Carcinoid tumour of the lung

Definition

A neuroendocrine tumour composed of uniform cells with finely granular cytoplasm

• Typical carcinoid: less than 2 mitoses per 2 mm³ and lacking necrosis²⁸

• Atypical carcinoid: 2 to 10 mitoses per 2 mm³ or foci of necrosis²⁸. Atypical carcinoids account for about 15% of all carcinoids.²⁵

Epidemiology

Carcinoids usually occur in young adults³⁰. Rare cases are associated with MEN1 syndrome^8-20.

Clinical features

The most common symptoms are cough and haemoptysis. Cushing's syndrome³ and ectopic ACTH production are rare. The carcinoid syndrome does not occur until there are widespread metastases.

Radiology

Carcinoid tumours commonly present as incidental radiological findings. Typical carcinoids are usually central³⁰. Atypical carcinoids are more often peripheral³⁰.

Macroscopic appearances

Carcinoids are tan to yellow. Particularly central typical carcinoids often form a dumbbell with endobronchial and extra-bronchial lobes.

Histopathology

Cells are uniform with finely dispersed chromatin and inconspicuous nucleoli. If atypia occurs, it is not a reliable indicator of malignancy. In most cases they are polygonal but may be spindled¹³. There are clear cell¹¹ and oncocytic variants. Cells may contain melanin¹². The architecture varies from trabecular and organoid to papillary¹⁹, pseudoglandular or follicular. The stroma is usually highly vascular but may be hyalinised and may form cartilage or bone. Stromal amyloid may occur^1,10. Sustentacular cells may be seen, particularly in typical carcinoids¹⁴.

There is an association with neuroendocrine hyperplasia and airway fibrosis¹⁸; rarely there are multiple carcinoids¹⁷.

Immunohistochemistry

See immunohistochemistry of malignant epithelial tumours of lung.

	Cytokeratins	positive in >80% of cases
	Chromogranin	positive: may be focal in atypical carcinoids
	Synaptophysin	positive: may be focal in atypical carcinoids
	CD56	positive: may be focal in atypical carcinoids
	CD57	positive: may be focal in atypical carcinoids
	CD99	often positive23
	S-100	positive in sustentacular cells3, 3/3 (tumour cells positive in three pigmented carcinoids)12
	TTF-1	variable results21,26

Ki-67 expression is higher in atypical carcinoids than in typical carcinoids⁶.

Ultrastructure

Desmosomes and dense core granules are present. In pigmented cases, the sustentacular cells contain melanosomes¹².

Molecular genetics

Rb expression is preserved in typical carcinoids⁵. There is an intermediate level of loss of Rb expression in atypical carcinoids⁵. Immunoreactivity for the Rb gene product has been proposed as differentiating carcinoids (typical and atypical, positive) from small and large cell neuroendocrine carcinomas^7,15. Mutations of the MEN1 gene at 11q13 may occur in sporadic carcinoids⁸. Mutations of p53 are less common in carcinoids than in high grade neuroendocrine carcinomas^22-24. LOH at 5q21 was correlates with poor survival in carcinoid tumours³¹.

Differential diagnosis

• Other neuroendocrine tumours:

  • Tumourlets are only differentiated from typical carcinoids by size, being less than 5 mm in diameter.

  • Sufficient material for a mitotic count to differentiate typical from atypical carcinoid often requires a surgical specimen.

  • Carcinoid tumours metastatic from the gastrointestinal tract.

  • LCNEC: mitotic count greater than 10 / 2 mm³ (usually much higher)²⁹

  • small cell carcinoma: mitotic count greater than 10 /2 mm³ (usually much higher)²⁹

• Pseudoglandular pattern:

  • adenocarcinoma: show more atypia

  • mucoepidermoid carcinoma: negative for neuroendocrine markers, positive for mucin

  • adenoid cystic carcinoma: negative for neuroendocrine markers

• Organoid carcinoid:

  • Paraganglioma: also contain S-100 positive sustentacular cells³ but are negative for cytokeratin

  • Glomus tumour: positive for SMA and negative for neuroendocrine markers¹⁶

• Spindle cell carcinoid:

  • smooth muscle tumours

• Papillary carcinoid¹⁹:

  • sclerosing haemangioma: negative for neuroendocrine markers

• Metastatic breast carcinoma

• Cribriform pattern: metastatic prostatic carcinoma²: positive for PSA, negative for neuroendocrine markers

Management

Resection with minimal but clear margins³⁰.

Prognosis

At presentation, 10-15% of typical carcinoids have metastasized to regional lymph nodes: 40-50% of atypical carcinoids will have metastasized (20% stage II, 15% stage III and 10% stage IV, using the TNM staging)⁹.

Survival:	5 year	10 year
Typical carcinoid	89-98%9,25	82-95%9,25
Atypical carcinoid	69-75%9,25	35-59%9,25

The presence of metastases predicts subsequent survival²⁷:

Survival:	5 year	10 year
Carcinoid without metastases	98%25	95%25
Carcinoid with metastases	73%25	53%25

For atypical carcinoids, female gender, a tumour larger than 3.5 cm, a higher stage and a mitotic rate of 6 to 10 per 2mm² are associated with a worse prognosis⁴.

References

⁰Tumours of the Lung, Pleura, Thymus and Heart. WHO Classification of Tumours. IARC Press 2004.

¹Al-Kaisi N, Abdul-Karim FW, Mendelsohn G, et al. Bronchial carcinoid tumor with amyloid stroma. Arch Pathol Lab Med 1988; 112:211-4

²Anton RC, Schwartz MR, Kessler ML, et al. Metastatic carcinoma of the prostate mimicking primary carcinoid tumor of the lung and mediastinum. Pathol Res Pract 1998; 194:753-8

³Barbareschi M, Ferrero S, Frigo B, et al. Bronchial carcinoid with S-100 positive sustentacular cells. Tumori 1988; 74:705-11

⁴Beasley MB, Thunnissen FB, Brambilla E, et al. Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000; 31:1255-65

⁵Beasley MB, Lantuejoul S, Abbondanzo S, et al. The P16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung. Hum Pathol 2003; 34:136-42

⁶Costes V, Marty-Ane C, Picot MC, et al. Typical and atypical bronchopulmonary carcinoid tumors: a clinicopathologic and KI-67-labeling study. Hum Pathol 1995; 26:740-5

⁷Cagle PT, el-Naggar AK, Xu HJ, et al. Differential retinoblastoma protein expression in neuroendocrine tumors of the lung. Potential diagnostic implications. Am J Pathol 1997; 150:393-400

⁸Debelenko LV, Brambilla E, Agarwal SK, et al. Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum Mol Genet 1997; 6:2285-90

⁹Fink G, Krelbaum T, Yellin A, et al. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001; 119:1647-51

¹⁰el-Gatit A, al-Kaisi N, Moftah S, et al. Atypical bronchial carcinoid tumour with amyloid deposition. Eur J Surg Oncol 1994; 20:586-7

¹¹Gaffey MJ, Mills SE, Frierson HF, Jr., et al. Pulmonary clear cell carcinoid tumor: another entity in the differential diagnosis of pulmonary clear cell neoplasia. Am J Surg Pathol 1998; 22:1020-5

¹²Gal AA, Koss MN, Hochholzer L, et al. Pigmented pulmonary carcinoid tumor. An immunohistochemical and ultrastructural study. Arch Pathol Lab Med 1993; 117:832-6

¹³Fekete PS, Cohen C,DeRose PB Pulmonary spindle cell carcinoid. Needle aspiration biopsy, histologic and immunohistochemical findings. Acta Cytol 1990; 34:50-6

¹⁴Gosney JR, Denley H,Resl M Sustentacular cells in pulmonary neuroendocrine tumours. Histopathology 1999; 34:211-5

¹⁵Gouyer V, Gazzeri S, Brambilla E, et al. Loss of heterozygosity at the RB locus correlates with loss of RB protein in primary malignant neuro-endocrine lung carcinomas. Int J Cancer 1994; 58:818-24

¹⁶Gaertner EM, Steinberg DM, Huber M, et al. Pulmonary and mediastinal glomus tumors--report of five cases including a pulmonary glomangiosarcoma: a clinicopathologic study with literature review. Am J Surg Pathol 2000; 24:1105-14

¹⁷Miller MA, Mark GJ,Kanarek D Multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type, with restrictive and obstructive lung disease. Am J Med 1978; 65:373-8

¹⁸Miller RR,Muller NL Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors. Am J Surg Pathol 1995; 19:653-8

¹⁹Mark EJ, Quay SC,Dickersin GR Papillary carcinoid tumor of the lung. Cancer 1981; 48:316-24

²⁰Nakhoul F, Kerner H, Levin M, et al. Carcinoid tumor of the lung and type-1 multiple endocrine neoplasia associated with persistent hypercalcemia: a case report. Miner Electrolyte Metab 1994; 20:107-11

²¹Oliveira AM, Tazelaar HD, Myers JL, et al. Thyroid transcription factor-1 distinguishes metastatic pulmonary from well-differentiated neuroendocrine tumors of other sites. Am J Surg Pathol 2001; 25:815-9

²²Onuki N, Wistuba, II, Travis WD, et al. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer 1999; 85:600-7

²³Pelosi G, Fraggetta F, Sonzogni A, et al. CD99 immunoreactivity in gastrointestinal and pulmonary neuroendocrine tumours. Virchows Arch 2000; 437:270-4

²⁴Przygodzki RM, Finkelstein SD, Langer JC, et al. Analysis of p53, K-ras-2, and C-raf-1 in pulmonary neuroendocrine tumors. Correlation with histological subtype and clinical outcome. Am J Pathol 1996; 148:1531-41

²⁵Soga J,Yakuwa Y Bronchopulmonary carcinoids: An analysis of 1,875 reported cases with special reference to a comparison between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg 1999; 5:211-9

²⁶Sturm N, Rossi G, Lantuejoul S, et al. Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids. Hum Pathol 2002; 33:175-82

²⁷Thomas CF, Jr., Tazelaar HD,Jett JR Typical and atypical pulmonary carcinoids : outcome in patients presenting with regional lymph node involvement. Chest 2001; 119:1143-50

²⁸Travis WD, Rush W, Flieder DB, et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998; 22:934-44

²⁹Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 1991; 15:529-53

³⁰Warren WH, Faber LP,Gould VE Neuroendocrine neoplasms of the lung. A clinicopathologic update. J Thorac Cardiovasc Surg 1989; 98:321-32

³¹ Onuki N, Wistuba, II, Travis WD, et al. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer 1999; 85:600-7

This page last revised 29.3.2005.

©SMUHT/PW Bishop