IV(M1a) by virtue of pleural or pericardial effusion or contralateral pulmonary metastasis was demonstrated in a cohort of 10,660 patients from the California Cancer Registry [42]. Patients with stage M1a disease had outcomes for survival that were intermediate between stages I-IIIB and stage IV(M1b), as is also the case for patients with NSCLC.

TNM staging does not alter clinical management frequently due to the predominance of advanced stage at presentation, and it is less powerful in prognostication for SCLC than for NSCLC. TNM staging is most useful in the identification of patients for whom resection may be beneficial (ie, for patients that are thoroughly evaluated and have clinical stage I [T1-2N0] disease). In these cases, resection followed by adjuvant chemotherapy is recommended; however, this applies to fewer than 5 percent of patients. (See "Limited-stage small cell lung cancer: Initial management", section on 'Surgery'.)

While recognizing the limitations of influence on management, TNM staging should be incorporated into clinical research and in cancer registries for future reference since more precise stage classification could influence treatment approaches in the future.

Staging workup — Systemic therapy is required for all patients with tissue diagnosis of SCLC, including those with stage I. Therefore, the major therapeutic significance of staging is to guide the use of definitive chemoradiation and to lesser extent, surgery.

Prompt treatment is of greater importance than the complete ascertainment of every involved site of disease because of the rapid tempo of untreated SCLC. Most patients are diagnosed within three months of symptom onset, reflecting a short tumor doubling time, and may die quickly in the absence of effective therapy. Staging should not delay initiation of treatment more than seven days. Patients who are very symptomatic should be treated urgently with chemotherapy despite the absence of complete staging information. Staging can continue during and immediately after initial treatment.

A complete staging workup includes the following:

●Physical examination

●Hematologic and chemical laboratory profiles

●Computed tomography (CT) of chest, abdomen, and pelvis

●Magnetic resonance imaging (MRI, preferred) or CT imaging of brain [43], and

●Positron emission tomography (PET)-CT. PET-CT is especially useful to confirm limited stage or to clarify the nature of nonspecific CT findings. If PET-CT is not available, skeletal imaging with technetium should be performed.

●Other tests that may be clinically indicated in selected cases include bone marrow biopsy in the case of cytopenias, lumbar puncture for suspected leptomeningeal disease, and thoracentesis/pericardiocentesis to evaluate pleural/pericardial effusions.

For the patient with obvious extensive disease, for example, based on initial CT imaging, it is reasonable to use a clinically oriented approach and limited staging algorithm. However, all patients should have brain imaging given the importance of brain radiation in reducing chronic neurologic morbidity from metastatic disease. Again, the major goal of complete staging is to identify the patient with limited disease who merits definitive chemoradiation.

PROGNOSIS — The median ranges of survival from the time of diagnosis for limited and extensive disease are 15 to 20 months and 8 to 13 months, respectively. Approximately 20 to 40 percent of limited-stage and less than 5 percent of extensive-stage patients survive two years [44,45]. The respective values for five-year survival are 10 to 13, and 1 to 2 percent, respectively [46-48]. Long-term survival data for patients with extensive-stage disease treated with front-line immunotherapy-chemotherapy are awaited. (See "Extensive-stage small cell lung cancer: Initial management" and "Overview of the initial treatment and prognosis of lung cancer".)

Apart from initial stage, the most important adverse prognostic factors are poor performance status and weight loss [49]. It is also noteworthy that continuation of smoking contributes to chemoresistance [50].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Small cell lung cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Small cell lung cancer treatment (Beyond the Basics)")

SUMMARY

●Small cell lung cancer (SCLC) typically arises in the central airways of smokers, and due to its short doubling time and biological aggressiveness, patients have only a brief period of pre-diagnosis symptoms. Despite this, 60 to 70 percent of patients present with overt metastatic disease.

●SCLC is distinguished from non-small cell lung cancer by its rapid doubling time, high growth fraction, and the early development of widespread metastases. Although SCLC is highly responsive to chemotherapy and radiotherapy, the disease usually relapses within two years despite treatment. Overall, only 10 to 15 percent of patients with limited stage SCLC and 1 to 2 percent of patients with extensive stage SCLC survive beyond five years. (See 'Prognosis' above.)

●SCLC is generally diagnosed by light microscopy. On routine hematoxylin and eosin staining, it is a small, blue, round cell tumor with cells two to three times the size of mature lymphocytes. The cytoplasm is sparse, and nuclear features include finely dispersed chromatin without distinct nucleoli. (See 'Clinical presentation' above and 'Pathology' above.)

●In most clinical settings, patients are evaluated as having either limited-stage disease or extensive-stage disease. This distinction has important therapeutic and prognostic implications. The Tumor, Node, Metastasis (TNM) staging system provides more detailed information (table 2), which may be particularly important in identifying patients for whom resection may be indicated. Furthermore, the TNM system should be adopted for clinical trials and tumor registry information as precise staging information may inform therapeutic advances in the future for identifying that small number of patients who may be surgical candidates (T1-2N0). (See 'Staging' above.)

●The goal of the staging evaluation is to determine whether or not the patient has limited-stage disease and merits definitive chemoradiation. In addition to a physical examination, hematology, and chemical laboratory profiles, imaging of the chest, abdomen, skeleton, and brain is generally indicated. However, prompt treatment is of greater importance than the complete ascertainment of every involved site of disease because of the rapid tempo of untreated disease. An abbreviated evaluation is often sufficient to begin treatment, especially in the case of obvious extensive-stage disease. Completion of staging can proceed during and immediately following initial chemotherapy. (See 'Staging workup' above.)