Lung carcinoma C34.9

From 1838, there is an account by Hare in which the typical symptoms of a Pancoast tumor are described for the first time (Büttner 2004). The first description of a primary bronchial carcinoma is by Langhans in 1873, and the first cytological description using sputum was by Hampeln in 1887 (Schubert 2018). In 1932, radiologist Henry Pancoast presented a tumor in the superior pulmonary sulcus to the American Medical Association, which would later be named after him (Harvey 2012). The first two cases of occupational cancer in asbestos workers were described by M. Nordmann in 1938 (Buettner 2004). Pancoast tumor was considered inoperable until the 1950s. It was not until 1953 that Chardack and MacCallum successfully resected a Pancoast tumor for the first time. In 1961, Shaw and Paulsen were the first to perform preoperative radiotherapy followed by resection (Ewig 2014).

According to the WHO, lung carcinoma is a malignant tumor that originates from the epithelium of the respiratory tract (bronchi, bronchioles, alveoli) (Kasper 2015). Lung carcinoma is the most common type of lung tumor(Huber 2006).

Classification of the WHO:

Lung carcinoma is differentiated into 4 main cell types:

• small cell carcinoma
• adenocarcinoma
• squamous cell carcinoma
• large cell carcinoma

The latter three carcinomas are also referred to as non-small cell carcinoma (Kasper 2015). The differentiation small cell / non-small cell determines the therapeutic consequences (Huber 2006).

Macroscopic classification according to location and spread.

• Hilar (central) lung CA: This occurs most frequently with 70%. Histologically, it is almost always a small cell or squamous cell carcinoma.
• Peripheral lung carcinoma: Occurs in 25% of cases. Radiologically it presents as a so-called "round focus".
• Diffuse growing carcinoma: This is the rarest type with 3%. It is also called "cancerous pneumonia" or "alveolar carcinoma" (Herold 2022).

Degree of differentiation

• G1 well differentiated
• G2 moderately differentiated
• G3 poorly differentiated
• G4 undifferentiated

Adenocarcinomas, squamous cell carcinomas, and adenosquamous carcinomas are graded G1 - G3; small- and large-cell are generally graded G4 (Herold 2022).

TNM- classification lung carcinoma UICC (Union for International Cancer Control) 2017 (8th edition).

• Tis: Carcinoma in situ
• T 1: largest diameter ≤ 3 cm, surrounded by lung tissue or visceral pleura, main bronchus not involved
  • T1a(mi): Minimally invasive adenocarcinoma (adenocarcinoma with lepidic growth pattern ≤ 3cm in greatest dimension, with a solid portion < 5mm in diameter).
  • T1a: largest diameter ≤ 1cm
  • T1b: largest diameter 1 cm but ≤ 2 cm
  • T1c: largest diameter > 2 cm but ≤ 3 cm.
• T2: largest diameter >3 cm but ≤ 5 cm or
  • Infiltration of the main bronchus regardless of distance from the carina but without direct invasion of the carina or
  • Infiltration of the visceral pleura or
  • Tumor-related partial atelectasis or obstructive pneumonia extending into the hilus, involving parts of the lung or the entire lung
    • T2a: largest diameter 3 cm but ≤ 4 cm
    • T2b: largest diameter > 4 cm but ≤ 5 cm.
• T3: largest diameter > 5 cm but ≤ 7 cm or
  • Infiltration of thoracic wall (including parietal pleura and superior sulcus (so-called superior sulcus tumor or Pancoast tumor), phrenic nerve, or parietal pericardium or
  • additional tumor nodule in the same lung lobe as the primary tumor
• T4: largest diameter > 7cm or
  • with direct infiltration of diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina, or
  • Additional tumor nodules in another ipsilateral lobe of the lung (Herold 2022 / Ukena 2018).

Lymph nodes

• N0: no lymph node metastasis(s)
• N1: metastasis(s) in ipsilateral, peribronchial, and/or ipsilateral hilar lymph nodes and/or intrapulmonary lymph nodes or direct invasion of these lymph nodes
• N2: Metastasis(s) in ipsilateral mediastinal and/or subcarinal lymph nodes
• N3: Metastasis(s) in contralateral mediastinal, contralateral hilar, ipsi or contralateral deep cervical, supraclavicular lymph nodes (Herold 2022 / Ukena 2018).

Metastases

• M0: No distant metastasis(s)
• M1: distant metastasis(s) present.
  • M1a: Separate tumor nodule(s) in a contralateral lung lobe or
  • Pleura with nodular involvement or
  • malignant pleural effusion or
  • malignant pericardial effusion
• M1b: A solitary distant metastasis(s) in a solitary extrathoracic organ
• M1c: Multiple distant metastases (> 1) in one or more organs (Herold 2022 / Ukena 2018).

Staging

• Stage 0: Tis - N0 - M0
• Stage IA1: T1a(mi) - N0 - Mo or T1a - N0 - M0
  • Stage IA2: T1b - N0 - M0
  • Stage IA3: T1c - N0 - M0
  • Stage IB: T2a - N0 - M0
• Stage IIA: T2b - N0 - M0
  • Stage IIB: T1a, b, c - N1 - M0
  • Stage IIB: T2a, b - N1 - M0
  • Stage IIB: T3 - N0 - M0
• Stage IIIA: T1a-c - N2 - M0
  • Stage IIIA: T2a,b - N2 - M0
  • Stage IIIA: T3 - N1 - M0
  • Stage IIIA: T4 - N0 - M0
  • Stage IIIA: T4 - N1 - M0
    • Stage IIIB: T1a-c - N3 - M0
      • Stage IIIB: T2a,b - N3 - M0
      • Stage IIIB: T3 - N2 - M0
      • Stage IIIB: T4 - N2 - M0
    • Stage IIIC: T3 - N3 - M0
      • Stage IIIC: T4 - N3 - M0
• Stage IVA: any T - any N - M1a
  • Stage IVA: any T - any N - M1b
  • Stage IVB: any T - any N - M1c (Ukena 2018).

Subdivision of lymph node involvement in stage IIIA according to Robinson:

• Stage IIIA1: In this case, lymph node metastases are found postoperatively in one station.
• Stage IIIA2: Intraoperatively, a lymph node metastasis is discovered in one station
• Stage IIIA3: Preoperatively confirmed lymph node metastases in one or more wards
• Stage IIIA4: Extensive extracapsular lymph node metastases, so-called "bulky disease" > 2 - 3 cm (Jähne 2016).

Classification in small cell lung cancer (SCLC):

Since metastases are usually already present in SCLC at diagnosis, the following classification has proven useful:

• Very limited disease: Metastases are found in several lymph node stations. It is the rarest stage with about 5 %.
• Limited disease: Approximately 20 % of patients are in this stage (Herold 2022). It includes stages I - IIIB (Huber 2017).
• Extensive disease: Most patients are in this stage with 75% (Herold 2022). In this case, there is always metastasis outside the primary affected hemithorax (Huber 2017).

Lung carcinoma was considered a rare carcinoma in the literature before 1900, with fewer than 400 cases described (Kasper 2015).

It is now the most common cause of cancer death in men, and ranks 2nd in women (behind breast carcinoma). The incidence in Europe is 52 / 100,000 persons / year (Herold 2022). In Germany, it is 87.1 in men and 46.7 in women (Huber 2020). Men are now affected up to 3 times as often as women, only in adenocarcinoma the sex ratio is m: w = 1: 6 (Herold 2022).

Incidence is dependent on race and ethnic group. For example, the highest age-adjusted incidence is found in African Americans. Native Americans, Hispanics, and Asians have incidence rates approximately 40-50% higher than whites (Kasper 2015). Socioeconomic status also plays a major role. For example, significantly more patients with low income and poor education develop lung cancer (Ukena 2018).

The incidence of small cell lung cancer (SCLC) is 16 / 100,000 per year and that of non-small cell (NSCLC) is 40 / 100,000 per year (Thomas 2010). This is the only one to show a slightly decreasing incidence (in the USA in 1973 at 17% and in 2003 at 13% [Ukena 2018]).

Female smokers have a significantly higher risk of developing the disease than men (Höpker 2013).

Lung cancer occurring without a history of smoking is more common in women and East Asians (Kasper 2015).

Occupational carcinogens cause approximately 5% of all lung carcinomas, with asbestos being the most common trigger at >90% (Herold 2022).

Several carcinogens play a role in the development of lung cancer:

• Active cigarette smoke inhalation: This group is responsible for 85% of lung carcinomas (Herold 2022). The association between nicotine and disease is particularly strong in small cell and squamous cell carcinoma, less so in adenocarcinoma. Cigarette smokers have a higher risk than pipe or cigar smokers (Thomas 2010). The risk of developing lung cancer depends on the duration and extent of cigarette use (Herold 2022). For example, according to the International Agency for Research on Cancer, 10 cigarettes/d increases the risk by 5-10 times and 20 cigarettes/d increases the risk by 15-20 times (Thomas 2010). The extent of cigarette consumption is measured in pack years, i.e., number of packs smoked per day multiplied by years smoked. At 40 py (pack years), for example, there is a 10-fold risk of cancer; if smoking begins in adolescence, this risk increases up to 30-fold (Herold 2022). If the risk of occupational carcinogens is also added, the risk of lung cancer is potentiated (Herold 2022).
• Passive smokers: In passive smokers, the risk is increased by a factor of 1.3 - 2.0 (Herold 2022). Here, too, there is a dose-dependent relationship. Non-smokers with occupational activity in the hospitality industry have up to a 10-fold increased risk of developing lung carcinoma after 40 years of occupation (Huber 2020).
• Occupationalcarcinogens: Occupational carcinogens cause about 5% of all lung carcinomas. These include the following groups of occupational substances:
• - Arsenic compounds
• - Asbestos species (these cause > 90% of occupational carcinogens; when combined with PAH [man-made mineral fibers], the probability of developing lung carcinoma is at least 50%).
• - Chromium VI compounds
• - haloethers
• - ionizing radiating substances
• - coke oven raw gases
• - nickel metal (Herold 2022)
• - Man-made mineral fibers (also known as MMMF = Man Made Mineral Fibers, lead to PAH- lung cancer (Ukena 2018)
• - polycyclic aromatic hydrocarbons (PAH- lung cancer)
• - Quartz dust and many others.
• Environmental carcinogens: These include e.g. diesel exhaust, passive smoking, radon in homes, industrial and traffic gases (Herold 2022).
• Dietary habits: A protective effect on lung cancer has a diet rich in fruits and vegetables (Ukena 2018), whereas raw meat, saturated fat, salted or smoked meat products seem to increase the risk of lung cancer (Huber 2020).
• Genetic predisposition: Individuals whose parent had lung cancer have a 2-3 fold increased risk. In addition, certain gene variants on chromosome 14 are known to increase the risk of lung cancer in smokers .
• Chronic lung disease: With regard to chronic lung disease, there is also an association with lung cancer that goes beyond smoking. The strongest association is found in COPD. In one study, 301 smokers with lung cancer were compared with 301 smokers without lung cancer. Patients with lung cancer were found to have a significantly increased prevalence of COPD ≥ grade 2 by GOLD, 50% versus 8% without lung cancer (Huber 2020).
• Other risk factors: These include lung scarring, malignant degeneration such as cicatricial carcinoma and cavernous carcinoma, and unknown factors such as in adenocarcinoma (Herold 2022). In addition, alpha1- antitrypsin deficiency and HIV infection are among the risk factors (Huber 2020).

Note: After smoking cessation, the risk of lung cancer decreases. After 15 years, for example, it is 2 - 4 times that of a non-smoker. Nevertheless, many patients are ex-smokers, as the mean latency period is 20 - 30 years (Thomas 2010).

Pathogenetically, a multistage concept is found in the development of lung cancer:

• 1. exposure to carcinogenic substances (latency period approx. 30 years)
• 2. genetic damage by carcinogens (latency period also approx. 30 years [Herold 2022]).

The above mutagenic substances are first metabolized and then bound to DNA by adducts. They can thereby cause malignant transformation or - in later stages - contribute to the evolution of the malignant phenotype (Thomas 2010).

• 3. dysplasia of the epithelium with development of a carcinoma in situ (Herold 2022).

There is a frequency peak between the 55th - 60th year of life (Herold 2022), which increases up to the 80th year of life and then only decreases (Kasper 2015). Only 5% of patients are < 40 years old (Herold 2022).

In the early stage there are usually no symptoms.

Suspicious for lung carcinoma in > 40 years old are: asthma or bronchitis with short history, therapy-resistant colds, recurrent pneumonia. Only in the further course of the disease occur:

• Cough
• chest pain
• dyspnea

and as late symptoms:

• Hemoptysis
• Phrenic nerve palsy
• Pleural exudate
• recurrent paresis
• upper influence congestion
• First manifestation due to metastasis with initially unknown primary tumor (so-called CUP syndrome = cancer of unknown primary site)
• Dysphagia (in case of obstruction of the esophagus)
• Anorexia
• general weakness
• Night sweats
• fever (Kasper 2015)

Symptom in the rarely occurring bronchoalveolar adenocarcinoma is:

• Irritable cough with mucous watery sputum (Herold 2022).

Typical of Pancoast tumor - a peripheral lung tumor located near the apex (Harvey 2012) - are:

• Horner symptom complex with
  • Ptosis
  • Miosis
  • Enophthalmos
• Intercostal neuralgia
• Bone destruction of the 1st rib and / or 1st BWK.
• Arm pain due to plexus neuralgia
• Swelling of the arm due to lymphatic or venous congestion (Herold 2022)

Paraneoplastic symptoms are common in small cell carcinoma (see Paraneoplastic Syndromes below):

Paraneoplastic neuropathies and myopathies such as:

• Lambert- Eaton syndrome with difficult stair climbing due to myasthenia-like weakness of proximal limb muscles, ptosis and double vision.
• paraneoplastic cerebellar degeneration
• Polymyositis
• Dermatomyositis

Neurological disorders (Herold 2022)

Paraneoplastic endocrinopathies such as:

• Cushing's syndrome: This results from ectopic ACTH production and is the most common paraneoplastic disorder.
• Hypoglycemia: Insulin-like growth factor II (IGF- II) is produced.
• Tumor hypercalcemia due to ectopic production of peptides related to parathyroid hormone, so called PTHrP
• syndrome of inadequate ADH secretion
• hypertrophic pulmonary osteoarthropathy (so-called Pierre- Marie- Bamberger syndrome):
  • Clock glass nails
  • Drumstick fingers (in 0 - 20% [Ukena 2018]).
  • Joint pain in hands, ankles, knees.
• Thrombocytosis: This is found in about 1/3 of patients, often combined with a tendency to thrombosis (Herold 2022).

Cutaneous paraneoplastic syndromes: The following paraneoplastic symptoms/diseases may also occur in association with lung carcinoma:

• Erythema multiforme
• Erythema gyratum repens
• Exfoliative dermatitis
• Erythroderma
• Necrolytic migratory erythema
• Sweet syndrome
• Acanthosis nigricans
• Tylosis
• Pruritus and urticaria (Ukena 2018).

Metastases

In metastases, in addition to the above symptoms, there may be:

• Brain metastases:
  • Nausea
  • Vomiting
  • Headache
  • seizures
  • neurological deficits
• Bone metastases:
  • pain
  • pathological fractures
  • signs of spinal cord compression
  • cytopenia of blood cells
  • leukoerythroblastosis
• Liver metastases:
  • pain in the right upper abdomen
  • Hepatomegaly
  • Liver dysfunction or biliary obstruction rarely occurs
• Adrenal metastases (frequently occurring):
  • rarely pain (Kasper 2015)

The diagnosis of lung cancer includes - in addition to a detailed medical and occupational history with regard to carcinogenic dusts such as asbestos - the examinations and laboratory findings mentioned below.

Patients with lung carcinoma often have concomitant smoking-related diseases such as COPD, cardiovascular diseases, etc.. In them, problems that can be corrected preoperatively such as electrolyte and fluid disturbances, anemia, infections, cardiac arrhythmias, heart disease, etc. should be treated appropriately (Kasper 2015).

The Karnofsky index is used to assess exercise capacity and general condition (Ukena 2018).

To exclude distant metastases should be done:

• Sonography (especially of the liver)
• Bone scintigraphy
• CT or MRI of the brain
• Bone marrow aspiration (to exclude M1- status in small cell lung cancer [Meyer 2020]).
• PET (positron emission tomography) (Herold 2022)

X-ray thorax in 2 planes

Round focus: There is no reduction in transparency that cannot be caused by lung carcinoma (Herold 2022).

• Mediastinal widening
• Atelectasis
• Pleural effusion (Ukena 2018).

In bronchoalveolar adenocarcinoma:

• Signs of chronic pneumonia (Herold 2022).

The following factors are particularly suspicious for carcinoma:

• history of smoking
• age > 40 y.
• increase in size of the round focus (compared to previous images)
• spicules radiating from the round focus into the lung parenchyma
• absence of calcification (Herold 2022)

Computed tomography / spiral CT with 3D images / HRCT: CT, always contrast-enhanced, should be performed before bronchoscopy in order to target it. However, to establish the diagnosis of a solitary round focus, the morphological signs in the CT are usually not sufficient, because although the sensitivity is very high, the specificity is only low (Ukena 2018).

PET- CT: PET- CT represents the most sensitive method in cases of previously unknown primarius or possible metastases (Herold 2022). They appear as a so-called "hot spot" (Kasper 2015). PET- CT has recently also been used for accurate staging in NSCLC and to detect pathologically enlarged mediastinal lymph nodes.

False negative results occur in:

• Diabetes mellitus
• lesions < 8 mm
• Slow-growing tumors such as well-differentiated adenocarcinoma and carcinoid tumor.

False positive results are found in:

• certain infections and granulomatous diseases such as tuberculosis (Kasper 2015).

MRI: MRI is the most effective method for imaging brain metastases. It is equally used in imaging tumors in the superior sulcus (Kasper 2015). MRI with contrast medium administration is also suitable for staging lung carcinoma - just like CT - or is even more suitable due to the higher soft tissue contrast (Ukena 2018).

Sonography: Both abdominal sonography and thoracic sonography should be used.

Abdominal sonography is particularly important with regard to any liver metastases, while thoracic sonography (TTUS) can provide indications of pleural effusion and enables the puncture of tumors close to the chest wall (Ukena 2018).

Sputum cytology: Although this is non-invasive and inexpensive, the yield is significantly lower than other examination methods. The specificity is close to 100%, but the sensitivity is < 70%. It is recommended that at least 3 sputum samples be examined (Kasper 2015).

Preoperative pulmonary function diagnosis: Pulmonary function should be checked even before invasive diagnostic tests, as poor pulmonary function represents functional inoperability.

• Prerequisites for pneumectomy are:
  • FEV1 > 2.0 l (80% target).
  • Diffusion capacity (DLCO) > 60 % target
• Prerequisites for lobectomy are:
  • FEV1 > 1.5 l
  • Diffusion capacity (DLCO) > 60 % target (Herold 2022)

If values are poor, additional diagnostics of spirometry, pulmonary function scintigraphy and blood gases are recommended.

• Postoperative pulmonary function:

In addition, the lung function to be expected postoperatively should be calculated (Herold 2022). This can be done with the following formula:

Postoperative FEV1 in liters = preoperative FEV1 x (100 - percentage of lung perfusion of the portion to be resected relative to total perfusion).

• Spiroergometry:
  • low risk at oxygen uptake of > 20 ml / kg / min
  • medium risk at 16 - 20 ml / kg / min
  • high risk at 10 - 15 ml / kg / min
  • Inoperability even for lobectomy at < 10 ml / kg / min (Herold 2022).

Trial laparotomy: A trial laparotomy is often required to clarify the exact stage and thus the operability (Ukena 2018).

Mediastinoscopy: In patients with enlarged lymph nodes, mediastinoscopy is indicated for further diagnosis. The sensitivity is between 80-90% (Ukena 2018).

Biopsies: Biopsies can be obtained by different techniques:

• 1. bronchoscopy: Bronchoscopy can be used to confirm the diagnosis bioptically-histologically. Identification of cancerous tissue can be improved by auto-fluorescence bronchoscopy (LIFE = Lung Imaging Fluorescence Endoscopy) (Herold 2022). Bronchoscopy represents the most important method to confirm the diagnosis of lung carcinoma (Ukena 2018).
• 2. EBUS: Endobronchial ultrasound (EBUS) can be used to confirm mediastinal lymph nodes and obtain tissue by fine needle biopsy (Herold 2022).
• 3. transthoracic puncture: This is used for peripheral round lesions > 2 cm by CT- or sonography-guided puncture (Herold 2022).
• 4. video-assisted thoracoscopy (VATS).
• 5. mediastinoscopy
• 6. diagnostic thoracotomy (Herold 2022)

CSF puncture: In patients with signs of spinal cord compression, such as weakness, paralysis urinary retention, etc., CSF should be collected in addition to CT or MRI. Likewise in patients with symptoms of leptomeningitis (Kasper 2015).

Bone marrow aspiration: This is indicated to exclude M1 status in small cell lung carcinoma (Meyer 2020).

Thoracentesis: If pleural effusions are detected, they should be punctured and subsequently examined histologically (Ukena 2018).

Small cell carcinoma:

• In Lambert- Eaton syndrome:
  • Antibodies against VGCC (voltage gated calcium channel [Herold 2022])
• In paraneoplastic cerebellar degeneration:
  • Anti-Yo antibodies
  • Anti- Hu antibodies (found in about 15% [Herold 2022])
• Thrombocytosis (occurs in about 1/3 of patients and increases the risk of thrombosis [Herold 2022])
• ACTH elevated
• BG daily profile
• PTHrP (peptide related to parathyroid hormone)
• ADH (sometimes decreased)
• LDL (a steadily increasing level is associated with a poor prognosis)
• Tumor markers: These are not important in lung cancer either in terms of diagnosis or follow-up (Herold 2022), as both sensitivity and specificity are too low (Ukena 2018).
• Hyponatremia: This can occur in the context of SIADH (syndrome of inadequate ADH- secretion) (Herold 2022).
• Leukoerythroblastosis (in bone metastases).
• Blood cell cytopenia (may be increased in liver metastases).
• Liver function values (increased in liver metastases) (Kasper 2015).
• paraneoplastic endocrinopathies in SCLC with:
  • Hypoglycemia
  • Hypercalcemia
  • ACTH elevation
  • Disturbance of ADH secretion (inadequate secretion) (Herold 2022).

The following histological forms of lung cancer can be found:

• small cell lung cancer = SCLC: SCLC occurs in approximately 15% of lung cancers (Herold 2022). The cells are small and contain little cytoplasm. the nuclear chromatin is finely granulated, the cell borders are blurred, there are absent or inconspicuous nucleoli and a strikingly high mitotic count (Kasper 2015)
• Non-small cell lung cancer = NSCLC (the most common type, accounting for 80%). These include:
  • Squamous cell carcinoma (approximately 35%). This is morphologically identical to extrapulmonary squamous cell carcinoma (Kasper 2015).
  • Adenocarcinoma (approx. 40 %). In this case, glandular differentiation or production of mucin is often found (Kasper 2015).
  • Large cell lung carcinoma (approx. 10 %).
  • Adenosquamous carcinoma
  • Bronchial gland tumor
  • Carcinoid tumor
  • Sarcomatoid carcinoma (Herold 2022).

In every 3rd lung carcinoma, different histological proportions are found in the same tumor. Therefore, the percentages of the individual histological types often differ (Herold 2022). For subsequent treatment, it is important to differentiate between small cell and non-small cell carcinoma, as their treatment is fundamentally different (Ukena 2018).

• Immunophenotyping

If neuroendocrine lung tumor is detected, the diagnosis should be confirmed by immunohistochemistry (Ukena 2018).

metastases of other primary tumors (Kraus 2020): Additional immunohistochemical testing (biomarker PD- L1) usually allows delineation of the individual tumor types or pulmonary metastases (Herold 2022).

DD Round tumor

• malignant:
  • Lung carcinoma (in approx. 40 %)
  • isolated metastasis (in approx. 10%)
• benign:
  • Tuberculoma (in approx. 25 %)
  • Chondroma
  • Fibroma
  • neurinoma etc. (Herold 2022)

Metastasis of bronchial carcinoma occurs early to regional lymph nodes, then hematogenously to the liver, brain, adrenal glands, and skeleton (in the latter, particularly frequently to the spine). In small cell carcinoma, hematogenous spread is found very early, often at diagnosis (Herold 2022).

The most important distinction in therapy is whether or not surgical resection is an option and whether inoperable patients may benefit from chemotherapy and/or radiotherapy (Kasper 2015).

Age: Patients > 70 years of age undergoing lung resection are more likely to require intensive perioperative care. Those over 80 years of age have increased perioperative lethality.

Patients of advanced age, however, should not be excluded from a therapeutic modality such as surgery, chemotherapy, or radiotherapy on the basis of age alone. The spectrum of comorbidities is of far greater relevance with regard to the therapeutic approach (Ukena 2018).

Radiological criteria for operability are:

- certain T3 or T4 situations such as thoracic wall infiltration, infiltration of mediastinal organs).

- no contact with the mediastinum

- contact with the aorta < 90 degrees of circumference.

If these signs are absent, inoperability can be expected in up to 50% (Ukena 2018).

Clinical Predictors:

High risk:

- unstable or severe angina pectoris

- recent myocardial infarction (see also "Surgical Therapy" contraindications)

- decompensated heart failure

- severe valvular heart disease

- Significant arrhythmias such as grade II and III AV block, supraventricular arrhythmias with uncontrolled heart rate, symptomatic ventricular arrhythmias with the presence of heart failure (Ukena 2018)

Intermediate risk:

- Previous myocardial infarction still manifested by pathologic Q- jags

- mild angina pectoris

- diabetes mellitus with vascular complications

- compensated heart failure (Ukena 2018).

Low risk:

- abnormal ECG such as left bundle branch block, ventricular end part changes, left ventricular hypertrophy

- Older age (> 70 years)

- stroke with residuals

- poorly controlled arterial hypertension

- absence of sinus rhythm with normal-frequency ventricular action such as atrial fibrillation

- low exercise capacity (Ukena 2018)

1. small cell carcinoma:

The treatment of SCLC is fundamentally different from that of NSCLS. SCLC has a high sensitivity to therapy, therefore polychemotherapy should be initiated immediately after the diagnosis is made. The following drugs have proven activity:

- Adriamycin

- bendamustine

- carboplatin

- cisplatin

- cyclophosphamide

- epirubicin

- etoposide

- ifosfamide

- irinotecan

- methotrexate

- paclitaxel

- teniposide

- topotecan

- vincristine

(Ukena 2018).

Regarding the therapy, we differentiate between Limited disease and Extensive disease:

• 1. limited disease (LD)

Approximately 25% of patients are in stage T2 N0 M0 at diagnosis. In this case, a bimodular therapy can be applied in addition to a resection with curative objective. The latter includes polychemotherapy and radiotherapy (Herold 2022).

- Polychemotherapy

Cisplatin plus etoposide according to the PE regimen, 4 - 6 cycles every 3 weeks. Remission rates are very high in this setting (Herold 2022).

- Radiation

Hyperfractionated irradiation of the mediastinum with 40 Gy. in the 1st therapy cycle simultaneous to chemotherapy (Herold 2022)....

- Cranial irradiation

If remission is achieved, whole-skull irradiation should be performed prophylactically to improve the diagnosis (Herold 2022), as this can significantly reduce the incidence of symptomatic brain metastasis (Meyer 2020).

• 2. extensive disease (ED).

Approximately 75% of patients are already in an advanced stage at diagnosis. The treatment approach is palliative and unimodal with:

- Chemotherapy

Here, polychemotherapy with carboplatin plus etoposide plus atezolizumab (Herold 2022) is recommended. The success of chemotherapy is measured by the decrease in clinical symptoms such as cough, dyspnea (Meyer 2020).

- Radiation.

Radiation should be used exclusively for upper influence congestion and skeletal metastases.

- Cranial irradiation

If there is a response to chemotherapy, prophylactic whole-skull irradiation should be performed (Herold 2022).

Sufficient pain therapy according to the WHO staged regimen is essential (Meyer 2020).

- Lambert-Eaton syndrome

If the above-mentioned Lambert-Eaton syndrome occurs (see "Clinical symptoms"), prednisolone or immunoglobulins should be administered i.v. in addition to treatment of the underlying disease (Herold 2022).

2. non-small cell lung cancer:

In patients with NSCLC, primary surgical therapy is possible in up to 85% (see "Surgical Therapy" [Ukena 2018]).

Adjuvant chem otherapy: Adjuvant chemotherapy is possible in stages II / IIIA1 / IIIA2. If functional inoperability is present, parenchyma-sparing surgery or radiotherapy is recommended (Herold 2022). In stage IA, adjuvant chemotherapy worsened survival in studies, and stage IB showed a small improvement in survival, but its clinical significance is questionable (Kasper 2015). Adjuvant chemotherapy should be given after the patient has fully recovered, usually 6-12 weeks after surgery, should be given over 4 cycles, and should preferably be cisplatin-based (Kasper 2015).

Neoadjuvant chem otherapy: Neoadjuvant chemotherapy is advocated by some experts on the assumption that it can more effectively destroy occult micrometastases, but also on the other hand to make unresectable tumors resectable. The decision to use neoadjuvant chemotherapy should always be made in consultation with the surgeon (Kasper 2015).

A meta-analysis of 15 randomized trials indicated a modest survival benefit of approximately 5% in 5-year survival in stage I - III (Kasper 2015).

Postoperative radiotherapy (PORT): PORT depends primarily on the presence or absence of N2 involvement. A meta-analysis showed a significant increase in survival after radiotherapy in the presence of N2- involvement (Kasper 2015).

Patients in stage I / II who refuse surgery or for whom surgery is contraindicated should receive high-dose radiation of 60 - 70 Gy (Meyer 2020).

Stage I / II / IIIA (T3 N1 M0):

Primary surgical treatment (see below "Surgical Therapy"). Adjuvant cisplatin-based chemotherapy showed a 5-year survival benefit of 5% in pooled analyses in randomized trials, up to 20% in stage II in exploratory subgroup analyses, and up to 16% in stage IIIA. Technically operable patients in stage IIIA benefit from neoadjuvant chemotherapy (Meyer 2020).

Stage IIIA1 and IIIA2:

At this stage, neoadjuvant chemotherapy, surgery, and subsequent radiation to the mediastinum are appropriate (Herold 2022).

Stage IIIA3:

Here, there are 2 different treatment options:

- Neoadjuvant radiotherapy followed by surgery

or

- definitive radio-chemotherapy (Herold 2022)

Stage IIIA4 and IIIB:

From stage IIIA4, surgical intervention is not recommended (Jähne 2016). The patient should rather receive combined radio- chemotherapy. In PD- L1 positive patients, subsequent treatment with durvalumab for 1 year as consolidative immunotherapy is recommended (Herold 2022).

Stage IIIB and IV:

Over 4 - 6 cycles, chemotherapy with a cisplatin- based combination should be given. In all patients with non-squamous cell carcinoma, the humanized monoclonal antibody bevacizumab (Herold 2022) is also recommended.

Stage IV:

1. if PD- L1 expression is ≥ 50%: pembrolizumab or immunotherapy plus platinum-containing chemotherapy.

2. if PD- L1 expression is < 50 %, ECOG 0 - 1: platinum-containing combination chemotherapy or alternative immunotherapy for non-squamous cell carcinoma: paclitaxel / carboplatin plus bevacizumab

3. ECOG2: platinum-based combination chemotherapy, possibly also monotherapy

4. non-squamous cell carcinoma: initially cisplatin / pemetrexed, followed by maintenance therapy with pemetrexed (Herold 2022)

Stage IVB:

In oligometastatic disease, where up to 40% of patients are already at diagnosis (Kasper 2015), definitive combination chemotherapy plus local treatment such as stereotactic radiation of brain metastases, surgery of metastases, etc. is recommended (Herold 2022).

Personalized tumor therapy:

Targeted treatments become possible by mutational analysis of cell surface structures such as ALK, BREF V 600 mutation, EGFR, NTRK- fusions, ROS 1 (Herold 2022).

1. patients with detected EGFR mutation: tyrosine kinase inhibitors such as afatinib, erlotinib, gefitinib, osimertinib are recommended.

2. anti-EGFR antibodies such as necitumumab.

3. in case of ALK positivity, ALK inhibitors are used, e.g. alectinib, brigatinib, ceritinib, crizotinib

4. ROS1 translocation: crizotinib

5. BRAF V 600 mutation: dabrafenib or trametinib

6. immune checkpoint inhibitors: nivolumab, pembrolizumab

7. PD1 inhibitors: nivolumab, pembrolizumab

8. PDL1 inhibitors: atezolizumab, avelumab

9. monoclonal antibody anti- CTLA- 4- Ak: ipilimumab (Herold 2022)

10. cemiplimab: By decision of 20/01/2022, the monoclonal antibody cemiplimab was approved as monotherapy for the first-line treatment of patients with locally advanced NSCLC who are not eligible for radiochemotherapy or with metastatic NSCLC in whom PDL1 is expressed in ≥ 50% of tumor cells and no EGFR, ALK, or ROS1 aberrations are detectable (Hedges 2022).

Pancoast tumor:

In stage II - IIIB, neoadjuvant chemotherapy is recommended followed by surgery (Herold 2022). Kasper (2015) recommends preoperative combined chemo-radiotherapy followed by surgery.

Adenocarcinoma:

Since 2004, it has been known that a small percentage of adenocarcinomas have an EGFR- mutation (see above), which makes the tumors particularly sensitive to inhibitors of EGFR- tyrosine kinases (such as erlotinib and gefitinib). At the time, this led to a revision of the WHO classification system (Kasper 2015).

Bronchoalveolar adenocarcinoma:

This rare tumor is almost always inoperable because it is diffusely localized (Herold 2022).

Tumor immunotherapy:

In recent years, tumor immunotherapy has made great progress.

- Cancer vaccines

These include melanoma-associated antigen A3 (MAGE- A3) and liposomal BLP25. These are used particularly in NSCLC at stages IB / II and III (Schultheis 2013).

Palliative therapy:

In palliative therapy, primarily the optimal pain therapy (see d.) according to the WHO- step scheme plays a role.

In addition, the following have proven to be effective:

- chemotherapy with gemcitabine

- bronchoscopic procedures such as laser therapy, photodynamic therapy, stenting

- external and possibly endoluminal radiotherapy with 192 iridium

- image-guided thermal ablation

- maintenance therapy with pemetrexed

- Bisphosphonates for bone metastases (Herold 2022)

In SIADH (syndrome of inadequate ADH secretion) with hyponatremia, tolvaptan, a selective antagonist of arginine vasopressin receptor 2, has been shown to be effective (Herold 2022).

Early integration of palliative care should occur or the offer of palliative care should be explained to the patient at an early stage. Studies have shown that this improved quality of life, depression, and even prolonged overall survival. Also, more advance directives regarding possible resuscitation were made in this group (Ukena 2018).

The standard surgical procedure consists of lobectomy plus systematic dissection of ipsilateral lymph nodes. Cuff resection is possible only in the case of specific tumor localization. It allows a parenchyma-sparing approach. Only rarely is a pneumectomy necessary (Ukena 2018).

Since the diagnosis is often made at an advanced stage, surgical resection is primarily possible in NSCLC (Kasper 2015). It is recommended in stage I / II with adequate cardiopulmonary function in the form of a flap resection (Ukena 2018).

Regardless of the patient's age, pneumectomy is associated with a higher lethality than lobectomy, especially this concerns right-sided pneumectomy (Ukena 2018).

Ideally, surgical procedures should be performed in hospitals with high surgical volume and by a thoracic or cardiothoracic surgeon (Kasper 2015).

Contraindications

• Myocardial infarction: A previous myocardial infarction in the last 3 months is an absolute contraindication for thoracic surgery, as in this case 20% of patients die from reinfarction. Myocardial infarction in the last 6 months is a relative contraindication (Kasper 2015).
• Uncontrolled cardiac arrhythmias
• FEV1 < 1 l
• DlCO < 40
• CO2 - retention (resting PCO2 < 45 mmHg)
• Severe pulmonary hypertension (Kasper 2015).

1. small cell carcinoma: Surgical measures do not represent a standard method with regard to therapy in this case. Up to stage T1- 2 / N0 - 1, primary surgery can be considered for SCLC. Postoperatively, adjuvant chemotherapy and prophylactic radiatio of the skull should always be performed (see Internal Therapy) (Ukena 2018).

2. non-small cell lung cancer: In patients with NSCLC, primary surgical therapy can be performed in up to 85% (Ukena 2018). Radical surgery with dissection of the lymph nodes is possible in stages I / II / IIIA (T3 N1 M0). If the chest wall is infiltrated, postoperative local radiotherapy is recommended. Adjuvant chemotherapy should be given in stages II / IIIA1 / IIIA2 (see Internal Therapy). (Herold 2022). Stage I and II patients who are not candidates for surgery or who decline surgery should be treated with curative radiotherapy (see "Internal Therapy" above [Kasper 2015]).

Contraindications to curative resection. The following are contraindications to curative resection:

• superior vena cava syndrome
• extrathoracic metastases
• vocal cord or diaphragmatic paralysis
• cardiac tamponade
• malignant pleural effusion
• Metastases:
  • of the contralateral lung
  • involvement of the main pulmonary artery
  • contralateral mediastinal nodes (curable with combined chemotherapy)
  • supraclavicular lymph nodes
• Tumor within 2 cm of the carina (this is potentially curable with combined chemotherapy) (Kasper 2015)

Overall, lung cancer has a poor prognosis. The late diagnosis and the insufficient screening examinations to date (in CT screening, for example, the rate of false positive findings is high [Ukena 2018]) are certainly partly responsible for this.

The prognosis is determined by:

• Tumor stage
• immunological type (patients with low lymphocyte counts and negative delayed-type skin test have a particularly poor prognosis)
• histological type
• age and sex (women have a higher 5-year survival rate)
• general condition of the patient (Herold 2022)
• Weight loss of >10% of body weight is a prognostically unfavorable sign (Kasper 2015).

According to a 2013 Robert Koch Institute study, the 5-year relative survival rate was 21% in women and 16% in men, and the 10-year relative survival rate was 16% in women and 12% in men (Niehoff 2017).

However, survival rates differ by histology. For example, in a study between 2000 and 2010, the 5-year survival rate was 5.6% for SCLC and 16.1% for NSCLC, and the 10-year survival rates were <5% and approximately 10%, respectively (Huber 2020). In patients with SCLC, despite good first-line therapy responses of up to 80%, median survival ranges from 12-20 months in stage limited disease and only 7-11 months in stage extensive disease (Kasper 2015).

Patients with Pancoast tumors have a 5-year survival rate of > 50% after appropriate therapy (Kasper 2015).

Even after lung cancer has been diagnosed, patients should be urged to refrain from smoking, as smoking alters the metabolism of many chemotherapeutic agents and survival has been shown to be improved after smoking cessation (Kasper 2015).

In 2013, 29,560 men and 15,524 women died of lung cancer in Germany (Ukena 2018).

At autopsy, extrathoracic metastases are found in patients with

- Large cell carcinoma in > 95%.

- Adenocarcinoma in approx. 80 %

- Squamous cell carcinoma in > 50 % (Kasper 2015).

1st degree relatives of lung cancer patients have a 2-3 fold increased risk of also developing the disease. This suggests a certain genetic disposition (Kasper 2015).

Prevention

Primary Prevention:

• Avoidance of all tobacco use
• Avoidance of passive smoking
• Compliance with occupational health and safety measures required by law in case of occupational exposure
• Diet rich in fruits and vegetables (Ukena 2018), avoidance of raw meat, saturated fat, and salted or smoked meat products (Huber 2020)

Secondary prevention:

General screening has not been recommended for lung cancer to date (Fischer 2008).

• Patients with severe atypia in sputum cytology have an increased risk of developing lung cancer (Kasper 2015)

High-risk groups such as those exposed to asbestos, former uranium mining workers should be closely monitored by:

• Sputum cytology with DNA cytometry for reliable detection of tumor cells.
• Low dose spiral CT with 0.2 - 1.0 mSv (tumor detection from a size of 2 mm diameter)

Smoking cessation: Since smoking is the main risk factor for lung cancer, patients should always be encouraged to quit smoking. Even in patients who stop smoking only in middle age, the risk of lung cancer is minimized (Kasper 2015).

Follow-up

The timing of follow-up examinations should depend on the individual case. They are usually days or weeks. Here, imaging techniques should be used in addition to physical examination, as well as laboratory analyses. However, routine bronchoscopy is not indicated (Meyer 2020).

Regression grades

The regression grades (regression grading) according to Junker are differentiated as follows:

• RG I: no tumor regression or exclusively spontaneous tumor regression in the area of the primary tumor and regional lymph nodes.
• RG IIa: morphological evidence of therapy-induced tumor regression with at least 10% vital residual tumor in the area of the primary tumor and/or more than small foci of vital tumor tissue in the regional lymph nodes
• RG IIb: morphological evidence of therapy-induced tumor regression with less than 10% vital residual tumor in the area of the primary tumor and/or only small-foci evidence of vital tumor tissue in the regional lymph nodes.
• RG III: complete therapy-induced tumor regression without evidence of vital tumor tissue in the area of the primary tumor and regional lymph nodes (Ukena 2018).

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