The Picayune Metamorphosis-Small Cell Carcinoma Lung

Bajaj A

Published on: 2022-08-05

Abstract

Small cell carcinoma is an extremely malignant neoplasm which commonly arises within pulmonary parenchyma although sites such as cervix, prostate and gastrointestinal tract can be incriminated. Small cell carcinoma exhibits a reduced cancer doubling time, enhanced growth fraction and rapid tumour dissemination with occurrence of metastases along with a dramatic response to chemotherapy and radiotherapy [1,2].

Keywords

Stem cells; Lung

Editorial

Small cell carcinoma is an extremely malignant neoplasm which commonly arises within pulmonary parenchyma although sites such as cervix, prostate and gastrointestinal tract can be incriminated. Small cell carcinoma exhibits a reduced cancer doubling time, enhanced growth fraction and rapid tumour dissemination with occurrence of metastases along with a dramatic response to chemotherapy and radiotherapy [1,2].

Small cell carcinoma lung emerges within centric respiratory tract with submucosal infiltration and consequent narrowing of bronchial tract. Smoking contributes significantly to occurrence of small cell carcinoma lung [1,2].

Additionally designated as ‘oat cell carcinoma’, small cell carcinoma lung depicts significant, antecedent tumour metastasis with frequent and rapid metastases into diverse sites besides preliminary incrimination of hilar and mediastinal lymph nodes [1,2].

High-grade, neuroendocrine small cell carcinoma lung can engender ectopic hormones such as adrenocorticotrophic hormone (ACTH) and anti diuretic hormone (ADH). Significant quantities of ectopic anti diuretic hormone induces syndrome of inappropriate anti diuretic hormone hypersecretion (SIADH). Additionally, paraneoplastic conditions such as Lambert- Eaton myasthenic syndrome (LEMS) can be associated with the neoplasm [1,2].

Majority (~90%) of small cell carcinoma lung depict genomic mutation of TP53 gene along with mutation of PTEN gene and amplification of MYC gene. Also, retinoblastoma pathway and RB1 gene is inactivated in significant proportion of neoplasms. Loss of heterozygosity (LOH) upon chromosome 3p appears within > 80% of tumefaction along with loss of FHIT protein which concurs with elevated proliferation index and decimated apoptotic index of neoplastic cells [1,2].

Contingent to appearance of distant metastases, tumour confinement to thoracic region and encompassing thoracic tumour burden within a singular radiotherapy portal, small cell carcinoma lung is subdivided into distinct clinic-pathological stages as

  • limited stage
  • extensive stage [1,2]

Generally, tumefaction confined to singular lung and abutting regional lymph nodes is designated as ‘limited stage’ disease. Dissemination of malignancy beyond aforesaid parameters is expounded as ‘extensive stage’ disease [1,2].

In consequence, small cell carcinoma lung is subcategorized into

  • localized where tumefaction is confined to pulmonary parenchyma or limited stage disease.
  • regional manifests a stage between limited and extensive stage where neoplasm has disseminated to regional lymph nodes or bronchial glands although confined to thoracic cavity
  • distant where carcinoma metastasizes to distant viscera or organs, akin to extensive stage disease [1,2].

Majority (> 70%) of neoplasms manifest with distant metastasis into hepatic parenchyma, adrenal glands, bone and brain. Around ~70% neoplasms delineate distant metastasis at initial tumour discernment [1,2].

Commonly, small cell carcinoma lung depicts clinical symptoms such as cough, dyspnoea, weight loss or generalized debilitation [1,2].

The undifferentiated small cell carcinoma lung is constituted of primitive-looking cells. Tumour cells are miniature, exhibit flattened cellular outline, scanty cytoplasm and appear circumscribed by a cytoplasmic perimeter [1,2].

Small cell carcinoma lung requires segregation from an extremely exceptional small cell mesothelioma incriminating pulmonary parenchyma [1,2].

Small cell carcinoma lung is engendered from bronchial neuroendocrine (APUD) cells, additionally designated as Feyrter cells which expound diverse neuroendocrine markers. Consequent ectopic production of adrenocorticotrophic hormone (ACTH) and anti diuretic hormone (ADH) engenders Cushing’s syndrome and various paraneoplastic syndromes. An estimated 50% of Lambert-Eaton myasthenic syndrome appear associated with small cell carcinoma lung [1,2].

Figure 1: Small cell carcinoma lung depicting miniature cells with compressed, flattened, hyperchromatic nuclei and scanty cytoplasm [5].

Figure 2: Small cell carcinoma lung delineating miniscule cells with flat, hyperchromatic nuclei, minimal cytoplasm and mitotic figures [6].

Small cell carcinoma lung can concur with diverse, differentiated, histological variants of pulmonary cancer, especially squamous cell carcinoma or adenocarcinoma. Aforesaid concordance of malignant neoplasms confers an established subtype of small cell carcinoma lung designated as ‘combined small cell carcinoma lung’ [1,2].

Table: TNM classification of small cell carcinoma lung [1,2].

Tumour

Node

Metastasis

TX: Primary carcinoma cannot be assessed

NX: Lymph nodes cannot be assessed

M0:Tumour dissemination to adjacent pulmonary lobe or distant organ is absent

T0: Tumefaction is non discernible

N0: Lymph nodes are devoid of tumour cell deposits

M1: Distant tumour metastasis •M1a: Bilateral pulmonary, pleural, pericardial involvement with malignant pleural or pericardial effusion

•M1b:Single metastatic focus as in liver, brain or lymph node

•M1c: Multiple foci of tumour dissemination into diverse viscera

Tis: In situ tumefaction confined by visceral pleura

N1: Tumour cells discernible within intrapulmonary or hilar lymph nodes

 

T1:Tumefaction confined to pulmonary parenchyma

N2:Tumour cells infiltrating ipsilateral mediastinal or tracheobronchial lymph nodes

 

T2:Tumour incriminates main bronchus or visceral pleura although appears distant from tracheobronchial region. Pulmonary collapse with bronchopulmonary inflammation occurs.

•T2a: Tumour magnitude extends between 3 cm to 4 cm •T2b: Tumour magnitude extends between 4cm to 5cm

N3:Tumour cells disseminated within contralateral mediastinal, supraclavicular or intrapulmonary lymph nodes

 

T3: Tumour magnitude between 5 cm to 7 cm. Multiple, lobar tumour nidus or tumour extension into chest wall, parietal pleura, phrenic nerve or pericardium

 

 

T4: Tumour magnitude >7cm or extension beyond single pulmonary lobe. Tumour extension into diaphragm, mediastinum, cardiac tissue, major blood vessels, trachea, oesophagus, recurrent laryngeal nerve, vertebral column or tracheobronchial region.

 

 

Miniature, asymptomatic focus of limited stage small cell carcinoma lung devoid of regional lymph node metastasis can be subjected to surgical excision prior to instituting adjuvant chemotherapy, a manoeuver which ameliorates proportionate survival [3,4].

Small cell carcinoma lung is commonly and optimally treated with an efficacious combined drug regimen, in contrast to a singular agent. Limited stage small cell carcinoma lung can be treated with combination chemotherapy comprised of cisplatin or carboplatin and etoposide in concurrence with chest radiotherapy [3,4].

Generally, combination of cisplatin and etoposide or carboplatin and etoposide are adopted. Paclitaxel is beneficial in treating tumefaction resistant to cisplatin [3,4].

Singular chemotherapy prescribed in limited stage small cell carcinoma lung exhibits significant initial response rate (RR) wherein majority (~75%) of individuals demonstrate complete response associated with comprehensive disappearance of radiological and clinical signs of the neoplasm. However, proportionate tumour relapse is significant and median survival is up to 24 months [3,4].

Targeted immunotherapy is employed with agents such as nivolumab and atezolizumab [3,4].

Thoracic cavity irradiation extends overall survival by annihilating neoplastic cells and circumventing tumour reoccurrence. Singular radiotherapy administered to thoracic cavity enhances survival within limited stage disease [3,4].

Extensive stage small cell carcinoma lung is an exceptional disease with proportionate 10 year survival at ~ 3.5%, contingent to factors such as prospective cancer stage, age of incriminated individual, gender and racial preferences [3,4].

Extensive stage small cell carcinoma lung is optimally treated with platinum-based combination chemotherapy [3,4].

Trilaciclib is a CKD4/6 inhibitor which decimates frequency of chemotherapy-induced myelosuppression encountered with extensive stage small cell carcinoma lung [3,4].

Radiotherapy is employed to palliate clinical symptoms as dyspnoea and pain emerging from hepatic or bone metastases. Typically, brain metastases occurring in small cell carcinoma lung exhibit a temporary, rapid response to whole brain radiotherapy [3,4].

Prophylactic cranial irradiation can be adopted to circumvent emergence or reoccurrence of brain metastasis and enhances overall survival. Combination chemotherapy is comprised of several agents such as cisplatin, cyclophosphamide, vincristine and carboplatin. Combination chemotherapy demonstrates significant complete response rates of ~30%. However, in extensive stage disease, therapeutic response is short-lived [3,4].

Relapsing small cell carcinoma lung can be subjected to combination salvage therapy with cyclophosphamide, doxorubicin, vincristine, paclitaxel or irinotecan [3,4].

Contemporary agents as temozolomide and bendamustine or combination of olaparib and temozolomide can be employed for treating relapsed small cell carcinoma lung [3,4].

Additionally, contemporary agent lurbinectedin can singularly or in combination with doxorubicin be advantageously utilized for treating relapsed small cell carcinoma lung with consequent increase in overall survival [3,4].

Current therapeutic recommendation for neoplasms relapsed beyond > 6 months from initial therapy appears with reinstatement of original chemotherapeutic regimen. Neoplasms relapsing within < 6 months can be subjected to singular chemotherapeutic agent topotecan or paclitexal [3,4].

Contemporary nivolumab is adopted to treat metastatic small cell carcinoma lung. Additionally, individuals subjected to standard carboplatin and etoposide along with atezolizumab delineate significant melioration of overall survival [3,4].

Therapeutic approach towards combined small cell carcinoma lung is similar to ‘pure small cell carcinoma lung’ [3,4].

Surgical intervention may ameliorate prognostic outcomes of preliminary stage disease. Proportionate 5 year survival of limited stage disease is ~21.3% and extensive stage disease is ~ 2.8% [3,4].

Besides, neoplasms subjected to chest irradiation, prophylactic cranial irradiation and a mean of 5 chemotherapy cycles may possibly achieve median survival exceeding > 5 years [3,4].

References

  1. Gesthalter Y, Smyth R. Treatment of small cell lung cancer. Am J Respir Crit Care Med. 2022; 205.
  2. Engelhardt KE, Feinglass JM, DeCamp MM, Bilimoria KY, Odell DD. Treatment trends in early-stage lung cancer in the United States, 2004 to 2013: A time-trend analysis of the national cancer data base. J Thorac Cardiovasc Surg. 2018; 156: 1233-1246.
  3. Moon SH, Kim J, Je-Gun J, Cha H, Woong-Yang P, Ahn JS, et al. Correlations between metabolic texture features, genetic heterogeneity, and mutation burden in patients with lung cancer. Eur J Nucl Med Mol Imaging. 2019; 46: 446-454.
  4. Qin J, Lu H. Combined small-cell lung carcinoma. Onco Targets Ther. 2018; 11: 3505-3511.
  5. Image 1 Courtesy: Libre Pathology
  6. Image 2 Courtesy: Icanwewill.com