Lung cancer in people who have never smoked can develop the same but of course the correlation with smoking and exposure to environmental pollutants and professional carcinogenic substances is undeniable, on a field of genetic mutations that favors their growth (see causes of lung cancer). The incidence is higher in countries where there is smoking, smoking and then atmospheric pollution. You see that it is a neoplasm that occurs at 40 years and also associated with other districts, it is clear that the pollutants also affect the mucous membranes of the oral cavity so that you breathe also passes through the mucous membranes of the respiratory tract and we can have other injuries. We must also think about substances inhaled under working conditions. They start to say 4800 compounds, of which 1200 are potential carcinogens and 60 effective carcinogens. The WHO also estimates that 25% of lung cancers worldwide affect non-smokers. This percentage is probably closer to 10-15% in Western countries. These carcinomas commonly affect women in the form of adenocarcinoma. Tumors in non-smokers tend to be more likely to have EGFR mutations (epithelial growth factor), and almost never KRAS mutations; TP53 mutations, however common, occur less frequently than in smoking-related neoplasms.
Clearly, since the tumor lesions originate from the structures of the lung, be they the bronchi or the mesenchinal structures, we will have lesions due to degeneration of the tissues that make up the various structures. First, the epithelia of the bronchi and the muciparous glands are the most affected structures from the genesis of the neoplasms: we will have carcinomas and adenocarcinomas. Furthermore, under the insult of the carcinogenic substances, the epithelium undergoes a squamous degeneration, as if it formed a protective scaly layer, but in reality cornea pearls are formed. From the cells of the bronchial epithelium they originate from the types of cells we have seen. Squamous carcinomas originate from the pseudo-stratified bronchial epithelium cells; from the present gland component, the adenocarcinomas originate, while from c. neuroendocrine epithelial cells originate neuroendocrine differentiation tumors and these are divided into low malignancy neoplasms that are carcinoids and up to small cell carcinomas
We distinguish 2 clinical forms, central and peripheral.The central form originates from the bronchi of 1-2 order, then we have the other type of peripheral form that arise in the respiratory and alveolar bronchioles, peripheral to the tree. The central forms are the carcinomas of the main bronchus that sweeps the trachea, involving carenal lymph nodes. The central forms have an endobronchial or peribronchial appearance. Peripheral tumors (25% of cases) do not show an apparent relationship to the bronchial tree: we see rounded shapes that gradually grow to become what we call "ball cancer". They are forms with more late lymph node involvement.
In most cases they are malignant epithelial tumors and there are a number of histotypes from the microscopic point of view, depending on the progenitor cell; for example. the original cell, e.g. the squamous cell ca, ca. small cell, adenocarcinoma, large cell ca and these first 4 histotypes are the main ones; then we have the form adenosquamoso, mixed form, then the sarcomatoid and the carcinoid. These histotypes that have always been identified by the pathologist, from a clinical point of view, have a subdivision to small cells and not to small cells. Because those non-small cells (80%) and then there was the small cell carcinoma, of neuroendocrine origin
Pre-cancerous (pre-invasive) lesions. Four types of precancerous epithelial
morphological lesions are recognized: (1) squamous dysplasia and in situ
carcinoma; (2) atypical adenomatous hyperplasia; (3) adenocarcinoma in situ; and
(4) idiopathic diffuse pulmonary hyperplasia of neuroendocrine cells. It should
be remembered that the precancerous term does not imply that progression to
invasive injury is inevitable. Currently, it is not possible to distinguish
between precancerous lesions subject to progression and those that will remain
localized.
Pulmonary carcinomas may arise in the peripheral lung (especially
adenocarcinomas) or in the central / hilar region (especially squamous cell
carcinomas), sometimes in association with recognizable precancerous lesions.
Atypical adenomatous hyperplasia is a small lesion characterized by dysplastic
pneumocytes that cover the alveolar walls if they are fibrotic. The lesion may
be single or multiple and may appear in the lung adjacent to the invasive tumor
or away from it.
In situ adenocarcinoma (previously called bronchioloalveolar carcinoma) is a
lesion of less than 3 cm composed of dysplastic cells that grow along
pre-existing alveolar septa. Cells exhibit higher dysplasia than atypical
adenomatous hyperplasia and may or may not have intracellular mucin (respectively,
mucinous and non-mucinous)
Adenocarcinoma is an invasive malignant epithelial tumor with glandular
differentials or mucin production by tumor cells. These modes are represented by
the acinar, lepidic, papillary, micropapillary and solid types with production
of mucus. Compared to the squamous cell tumor, the lesions are usually more
peripheral and tend to be smaller. They vary histologically from
well-differentiated tenors with evident glandular elements. We can have:
- to papillary lesions similar to other papillary carcinomas, to solid masses
that only occasionally have glands and mucin-secreting cells. The majority
express the thyroid transcription factor 1, identified for the first time in the
thyroid;
Tumors (<3 cm) with invasive component (<5mm) associated with scarring and with
a peripheral development at a lepidic level are called microinvasive
adenocarcinomas and have a better prognosis than invasive carcinomas of the same
size. Mucinous adenocarcinomas tend to spread by air, forming satellite tumors.
These may present as a single nodule or as multiple nodules, or affect, an
entire lobe, with a framework similar to that of lobar pneumonia, so they are
less suitable for surgical treatment. Squamous cell carcinoma is mostly found in
males and is closely related to smoking. The precancerous lesions that give rise
to invasive squamous cell carcinoma are often preceded by squamous metaplasia or
dysplasia in the bronchial epithelium, which then turns into in situ carcinoma,
a phase that can last for several years. Up to this point, atypical cells can be
identified in cytological findings of sputum or brushed or bronchial lavage,
although the lesion is asymptomatic and undetectable on radiographic examination.
Eventually an invasive squamous cell carcinoma appears. The tumor can then
follow a variety of evolutionary frameworks. It can continue to grow
exophysically in the lumen of the bronchi producing an altraluminal mass. With
further enlargement, the bronchus becomes obstructed, resulting in distal
atelectasis and infection. It can also quickly penetrate the bronchial wall by
infiltrating it along the peribronchial tissue to the hull or mediastinum region.
In other cases, the tumor grows along a broad forehead to produce a "cauliflower"
intraparenchymal mass that appears to compress the surrounding lung tissue. As
in almost all types of lung cancer, the neoplastic tissue is greyish-white in
color and has a hard consistency. Especially when the tumors are large, there
may be focal areas of hemorrhage or necrosis that produce soft red or yellowish
areas. These necrotic foci can sometimes cavitate.
Histologically, squamous cell carcinoma is characterized by
keratinization and / or the presence of intercellular bridges. Keratinization
can take the form of corneal pearls or individual cells with a dense
eosinophilous cytoplasm These features are predominant in well-differentiated
tumors, they are found, albeit not so easily, in moderly differentiated tumors
and are focally observed in tumors poorly differentiated. Mitotic activity is
higher in poorly differentiated tumors. In the past, most of the squamous cell
carcasses originated centrally from the segmental or subsegmentar bronchi.
However, the incidence of squamous cell carcinoma of the peripheral areas of the
lung is increasing. Squamose metaplasia, epithelial dysplasia and outbreaks of
a true in situ carcinoma can be observed in the bronchial epithelium adjacent to
the tumor mass.
Small cell carcinoma is a highly malignant tumor closely related to cigarette
smoking; only about 1% of cases concern non-smokers. It can occur in the main
bronchi or in the periphery of the lung. A pre-invasive phase is not known.
These are the most aggressive pulmonary neoplasms, with widespread metastases,
and practically always fatal.
Small cell carcinoma consists of relatively small cells with poor
cytoplasm, with well-defined cellular borders, with finely granular nuclear
chromatin (a "salt and pepper" type picture) and no apparent nuclei. The cells
are round, oval and spindle, with important nuclear remodeling. There is no
absolute dimension for tumor cells, but they generally have a diameter three
times smaller than quiescent lymphocytes (a size of about 25 microns). The
mitotic count is high. The cells grow in groups that do not have neither
glandular nor scaly organization. Necrosis is common and often very extensive.
Basophilic staining of the vascular walls due to encrustations of DNA from
necrotic tumor cells (effect of Azzopardi) is often present. Indeed, all small
cell carcinomas are considered to be of high grade. Combined small cell
carcinoma is a variant in which typical small cell carcinoma is mixed with
non-small cell histologies, such as large cell neuroendocrine carcinoma and even
sarcoma-like cast cell morphologies.
Electron microscopy shows, in two thirds of cases, electrondenser
neurosecretory granules with a diameter of about 100 nm. The appearance of
neurosecretory granules, the expression of neuroendocrine markers, such as
chromogranin, synaptophysin, CD57, and the ability of some of these tumors to
secrete hormones (for example, the proteine correlated to parathormone, the
cause of paraneoplastic hypercalcaemia ) indicate that this tumor originates
from the neuroendocrine progenitor cells that are present in the lining of the
bronchial epithelium. Among the various types of lung cancer, the small cell is
very often associated with ectopic hormonal production (treated further).
Immunohistochemistry shows high levels of BCL2 antiapoptotic protein expression
in 90% of tumors.
Large cell carcinoma is an undifferentiated malignant epithelial tumor
without the cytological features of other forms of lung carcinoma. Cells
typically have large nuclei, prominent nuclei and a moderate amount of cytoplasm.
That of large cell carcinoma is a diagnosis of exclusion, as this tumor does not
express any of the markers associated with adenocarcinoma (TTF-1, napsin
A) or squamous cell carcinoma (p63, p40). A histological variant is
represented by neuroendocrine large cell carcinoma, which has molecular
characteristics similar to those of small cell carcinoma, but is formed by
larger neoplastic cells.
Any type of lung cancer can extend to the pleural surface, then into the pleural
cavity or into the pericardium. In most cases, metastases to tracheal, bronchial,
and mediastinal lymph nodes can be detected. The frequency of lymph node
involvement is slightly variable with histological characteristics, but on
average it is more than 50%.
Remote diffusion of lung cancer occurs through the lymphatic and bloodways.
These tumors have the distinct characteristic of spreading widely throughout the
body and at an early stage of their evolution, except for the squamous cell
carcinoma that late metastasizes outside the thorax. Metastasis is often the
first manifestation of an underlying occult pulmonary lesion. The spread of
these lesions does not spare any organ or tissue, but the adrenals, for obscure
reasons, are interested in over half of the cases. The liver (30-50%), the brain
(20%) and the bone tissue (20%) are other common metastasis sites. Combined
carcinomas. Approximately 10% of all lung carcinomas have a combined
histological appearance, which includes two or more of the types described above.
Biomarkers used in clinical practice The biomarkers currently used in clinical practice, for which treatments already considered "standard" and available in all Italian facilities are combined: the mutation of the EGFR gene (Epidermal Growth Factor Receptor) the rearrangement of the ALK gene (Anaplastic Lymphoma Kinase) Their presence in patients with lung cancer allows to resort to targeted treatment. Many reference cancer centers perform molecular tests. EGFR: this mutation is found in 10-15% of Caucasian patients with pulmonary adenocarcinoma. Almost 50% of lung cancers with this mutation are diagnosed in people who have never smoked. The drugs that can be used in the presence of this mutation are: Erlotinib (Tarceva), Gefitinib (Iressa) and Afatinib (Giotrif).
The classification of tumors is important both for the treatment of the patient
and for providing the basis for epidemiological and biological studies. For each
type of lung carcinoma numerous histological variants have been described;
however, their clinical significance is yet to be determined, except as
mentioned here. The relative proportions of the most important categories are:
Adenocarcinoma (38%).
Squamocellular carcinoma (20%).
Small cell carcinoma (14%).
Large cell carcinoma (3%).
Others (25%).
Different histological pictures can be observed, even in the same tumor that
combines Therefore, combinations of squamous cell carcinoma and adenocarcinoma
or small cell and squamous cell carcinoma affect about 10% of patients. The
incidence of adenocarcinoma has increased significantly over the last two
decades. Adenocarcinoma is currently the most common form of lung carcinoma in
women, because for men, since smoking is still the cause of neoplasia, the form
of squamous carcinoma develops in them. The cause of this of this change in
incidence is not clear. But the data is changing: a possible factor is
represented by the increase in smoking in women, but this fact only gives us our
lack of knowledge about women tend to develop more adenocarcinomas. One
possibility is that variations in the type of cigarette (type of filter, lower
levels of tar and nicotine), have led smokers to inhale more deeply and
therefore to expose more the peripheral airways and cells (with a preference for
adenocarcinoma).
Squamous cell carcinoma
Papillary, clear cell, small cell, basaloid
Small cell carcinoma
Combined small cell carcinoma
Adenocarcinoma
Minimally invasive adenocarcinoma (non-mucinous, mucinous)
Lepidico; acinar; papillary, solid (based on the predominant picture)
Mucinous adenocarcinoma
Large cell carcinoma
Large cell neuroendocrine carcinoma
Adenosquamous carcinoma
Carcinomas with pleomorphic elements, sarcomatoids or sarcomatosis
Carcinoid tumor
Typical, atypical
Salivary gland type carcinomas
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