Small-cell carcinoma

Small-cell carcinoma, also known as oat cell carcinoma, is a type of highly malignant cancer that most commonly arises within the lung,<ref>Template:DorlandsDict</ref> although it can occasionally arise in other body sites, such as the cervix,<ref name='NasuHirakawa'>Template:Cite journal</ref> prostate,<ref name='CapizzelloPeponi'>Template:Cite journal</ref> and gastrointestinal tract. Compared to non-small cell carcinoma, small cell carcinoma is more aggressive, with a shorter doubling time, higher growth fraction, and earlier development of metastases.<ref name="Basumallik_2023">Template:Cite book</ref>

Extensive stage small cell lung cancer (SCLC) is classified as a rare disorder.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Ten-year relative survival rate (combined limited and extensive SCLC) is 3.5% (4.3% for women, 2.8% for men).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Survival can be higher or lower based on a combination of factors including stage, age, sex and race.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> While all lung cancers are associated with tobacco smoking, SCLC is very strongly associated with tobacco smoking.<ref name="Basumallik_2023" />

Types

Lung cancer

Small-cell lung carcinoma (SCLC) has long been divided into two clinicopathological stages, termed limited stage (LS) and extensive stage (ES).<ref>Template:Cite journal</ref> The stage is generally determined by the presence or absence of metastases, whether or not the tumor appears limited to the thorax, and whether or not the entire tumor burden within the chest can feasibly be encompassed within a single radiotherapy portal.<ref name='ArgirisMurren'>Template:Cite journal</ref> In general, if the tumor is confined to one lung and the lymph nodes close to that lung, the cancer is said to be LS. If cancer has spread beyond that, it is said to be ES.

Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for the highest mortality rates among both men and women. When associated with the lung, SCLC is sometimes called "oat cell carcinoma" due to the flat cell shape and scanty cytoplasm. Small cell mesothelioma – an extremely rare subtype of lung cancer – can be mistaken for small cell lung cancer.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Small-cell carcinoma is most often more rapidly and widely metastatic than non-small-cell lung carcinoma<ref name="isbn0-7216-0187-1">Template:Cite book</ref> (and hence staged differently). There is usually early involvement of the hilar and mediastinal lymph nodes.<ref name=Kumar-ssc>Template:Cite book</ref> The mechanisms of its metastatic progression are not well understood.<ref name="Tammela"/>

Combined

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} When SCLC is found with one or more differentiated forms of lung cancer, such as squamous cell carcinoma or adenocarcinoma, the malignant tumor is then diagnosed and classified as a combined small cell lung carcinoma (c-SCLC).<ref name="who2004" /> Small-cell lung carcinoma can occur in combination with a wide variety of other histological variants of lung cancer,<ref name='who2004'>Template:Cite book</ref> including extremely complex malignant tissue admixtures.<ref name='PelosiSonzogni'>Template:Cite journal</ref> <ref name='GotohYamamoto'>Template:Cite journal</ref> C-SCLC is the only currently recognized subtype of SCLC.<ref name="who2004"/>

Extrapulmonary

Very rarely, the primary site for small-cell carcinoma is outside of the lungs and pleural space; in these cases, it is referred to as extrapulmonary small-cell carcinoma (EPSCC). Outside of the respiratory tract, small-cell carcinoma can appear in the cervix, prostate, liver, pancreas, gastrointestinal tract, or bladder.<ref>Template:Cite journal</ref> It is estimated to account for 1,000 new cases a year in the U.S. Histologically similar to small-cell lung cancer, therapies for small-cell lung cancer are usually used to treat EPSCC.<ref>Template:EMedicine</ref> First-line treatment is usually with cisplatin and etoposide. In Japan, first-line treatment is shifting to irinotecan and cisplatin. When the primary site is in the skin, it is referred to as a Merkel-cell carcinoma.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Extrapulmonary localized in the lymph nodes

This is an extremely rare type of small cell, and there has been little information in the scientific community. It appears to occur in only one or more lymph nodes, and nowhere else in the body. Treatment is similar to small-cell lung cancer, but survival rates are much higher than other small-cell carcinomas.<ref>Template:Cite journal</ref>

Prostate

Small-cell carcinoma of the prostate (SCCP) is a rare form of prostate cancer (approximately 1% of prostate cancers).<ref name="pmid9227387">Template:Cite journal</ref> Symptomatic metastasis of SCCP to the brain is rare, and carries a poor prognosis.<ref name="pmid12463494">Template:Cite journal</ref>

Signs and symptoms

File:LK-small cell3683.jpg

Frontal chest X-ray showing a probable S2–S3 small cell carcinoma in the right side lung.

Small-cell carcinoma of the lung usually presents in the central airways and infiltrates the submucosa leading to the narrowing of bronchial airways. Common symptoms include cough, dyspnea, weight loss, and debility. Over 70% of patients with small-cell carcinoma present with metastatic disease; common sites include the liver, adrenals, bone, and brain.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Due to its high grade neuroendocrine nature, small-cell carcinomas can produce ectopic hormones, including adrenocorticotropic hormone (ACTH) and anti-diuretic hormone (ADH). Ectopic production of large amounts of ADH leads to syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH).<ref>Template:Cite journal</ref><ref name=Kumar-ssc/> Lambert–Eaton myasthenic syndrome is a well-known paraneoplastic condition linked to small-cell carcinoma.<ref name='TitulaerVerschuuren'>Template:Cite journal</ref> Approximately half of all individuals diagnosed with Lambert–Eaton myasthenic syndrome will eventually be found to have a small-cell carcinoma of the lung.<ref name="TitulaerVerschuuren"/>

Genetics

TP53 is mutated in 70 to 90% of SCLCs. RB1 and the retinoblastoma pathway are inactivated in most SCLCs. PTEN is mutated in 2 to 10%. MYC amplifications and amplification of MYC family members are found in 30% of SCLCs. Loss of heterozygocity on chromosome arm 3p is found in more than 80% of SCLCs, including the loss of FHIT.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> One hundred translocations have been reported in SCLCs.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Diagnosis

File:Histopathology of small cell carcinoma, annotated.png

CitationClass=web }} Last author update: 20 September 2022</ref>

File:Lung small cell carcinoma (1) by core needle biopsy.jpg

Histopathologic image of small-cell carcinoma of the lung. CT-guided core needle biopsy. H&E stain.

Small-cell carcinoma is an undifferentiated neoplasm composed of primitive-appearing cells. As the name implies, the cells in small-cell carcinomas are smaller than normal cells and barely have room for any cytoplasm. Some researchers identify this as a failure in the mechanism that controls the size of the cells.<ref>Template:Cite journal</ref>

At the time of diagnosis, 60–70% of people already have metastases.<ref name="Tammela">Template:Cite journal</ref>

LS-SCLC

Chest X-rays are typically the first step to evaluate someone for any type of lung cancer. If images show suspicious spots on the patient's lung, a healthcare provider may order chest CT, PET, needle biopsy or bronchoscopy for further check.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

It is possible to use bronchoscopic biopsy to diagnose Lung small-cell carcinoma. However, small-cell carcinoma tissue obtained through bronchoscopy is prone to tissue compression and unclear morphology. However, pathologists can stain lesions with immunohistochemistry Ki-67, CD56, TTF-1, CgA, Syn, P63, CK5/6, LCA, and 34βE12 to help, in order to make a differential diagnosis.<ref>Template:Cite journal
Template:Cc-notice</ref>

ES-SCLC

The common metastasis sites of SCLC include the lung, brain, bone, adrenal gland, liver, colorectum, and lymph nodes.

If the tumor metastasises to the brain, It is necessary to comprehensively evaluate the patient's condition in combination with PET/CT and MRI. In patients with brain metastases from small cell lung cancer, MRI has specificity and sensitivity of 75% to 90% and 70% to 85%, respectively.<ref>Template:Cite journal</ref> In MRI, T1- and T2-weighted images had medium-to-high signal intensity.<ref name="NCCN Guidelines" /> Presently, brain metastasis diagnosis by FDG-PET/CT often uses TBR ≥1.6 of increased absorption as the appropriate diagnostic index for positive brain metastasis.<ref name="NCCN Guidelines">Template:Cite journal</ref><ref name="What Does PET Imaging Bring to Neuro-Oncology in 2022">Template:Cite journal
Template:Cc-notice</ref> Researchers also found cerebellum is the risk site with a high incidence of metastasis.<ref>Template:Cite journal
Template:Cc-notice</ref> In patients with SCLC brain metastasis, the general manifestation on plain CT is of low and medium density, and high-density signals of lesions are rare. However, the imaging with enhanced CT is more clear, showing obvious enhanced signals of cancer lesions. The extensive low-density edema zone of finger edema can be observed.<ref name="What Does PET Imaging Bring to Neuro-Oncology in 2022" /> What's more, it is difficult to detect small metastasis in the brain <0.5 cm, which contributes to the high false-positive rate of brain CT.<ref name="NCCN Guidelines" /><ref>Template:Cite journal}
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Treatment

LS-SCLC

In cases of LS-SCLC, combination chemotherapy is administered together with concurrent chest radiotherapy.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name = "NCI_Treatment">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Sherman_2000">Template:Cite journal</ref> Chest radiotherapy has been shown to improve survival in LS-SCLC.<ref>Template:Cite journal</ref> Because SCLC usually metastasizes widely very early on in the natural history of the tumor, and because nearly all cases respond dramatically to chemotherapy and/or radiotherapy, there has been little role for surgery in this disease since the 1970s.<ref name='Mountain1978'>Template:Cite journal</ref> However, in cases of small, asymptomatic, node-negative SCLC's ("very limited stage"), surgical excision may improve survival when used prior to chemotherapy.<ref name='Shepard2011'>Template:Cite journal</ref>

ES-SCLC

In ES-SCLC, platinum-based combination chemotherapy is the standard of care.<ref name=pmid24282143>Template:Cite journal</ref>

Combination chemotherapy consists of a wide variety of agents, including cisplatin, cyclophosphamide, vincristine and carboplatin. Response rates are high even in extensive disease, with between 15% and 30% of subjects having a complete response to a combination chemotherapy, and the vast majority having at least some objective response. Responses in ES-SCLC are often of short duration, and the evidence surrounding the risk of treatment compared to the potential benefit of chemotherapy for people who have extensive SCLC is not clear.<ref name=pmid24282143/>

Chemotherapy

Small-cell lung cancer is most commonly treated with chemotherapy in a combination of two drugs, which is more effective than one drug alone.

1. Cisplatin and etoposide,
2. Carboplatin and etoposide.

Cisplatin-resistance

The drug paclitaxel may be useful in the treatment of cisplatin-resistant cancer. About 68.1% of cisplatin-resistant cells appear to be sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells to cisplatin. The mechanism for this activity is unknown.<ref name="pmid17881133">Template:Cite journal</ref> Paclitaxel-based chemotherapy showed modest activity in SCLC patients refractory to both etoposide- and camptothecin-based chemotherapy.<ref name="pmid29049199">Template:Cite journal</ref> The newer agent lurbinectedin is active in relapsed SCLC and was approved for medical use in the United States in June 2020.<ref name="FDA Zepzelca">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Zepzelca FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Zepzelca PR">Template:Cite press release</ref><ref name="FDA Zepzelca announcement">{{#invoke:citation/CS1|citation |CitationClass=web }} Template:PD-notice</ref><ref name="FDA snapshot">{{#invoke:citation/CS1|citation |CitationClass=web }} Template:PD-notice</ref>

Immunotherapy

The FDA has approved three immunotherapies for small cell lung cancer:

• Nivolumab (Opdivo), a PD-1 inhibitor (2018)<ref>{{#invoke:citation/CS1|citation

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• Atezolizumab (Tecentriq), a PD-L1 inhibitor (2018)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

• Tarlatamab, a bi-specific T-cell engager (2024)<ref name="FDA 20240516">{{#invoke:citation/CS1|citation

|CitationClass=web }} Template:PD-notice</ref><ref>Template:Cite press release</ref>

Canadian regulator rejected funding Tecentriq (Atezolizumab) for extensive-stage small-cell lung cancer in 2020 "as too costly" followed by the United Kingdom also citing "drug’s cost-effectiveness."<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Radiation therapy

Chest radiation helps SCLC patients live longer by killing cancer cells and helping prevention of cancer recurrence.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Another type of radiation, prophylactic cranial radiation, prevents central nervous system recurrence and can improve survival in patients with good performance status who have had a complete response or very good partial response to chemoradiation in LD or chemotherapy in ED.<ref name = "NCI_Treatment" />

In case of relapse

If small cell lung cancer comes back after treatment, the following combination of drugs may be used as salvage therapy:<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

1. Cyclophosphamide (Cytoxan, Procytox),
2. Doxorubicin (Adriamycin) and
3. Vincristine (Oncovin)
4. Paclitaxel (Taxol)
5. Irinotecan (Camptosar) <ref>Template:Cite journal</ref>

Guidelines recommended as of 2018 that patients who relapse > 6 months from initial therapy should be retreated with the original chemotherapy regimen. For patients who relapse in < 6 months, single-agent chemotherapy either topotecan second-line therapy, or paclitaxel can be used.<ref name=Qin2018>Template:Cite journal</ref>

Novel agents

Several newer agents, including temozolomide and bendamustine, have activity in relapsed SCLC. Of note, temozolomide yielded a response rate of 38% for brain metastases due to SCLC.<ref name=Qin2018/>

In a clinical trial of 50 patients, a combination of olaparib and temozolomide in relapsed small-cell lung cancer yielded an overall response rate of 41.7%, median progression-free survival of 4.2 months, and overall survival was 8.5 months.<ref name="pmid31416802">Template:Cite journal</ref>

Lurbinectedin showed an increased overall survival rate in relapsed small cell lung cancer in a trial.<ref>Template:Cite journal</ref> Lurbinectedin is Template:As of available in the U.S. under an expanded access program (EAP).<ref>Template:Cite press release</ref><ref name=pmid28961837>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Trilaciclib, a CKD4/6 inhibitor, reduces chemotherapy-induced toxicity in patients being treated for small-cell lung cancer.<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In 2021, the FDA approved trilaciclib (Cosela) as a treatment to reduce the frequency of chemotherapy-induced myelosuppression for patients receiving certain types of chemotherapy for extensive-stage small-cell lung cancer.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Prognosis

As of 2015, 5-year survival rates for small cell lung cancer (extensive and limited) range between 3.6% and 32.2% for women, and between 2.2% and 24.5% for men.<ref name="SEER_table_13">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Relative 5-year survival rate for both sexes has increased from 3.6% in 1975 to 6.7% in 2014.<ref name="SEER_table_13" /> In limited-stage disease, the relative 5-year survival rate (both sexes, all races, all ages) is 21.3%; however, women have higher 5-year survival rates, 26.9%, and men have lower survival rates, 21.3%.<ref name = "SEER_SCC_Male">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The prognosis is far grimmer in extensive-stage small-cell lung carcinoma where 5-year relative survival rate (both sexes, all races, all ages) is 2.8%; however, women have higher 5-year survival rates, 3.4%, and men have lower 5-year survival rates, 2.2%.<ref name="SEER_SCC_Male"/>

Small-cell carcinoma is very responsive to chemotherapy and radiotherapy, and in particular, regimens based on platinum-containing agents. However, most people with the disease relapse, and median survival remains low. The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Long-term survival of more than 5 years can be achieved with proper treatment. According to the 17th World Conference on Lung Cancer (WCLC), "patients who received chest radiation and prophylactic cranial irradiation along with a mean of five chemotherapy cycles could achieve a median survival of more than 5 years."<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="SEER_table_13"/> In some cases, long-term survival of 10+ years is achieved with chemotherapy and radiation alone.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A 2023 article stated that the median overall survival is about 1 year, the worst of any lung cancer subtype.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Epidemiology

File:Pie chart of lung cancers.svg

Pie chart showing the incidence of small-cell lung cancer (shown in red at right), as compared to other lung cancer types, with fractions of smokers versus non-smokers shown for each type.<ref>Smokers defined as current or former smokers of more than 1 year of duration. See image page in Commons for percentages in numbers. Reference: * Template:Cite journal</ref>

Small cell lung carcinoma accounts for 15% of lung cancers in the United States.<ref name=WCR20145.1>Template:Cite book</ref> Small cell lung cancer occurs almost exclusively in smokers – most commonly in heavy smokers and rarely in non-smokers.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Society

In 2013, the US Congress passed the Recalcitrant Cancer Research Act, which mandated increased attention to certain recalcitrant cancers (cancers having a 5-year relative survival rate of less than 50%), including small cell lung cancer. That led to the National Cancer Institute supporting small cell-specific research.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

Notable cases

• Dustin Diamond, perhaps best known as an actor on Saved by the Bell, died one month after the diagnosis.<ref>{{#invoke:citation/CS1|citation

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• Asbjørn Sennels, Danish football player, died three months after the diagnosis.<ref>Template:Cite journal</ref>

Additional images

• Carcinoma microcellulare oatcell carcinoma or anaplastic carcinoma (lung)H&E magn 200x.jpg

  Anaplastic (microcellular, oat cell) carcinoma from the lung (histopathology)

• Lung small cell carcinoma (2) by core needle biopsy.jpg

  Histopathologic image of small-cell carcinoma of the lung. CT-guided core needle biopsy.