TTF-1, CD56 -ve, CK7+/-
CK5/6, p40, CD56 -ve
TTF-1 + (70-80%)
(CK = cytokeratin, TTF-1 = thyroid transcription factor-1)
Sarcomatoid carcinoma
Some poorly differentiated non-small cell carcinomas show areas of sarcoma or sarcoma-like (spindle and/or giant cell) differentiation. These tumours, which have undergone divergent connective tissue differentiation, are rare and account for about 1% of all lung malignancies. Histologically, five subgroups, representing a morphological continuum, are recognized, and these are pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma (see Table 13.2)[2], although ‘sarcomatoid carcinoma’ is the appropriate term, as there is evidence that tumours that appear to be of mixed epithelial and connective tissue phenotype, or even purely sarcomatous, are epithelial and originate from the same clone[2,4].
Preinvasive lesions
Squamous dysplasia/carcinoma in situ (CIS)
Atypical adenomatous hyperplasia (AAH)
Adenocarcinoma in situ (AIS) (≤3 cm, formerly BAC)
Non-mucinous
Mucinous
Mixed non-mucinous/mucinous
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)
Squamous cell carcinoma
Variants
Papillary
Clear cell
Small cell (may be discontinued)
Basaloid
Small cell carcinoma
Combined small cell carcinoma
Adenocarcinoma
Minimally invasive adenocarcinoma (MIA) (≤3 cm, lepidic predominant tumour with ≤5 mm invasion)
Non-mucinous
Mucinous
Mixed non-mucinous/mucinous
Invasive adenocarcinoma
Lepidic predominant (formerly non-mucinous BAC with >5 mm invasion)
Acinar predominant
Papillary predominant
Micropapillary predominant
Solid predominant with mucin production
Variants of invasive adenocarcinoma
Invasive mucinous adenocarcinoma (formerly mucinous BAC, >3 cm)
Colloid
Fetal
Enteric
Large cell carcinoma
Large cell neuroendocrine carcinoma (LCNEC)
Combined LCNEC
Large cell carcinoma with rhabdoid phenotype
Basaloid carcinoma
Lymphoepithelioma-like carcinoma
Adenosquamous carcinoma
Sarcomatoid carcinomas
Pleomorphic carcinoma
Spindle cell carcinoma
Giant cell carcinoma
Carcinosarcoma
Pulmonary blastoma
Other
Carcinoid tumour
Typical carcinoid
Atypical carcinoid
Carcinomas of salivary gland type
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Epimyoepithelial carcinoma
The average age at diagnosis is 60 years, the male-to-female ratio is approximately 4 to 1 and tobacco smoking is a major aetiological factor, as for other histological types of lung cancer.
Pleomorphic carcinomas tend to be large, peripheral tumours with a tendency to invade the chest wall and a poor prognosis. Because of the histological heterogeneity of these tumours, adequate sampling of resection specimens is important, and pleomorphic carcinomas should have at least 10% of a spindle or giant cell component. In view of this, the diagnosis cannot be made based on small biopsies or cytology specimens. If the tumour has a purely spindle or giant cell morphology, the term ‘spindle cell’ or ‘giant cell carcinoma’ is used[3].
Carcinosarcomas are composed of a mixture of non-small cell carcinoma (squamous cell, adeno- or large cell carcinoma) and differentiated sarcomatous elements, such as malignant bone, cartilage or skeletal muscle. The metastases of a carcinosarcoma may consist of carcinoma or sarcoma or both.
Pulmonary blastoma is also a biphasic tumour with a glandular component that resembles well-differentiated fetal adenocarcinoma, composed of branching epithelial tubules or cords and undifferentiated stroma. Both components are malignant, and either or both may be seen in metastatic deposits. These tumours are often peripheral growths and form large, well-defined masses with foci of haemorrhage and cystic change. Pulmonary blastoma is a rare tumour, which can occur at any age, the mean age of presentation being earlier than that of carcinosarcoma, at about 40 years. It affects males three times more commonly than females[4].
Clinical outcome is stage dependent, but these tumours have a worse prognosis than conventional non-small cell carcinomas, and the 5-year survival is only about 20%, despite half the patients presenting with stage I disease[2].
The role of molecular pathology in non-small cell lung cancer
In recent years, a better understanding of mutations and rearrangements which alter the function or expression of several molecules that can either be located on the cell surface, acting as growth factor receptors, or participate in downstream intracellular pathways, leading to uncontrolled cell growth, can be used to generate prognostic information or to select patients for targeted therapies[16].
To date, effective molecularly targeted therapies have disproportionately impacted on adenocarcinomas compared to squamous cell carcinomas and on never or light smokers compared to heavy smokers. However, next-generation sequencing technologies are allowing better characterization of cancer genomes across a broad range of tumour types, and targets in squamous tumours and smokers will need to be developed to maker a greater impact on non-small cell lung cancer.
Lung cancers have a high rate of protein altering mutations, accounting for the genomic complexity of lung cancers and the comparative difficulty in effectively treating these tumours[17]. To effectively match drug therapies, it is important to distinguish ‘driver’ mutations, which confer growth advantage and are causally linked to cancer development, from ‘passenger’ mutations, which are biologically neutral[17].
These are some of the genomic changes which are currently of interest with regard to the development of targeted therapies:
EGFR
The epidermal growth factor receptor (EGFR) plays an important role in tumour development and progression through activation mechanisms including overexpression, mutation and autocrine ligand production. Derangements in the EGFR gene are associated with tumour cell proliferation, cell growth, invasion, metastatic spread, apoptosis and angiogenesis through the activation of the Ras/Raf/Mek/MAPK and PI3K/Akt/mTOR pathways.
Tumours with EGFR mutations are more frequent in East Asians (30% versus 8% in non-Asians), in women, in never smokers (66% versus 22% in ever-smokers) and in adenocarcinomas than in other types of non-small cell carcinomas[16].
Gefitinib and erlotinib are first-generation EGFR tyrosine kinase inhibitors which selectively target the intracellular tyrosine kinase domain of EGFR, blocking downstream signalling. However, patients who respond to this treatment eventually develop resistance, mostly due to the emergence of a secondary T790M mutation or amplification of mesenchymal-epithelial transition factor (c-Met)[16].
Whilst EGFR activating mutations are found in adenocarcinomas, high EGFR copy number and protein overexpression are observed more frequently in squamous cell lung cancers (82 versus 44% in adenocarcinomas)[17]. EGFR overexpression has been associated with a worse prognosis in some studies, but it has not been associated with a response to the EGFR tyrosine kinase inhibitors used clinically. One phase III study suggested that EGFR overexpression may be associated with better outcomes in the first-line chemotherapy plus cetuximab arm[18].
KRAS
Kirsten rat sarcoma viral oncogene homolog (KRAS), a member of the ras gene family, is an important downstream signalling target of EGFR and has been implicated in the development and prognosis of several cancers, including adenocarcinomas of the pancreas, colon and lung. Mutations that lead to loss of KRAS GTPase activity render the protein GT bound, resulting in sustained activation of downstream components and persistent proliferation.
Mutations in KRAS have been found in 15–30% of patients with non-small cell carcinoma[16].
KRAS mutations are most commonly detected in lung adenocarcinomas, and tumours with KRAS mutations are more frequent in Caucasian patients (20–30 versus 5% in East Asian patients) and in current or former smokers[16].
Several studies have shown that KRAS mutations correlated with poor survival in patients with non-small cell lung cancer.
Both KRAS and EGFR mutations have been described in AAH lesions, and EGFR mutations have been found in the non-neoplastic peripheral airways in the vicinity of invasive peripheral adenocarcinomas, indicating that mutations of both genes are early events that play a role in tumour initiation[19].
ALK gene rearrangements
The EML4-ALK fusion gene results from an inversion within chromosome 2p. The prevalence of EML4-ALK varies in different studies but is approximately 4% and is most commonly found in adenocarcinomas with a solid or signet ring morphology.[20] Patients with this gene rearrangement tend to be younger and are usually non-smokers or light smokers. Studies have demonstrated the therapeutic value of critozinib in patients found to be ALK-positive by fluorescence in situ hybridization (FISH).
BRAF
BRAF encodes a non-receptor serine/threonine kinase which is a member of the RAS/MAPK signalling pathway downstream of Ras protein.[16] Mutations of BRAF occur in approximately 3% of non-small cell lung cancers and are found predominantly in adenocarcinomas (97%), with just over half being V600E mutations (57%) and the remainder non-V600E. V600E mutations appear to be more prevalent in women, in never smokers and in more aggressive tumour subtypes characterized by micropapillary features and associated with a poorer prognosis. Non-V600E mutations were found in tobacco users[21].
FGFR1
FGFR1 is a member of the FGFR family of receptor tyrosine kinases, and activation leads to downstream signalling via the PI3K/AKT and RAS/MAPK pathways, which are important for growth, migration, survival and angiogenesis in many tumours[17]. FGFR1 mutations are rare, but FGFR1 amplification was found more frequently in squamous cell carcinomas (approximately 20%) than in adenocarcinomas, and mouse models with FGFR1 amplified tumours showed tumour growth inhibition and apoptosis on inhibition of FGFR1[22]. FGFR inhibitors are in development, many of which are multitargeted tyrosine kinase inhibitors.
PIK3CA
The PIK3CA-AKT pathway is central for survival and proliferation of many cancers, and PIK3CA copy number gains have been found in about 20% of lung cancers, with a higher frequency in squamous cell carcinomas[23]. In one study, PKI3CA mutations have also been detected more often in squamous cell carcinomas than adenocarcinomas (6.5 versus 1.5%)[24].
Preclinical data suggest that cancers with activating mutations in PIK3CA are sensitive to PIK3-pathway inhibitors, and combinations of PIK3 and other cancer-related pathway inhibitors are being developed[17].
PTEN
PTEN is a tumour suppressor gene, loss of which leads to constitutive PI3K-AKT signalling. Somatic PTEN deletions and mutations and inactivation of PTEN by an epigenetic mechanism are seen in multiple cancers. Reduction or loss of PTEN has been found in up to 70% of non-small cell carcinomas (squamous and adenocarcinomas). Mutations of PTEN are more common in squamous cell carcinomas (10.2 versus 1.7% for adenocarcinomas)[25]. Cancers with PTEN loss may be more sensitive to inhibitors of the PI3K pathway[17].
EphA2
The Eph receptor family is a group of tyrosine kinases, which are important in embryonic development such as vascular development, cell migration and tissue border formation. Overexpression of EphA2 is seen in multiple tumours, including non-small cell carcinomas, and is believed to promote cell motility, invasion, metastasis and angiogenesis. EphA2 expression has been correlated with smoking and reduced survival and has been reported to be higher in metastatic lesions compared to the primary. Mutations of EphA2 have also been described, and although they are rare, they appear to be more common in squamous cell carcinomas[17].
p53/MDM2
As in other tumours, mutations in p53 are frequent in lung cancer and are seen in more than half of non-small cell carcinomas and in approximately 65% of squamous cell carcinomas[26]. The spectrum of mutations seen is affected by smoking, with frequent G→T translocations, which are linked to polycyclic aromatic hydrocarbon adducts[17].
In a number of tumours, wild-type p53 is inactivated by MDM2 overexpression or amplification. MDM2 and p53 are regulated in a negative feedback loop, where MDM2 marks p53 for degradation. MDM2 amplification has been reported in 6–7% of non-small cell carcinomas (squamous cell and adenocarcinomas) and appears to be an exclusive event of p53 mutation. One potential treatment strategy is to try to develop small molecules that neutralize MDM2 and thereby increase p53 activity. Small molecules targeting mutant p53 are also under development[27].
DDR2
DDR2 is also a receptor tyrosine kinase involved in cell migration, proliferation and survival. Mutations have been found in lung cancer with varying frequency, with a rate of 3.8% in squamous cell carcinomas in one study[28].
Bronchopulmonary neuroendocrine tumours
Bronchopulmonary neuroendocrine tumours comprise about 20–25% of all invasive lung malignancies and represent a spectrum of tumours arising from the neuroendocrine cells of the bronchopulmonary epithelium. Although these tumours share morphological, immunohistochemical and ultrastructural features, they are classified into four subtypes: low-grade typical carcinoid tumours, intermediate-grade atypical carcinoid tumours and two high-grade malignancies: large cell neuroendocrine carcinoma and small cell carcinoma[29,30]. These exhibit different biological characteristics and data from histological and molecular studies suggests that carcinoid tumours are distinct from the more malignant large cell neuroendocrine and small cell carcinoma groups.
Large cell neuroendocrine and small cell carcinomas are strongly related to tobacco usage, whereas the link between carcinoid tumours and tobacco smoking is uncertain.[29]
Carcinoid tumours
Carcinoid tumours, typical and atypical, are well-differentiated neuroendocrine tumours which account for approximately 1–2% of all primary lung carcinomas[31]. These tumours show no sex predilection and tend to occur at a younger age than other lung cancers, with the average age at the time of diagnosis ranging from 45–55 years. Approximately 50% of patients are asymptomatic at presentation[30]. Symptoms include dyspnoea, haemoptysis, cough and post-obstructive pneumonia. The most common paraneoplastic syndromes include the carcinoid syndrome and Cushing’s syndrome[30]. Classical carcinoid syndrome with flushing and diarrhoea is rare and is generally associated with metastatic disease[32]. Approximately 5% of bronchopulmonary carcinoids may occur as a component of the multiple neuroendocrine neoplasia 1 syndrome.
Polypoid endobronchial growth is common in central carcinoids, which on bronchoscopic examination are usually red-brown masses with a smooth surface. They are often highly vascular and may bleed considerably on biopsy. Peripheral carcinoid tumours, usually within the subpleural parenchyma, occur in ~40% of cases.
Both typical and atypical carcinoid tumours are characterized histologically by an organoid growth pattern and uniform cytologic features with a moderate amount of eosinophilic cytoplasm and nuclei with finely granular chromatin. In typical carcinoid tumours nucleoli are inconspicuous, but they may be seen in atypical carcinoids, which are defined as carcinoid tumours with 2–10 mitoses per 2 mm2 area of viable tumour or the presence of necrosis, often punctate[30]. Since necrosis and mitosis may occur only focally, small biopsies may not be representative and in such situations the lesion should be classified as carcinoid tumour until adequate material is available[29]. Carcinoid tumours stain for neuroendocrine markers such as chromogranin, synaptophysin and CD56.
Since 5–20% of typical carcinoids and 30–70% of atypical carcinoids metastasize, lymph nodes should be assessed in all cases to ensure adequate staging[29]. TNM staging is recommended for pulmonary carcinoid tumours.
Distant metastases to other organs, including adrenal glands, liver, bone and brain, are rare, and atypical carcinoids account for most cases of metastatic disease, with ~25% of patients developing distant disease even long after initial diagnosis[32].
The primary approach to treatment of pulmonary carcinoid tumours is surgical resection, as these tumours are generally resistant to radiation and various chemotherapeutic agents have yielded minimal, mostly short-lasting results[29]. Both lung conserving and radical resections have been used, and all procedures should involve lymph node dissection or sampling, as a clearly identified prognostic factor is the presence or absence of lymph node involvement[32].
Patients with typical carcinoids have an excellent prognosis, with a 5-year survival rate of 87–100% and a 10-year survival rate of 87–93%[32]. The finding of metastases should not be used as a criterion to distinguish typical from atypical carcinoid tumours, as 5–20% of typical carcinoids show lymph node involvement. Compared with typical carcinoid tumours, atypical carcinoids tend to be larger, have a higher rate of metastases and the survival is significantly reduced with 5- and 10-year survival rates of 40–59% and 31–59%, respectively, although metastatic disease has a much poorer survival rate (~25%)[3,32]. As these tumours are relatively resistant to radiation and chemotherapy, when possible, metastatic disease is best managed surgically[30].
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