• Neuroendocrine tumor that arises in the hilum of smokers with a poor prognosis and no current targeted therapy

• ICD-10: C34.90 - malignant neoplasm of unspecified part of unspecified bronchus or lung

• 10 - 15% of lung cancer cases (J Clin Oncol 2006;24:4539)
• M = F
• 70% have metastasis at time of diagnosis (Cancer Treat Res 2016;170:301)

• Arises from neuroendocrine cells of basal bronchial epithelium

• Cough, dyspnea, weight loss
• Paraneoplastic syndromes (World J Clin Oncol 2014;5:197)
  • Adrenocorticotropic hormone (ACTH) production → Cushing syndrome
  • Antidiuretic hormone (ADH) → syndrome of inappropriate antidiuretic hormone secretion (SIADH) → hyponatremia
  • Lambert-Eaton
  • Limbic encephalitis
• Superior vena cava syndrome
• Staging (Cancer Treat Res 2016;170:301)
  • Limited: ipsilateral hemithorax and regional lymph nodes
  • Extensive: contralateral thorax and lymph nodes, metastasis or malignant effusions
  • TNM staging less useful

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• Adverse (Cancer Treat Res 2016;170:301)
  • Continued smoking → chemotherapy resistance
  • Labs: elevated lactate dehydrogenase (LDH), alkaline phosphatase, albumin
  • Metastasis to the liver, bone marrow and brain
  • Presence of paraneoplastic syndromes
• Favorable (Lung Cancer 2019;130:216)
  • Women

• Combined chemotherapy (platinum based) and radiation (Cancer Treat Res 2016;170:301, Lung Cancer 2019;130:216
• No targeted immunotherapy available
• Median survival time
  • 15 - 20 months (limited disease)
  • 8 - 13 months (extensive disease)
• 5 year survival rate: 10 - 13 % (limited), 1 - 2% (extensive)

Contributed by Carolyn Glass, M.D.


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Contributed by Carolyn Glass, M.D.

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• CD138, CD57, p63, PAX8, CK20 (Oncotarget 2017;8:73745)

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• Deletion of 3p → loss of MLH1, VHL (Nat Commun 2018;9:3114, Genes Chromosomes Cancer 1991;3:283, Biochim Biophys Acta 2012;1826:255, Semin Oncol 2001;28:3)
• p53 mutations due to deletion at 17p (90%) (Nat Commun 2018;9:3114, Biochim Biophys Acta 2012;1826:255, Semin Oncol 2001;28:3)
• RB1 loss of function at 13q14 (80 - 100%) (Nat Commun 2018;9:3114, Biochim Biophys Acta 2012;1826:255, Semin Oncol 2001;28:3)
• PTEN mutation (15 - 20%) (Nat Commun 2018;9:3114)
• Wild type c-Kit upregulation (80 - 90%) (Nat Commun 2018;9:3114)
• MYC (MYC, MYCL1 or MYCN) amplification (20%) (Nat Commun 2018;9:3114, Semin Oncol 2001;28:3)
• Telomerase activation (90%) (Nat Commun 2018;9:3114, Semin Oncol 2001;28:3)
• Rare EGFR mutations and ALK rearrangements (Nat Commun 2018;9:3114)

• Lung, left upper lobe, endobronchial biopsy:
  • Malignant tumor present, consistent with small cell carcinoma (see comment)
  • Comment: positive immunoreactivity for keratin, CD56 and TTF1 with negative staining for CD45 supports the diagnosis of small cell carcinoma

A 65 year old man presents to the clinic with generalized fatigue for 6 months. He says he has been feeling very down lately and that his mood has had a negative impact on his relationship with his wife of 30 years. He also reports recent acne flares, which he says he has not struggled with since college. He is a 25 pack per year smoker and has hypertension previously well controlled with on his current regimen. Vitals taken today show a BP of 155/95. Physical exam reveals an adipose deposit on the dorsal upper thorax and abdominal striae. A chest Xray reveals a hilar lung mass. Which of the following tumors most commonly produces the paraneoplastic syndrome seen in this patient?

1. Adenocarcinoma of the lung
2. Large cell carcinoma of the lung
3. Small cell lung cancer
4. Squamous cell lung cancer

C. Small cell lung cancer is associated with paraneoplastic syndromes and one of the most common is Cushing syndrome, as in this patient. This is caused by increased production of adrenocorticotropic hormone by the small cell tumor. Symptoms include weight gain, fatigue, glucose intolerance, moon face, buffalo hump, muscular weakness, skin manifestations (thinning, acne, abdominal striae), psychological symptoms (depression, anxiety, decreased libido), hypertension, increased risk of bone fracture and reproductive symptoms (irregular or absent menstruation in females and erectile dysfunction in males). Other paraneoplastic syndromes associated with small cell lung carcinoma include syndrome of inappropriate antidiuretic hormone secretion and Lambert-Eaton.

A 59 year old female smoker with no significant past medical history comes to the clinic complaining of dyspnea. She states that a month ago, she began experiencing shortness of breath during her morning 2 mile walk, which she had previously enjoyed without difficultly. Over the last week, she has started becoming short of breath throughout the day and also complains of headaches that are not relieved with ibuprofen. When asked about her diet, she says she has decreased her salt intake, as she thinks her face has become swollen. On physical exam, you note edema of the right arm and distention of right sided neck veins. Xray of the chest shows a right sided lung mass at the hilum. Fine needle aspiration of this mass would most likely reveal which of the following?

1. Granulomas with central necrosis and giant cells
2. Islands of large eosinophilic cells containing keratin
3. Nests of cells with large irregular shaped nuclei that are forming glands
4. Sheets of small round blue cells with finely dispersed chromatin

D. Small cell lung cancer is histologically described as small round / oval cells with high nuclear/cytoplasmic ratio. The nuclei have finely dispersed or salt and pepper chromatin and absent nucleoli. Small cell lung cancer is most often located at the hilum and grows along the bronchi. Growth of the tumor can cause compression of the superior vena cava leading to superior vena cava syndrome, characterized by swelling of the face and upper limbs, cough and distention of the neck veins, as venous blood flow is obstructed.

A 72 year old man was recently diagnosed with small cell lung cancer. His chest Xray shows a large hilar mass in the left thorax but is negative for pleural effusion. PET scan shows metastasis to 4 lymph nodes in the left thorax but no metastasis to other organs. He has had severe cough and shortness of breath and his labs show hyponatremia. He is anxious about his prognosis and asks about treatment options. How would you stage this tumor and which treatment regimen would you recommend?

1. Advanced stage: systemic therapy with doxorubicin followed by surgical removal
2. Limited stage; surgical removal after neoadjuvant radiation and systemic cisplatin therapy
3. Limited stage: systemic therapy with cisplatin and concurrent radiation therapy
4. Limited stage: systemic therapy with doxorubicin and concurrent radiation therapy
5. Limited stage: targeted radiation therapy followed by gene targeted chemotherapy

C. Small cell lung cancer is treated with concurrent radiation and chemotherapy, most often platinum based (like cisplatin). Doxorubicin is an anthracycline chemotherapy and would not be used to treat small cell lung cancer. Surgical removal of these tumors is rare, as they are most often located at the hilum and cannot be effectively removed, even with neoadjuvant chemo radiation therapy. There are currently no genes targetable by chemotherapy. In addition, this patient presents with limited stage disease, as his small cell lung cancer is currently confined to the left hemithorax. If the tumor spread to the right hemithorax, nonregional lymph nodes became positive, distant metastasis was present or he developed a malignant pleural effusion, then this tumor would be advanced stage. However, regardless of the therapy chosen, the overall prognosis for this patient is poor and he should be counseled about the rapid progression of the disease and offered hospice care.