Diagnostic approach to neuroendocrine tumors of lung
•Transferir como PPTX, PDF•
20 gostaram•2,854 visualizações
Diagnostic approach to neuroendocrine tumors of lung
Recomendados
Mais conteúdo relacionado
Mais procurados
Mais procurados (20)
Semelhante a Diagnostic approach to neuroendocrine tumors of lung
Semelhante a Diagnostic approach to neuroendocrine tumors of lung (20)
Último
Último (20)
Diagnostic approach to neuroendocrine tumors of lung
- 1. DIAGNOSTIC APPROACH TO NEUROENDOCRINE TUMORS OF LUNG PRESENTER: DR. HAJRA K. MEHDI MODERATOR: DR. KALYANI R
- 2. CONTENT • INTRODUCTION • CLASSIFICATION WHO 2015 • TYPES OF NET • APPROACH TO SMALL BIOPSIES/CYTOLOGY • CASES • SUMMARY • REFERENCES
- 3. INTRODUCTION • Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body. • Most commonly originate from the lungs, small intestine, and rectum. • Lung NETs originate from pulmonary neuroendocrine cells (PNECs) that occur as individual cells or small PNEC clusters (neuroepithelial bodies). • Approximately 25% of primary lung neoplasms.
- 4. WHO classification 2004 LARGE CELL NEUROENDOCRINE CARCINOMA CARCINOID TUMOR DIFFUSE IDIOPATHIC PULMONARY NEUROENDOCRINE CELL HYPERPLASIA
- 9. NET morphology on H&E Fewer than 2MF/10hpf No necrosis Typical carcinoid (Grade 1 or WD-NEC) 2-10MF/10hpf Punctate necrosis Atypical carcinoid (Grade 2 or MD-NEC) >10MF/10hpf Large necrosis NSCLC cytology LCNEC (Grade 3 or PD-NEC) SCLC cytology SCLC (Grade 3 or PD-NEC) CRITERIA FOR CLASSIFICATION OF NET
- 10. DIFFUSE IDIOPATHIC NEUROENDOCRINE CELL HYPERPLASIA • Precursor lesion for tumorlets • Seen as a reactive hyperplasia secondary to airway fibrosis and/or inflammation • Any age (5th -6th decade)
- 12. TUMORLETS • Comprised of increased numbers of individual cells, small group of cells, or nodular aggregates of cells confined to the bronchial/bronchial epithelium. • Once they break through the basement membrane, they give rise to tumorlets. (≤5mm) • Nodular proliferation of small spindle cells seen in relation to small bronchioles. • Sometimes seen with typical peripheral carcinoid.
- 13. DIFFUSE IDIOPATHIC NEUROENDOCRINE CELL HYPERPLASIA • Often associated with: • Bronchiectasis • Other conditions associated with scarring, including that associated with intralobular sequestration & pulmonary fibrosis • Diffuse proliferation of neuroendocrine cells in context of interstitial lung disease • Same ultrastructural and immunohistochemical features as those of peripheral carcinoid tumor.
- 15. TYPICAL CARCINOID TUMOR • 2% of all lung malignancy • 4th to 5th decade • Non smoker • Central carcinoid – symptomatic • Peripheral tumor – asymptomatic/incidental (COIN LESIONS) • 1-5% carcinoids present with carcinoid syndrome
- 16. TYPICAL CARCINOID TUMOR GROSS: • 2-4cm in maximum dimension • Tan-yellow to dark red
- 17. TYPICAL CARCINOID TUMOR MICROSCOPY: • Diverse growth patterns – trabecular, ribboning, insular and solid sheet-like configurations • Delicate fibrovascular stroma (hyalinized at times) • Composed of uniform polygonal cells with finely granular chromatin, inconspicuous nucleoli and scant to moderate eosinophilic cytoplasm
- 18. TYPICAL CARCINOID TUMOR MICROSCOPY: • Other variants – oncocytic, spindle cell, papillary, pseudoglandular, rosette formation, follicular. • Rarely – metaplastic bone, cartilage • Peripheral Carcinoids – identical, spindle cell growth pattern
- 20. 1st Edition
- 22. Grade 1 Neuroendocrine Carcinoma
- 24. TYPICAL CARCINOID TUMOR PROGNOSIS: • 5 year survival rate : 90 -95 % • Approximately 10-15% of grade 1 pulmonary NECs involve regional lymph nodes; 3-5% metastasize extrathoracically ( Bone, liver, skin, brain) • Prognosis for low-grade spindle cell peripheral lesions is equivalent to that of their central counterparts, despite a higher rate of LN metastasis • Complete Excision
- 25. TYPICAL CARCINOID TUMOR FROZEN SECTION: • Organoid pattern • Stromal hyalinisation • Spindle to ovoid cell proliferation • Finely dispersed chromatin • No necrosis • Absence of high mitotic activity • Distinction between typical and atypical not possible. • Distinction between primary and metastatic is difficult. Carcinoid tumor (NOS)
- 26. TYPICAL CARCINOID TUMOR IHC: • Most specific and sensitive : Chromogranin A, Synaptophysin, CD56/NCAM • Other NE markers (low specificity): PGP 9.5, CD57, NSE • CK 7, pan CK +ve • NapsinA, p40, p63 –ve • S100: peripheral +ve, central –ve • TTF1: peripheral +ve, central –ve
- 28. TTF -1CD 99
- 29. TYPICAL CARCINOID TUMOR SPECIAL STAINS: • Reduce silver solutions and form insoluble precipitates in tissue sections • Argentaffin Methods : Depend on presence of endogenous cellular reducing agents – Fontana Masson stains • Argyrophilic Methods: Depends on exogenous reducing agents – Grimelius or Churukian-Schenk procedures
- 30. Argyrophil reactivity of NEC with the Churukian-Schenck method
- 31. TYPICAL CARCINOID TUMOR ELECTRON MICROSCOPY:
- 32. TYPICAL CARCINOID TUMOR DIFFERENTIAL DIAGNOSIS: 1. Pulmonary paraganglioma: NE +ve, CK –ve 2. Glomus tumor: NE –ve, CK –ve, SMA +ve 3. Metastatic NET: history, multiple nodules, calcitonin, CDX2, TTF1 4. Sclerosing hemangioma: Dual cell component, NE –ve 5. Peripheral spindle cell carcinoid can be misdiagnosed with any spindle cell neoplasm: organoid pattern, CK +ve, NE +ve
- 33. ATYPICAL CARCINOID TUMOR • > 3 cm in maximum dimension • Linked to smoking • Peripherally located in lung • Potential associations with Cushing’s Syndrome and Eaton-Lambert Syndrome
- 34. ATYPICAL CARCINOID TUMOR GROSS: • Tan-yellow with few areas of hemorrhage and necrosis MICROSCOPY: • Tumor with carcinoid morphology with: • Mitosis of 2 – 10/10 hpf • Focal necrosis ( Punctate necrosis) • Discernible nuclear pleomorphism • At least focal loss of an organoid growth pattern
- 39. Grade 2 Neuroendocrine Carcinoma
- 40. ATYPICAL CARCINOID TUMOR PROGNOSIS: • Angiolymphatic invasion • Brisk mitotic activity • Aneuploidy • Large size ( > 3cm) • LN metastasis at time of diagnosis in 30-50% cases • 25% patients will have remote metastatic disease at presentation ( Brain) • 5 year survival rate is 61- 73 % Prognostic factors
- 41. ATYPICAL CARCINOID TUMOR IHC: • Ki67/MIB1 index: <5% in typical carcinoid 5-20% in atypical carcinoid • PAX5: typical –ve, atypical +ve, high grade +ve • Focal to diffuse ER/PR: Typical +ve, atypical –ve
- 42. LARGE CELL NEC • Non-small lung cancers that demonstrate evidence of NE differentiation on LM, IHC and EM. • 3% of all lung tumors. • Associated with smoking • M:F = 4 – 5:1; 60-65years of age • Poor prognosis
- 43. LARGE CELL NEC GROSS: • Large peripheral mass (4cms) in 80% • Lobulated mass • Grey white mass with areas of necrosis and haemorrhage • Increased FDG uptake on FDG-PET scan.
- 44. LARGE CELL NEC MICROSCOPY: • Neuroendocrine morphology (organoid nesting, rosette, palisading, trabeculae) • High mitotic rate (>10/10hpf) • Large areas of necrosis • Cytologic features of NSCLC: large cell size, low N:C ratio, vesicular, coarse or fine chromatin, frequent nucleoli, abundant cytoplasm. • Positive IHC for one or more NE markers (other than NSE) and/or NE granules by EM.
- 45. LARGE CELL NEC MICROSCOPY: • Strict criteria: 1. Features of NEC on H&E 2. NE +ve on IHC or NE granules on EM
- 50. LARGE CELL NEC DIFFERENTIAL DIAGNOSIS: 1. Atypical carcinoid: distinction impossible on small biopsies (Ki67/MIB1 index >25% in LCNEC) 2. SCLC: sometimes impossible even on large specimens. (Controversial cases :High grade NEC or Mixed SCLC-LCNEC) 3. NSCLC (adenocarcinoma, SCC, basaloid carcinoma): Strict criteria 4. Primary LCNEC vs extrapulmonary tumors: • TTF1 +ve in only 50% LCNEC • CDX2 in some primary lung LCNEC • Clinical correlation
- 51. SMALL CELL NEC • Small cell carcinoma is characterized by a proliferation of primitive-appearing, round to oval-shaped tumor cells. • Typically a central tumor in a heavy smoker • Approximately 10% of cases are peripheral; roughly 10% occur in non-smokers • Endocrine Syndromes : Hyponatremia(ADH), Hypercalcemia (Parathormone-like substance), Cushing’s Syndrome (ACTH) • Paraneoplastic Syndromes : Lambert-Eaton Syndrome, Retinopathy, Neuropathies, Encephalitis, GN, sarcoid-like granulomatous lesions, systemic vasculitis.
- 52. SMALL CELL NEC GROSS: • Gray-tan and fleshy • Areas of necrosis or hemorrhage
- 53. SMALL CELL NEC MICROSCOPY: • Small size ( < diameter of 3 resting lymphocytes) • Scant cytoplasm • Nuclei – finely granular chromatin; absent or faint nucleoli • High mitotic rate ( >10/10 hpf) • Frequent necrosis in large zones • Nuclear molding, fusiform • Prominent apoptosis • Azzopardi Phenomenon
- 60. SMALL CELL NEC • There is no diagnostic or prognostic importance in separating the traditional subtypes of SCNC (e.g., “oat-cell” carcinoma; SCNC with “intermediate” differentiation, etc.) • Necessary to be familiar with the microscopic subtypes to avoid misdiagnosis. • Because of artifacts of tissue preparation it may be exceedingly difficult to recognize SCNC with certainty in small samples.
- 62. MIXED SMALL CELL-LARGE CELL CARCINOMA • Mixed small cell–large cell carcinomas are characterized by the presence of a subpopulation of large, undifferentiated tumor cells occurring singly or in small cluster within an otherwise conventional small cell carcinoma of the lung. • The large cells are usually twice the size of the small cell component and show large, hyperchromatic nuclei surrounded by a scant rim of amphophilic to lightly eosinophilic cytoplasm.
- 63. MIXED SMALL CELL-LARGE CELL CARCINOMA • A large cell component admixed with the small cells is also frequently observed at metastatic sites of otherwise conventional small cell carcinomas. • Poorer survival. • More limited response to treatment than typical small cell carcinoma.
- 64. COMPOSITE (MIXED) NET Potential “partners” of neuroendocrine tumors in mixed carcinomas: • Squamous cell carcinoma • Adenocarcinomas of various subtypes • Transitional cell carcinoma • Spindle-cell carcinoma • Divergent sarcomatoid elements with mesenchymal phenotypes
- 65. NSCLC WITH OCCULT NE DIFFERENTIATION • Defined as neuroendocrine differentiation which is not obvious on conventional morphological LM examination • Detectable only by electron microscopy and/or immunohistology • May be present in tumors classified as SCC, Adenocarcinoma, or large-cell CA by routine microscopy
- 66. SMALL BIOPSY • Crush artefacts – mimic SCLC • Points favouring high grade NET: • Increased mitotic figures • Apoptotic bodies • Increased Ki67 index
- 67. SMALL BIOPSY/CYTOLOGY IN 2015
- 68. SMALL BIOPSY/CYTOLOGY IN 2015
- 69. Case 1 • A 22 year old man presented with progressive dyspnoea on exertion and non-productive cough of approximately 3 years duration. No history of smoking or lung disease. • Physical examination and routine laboratory evaluation were normal. • The chest radiograph showed diffuse reticulonodular infiltrates without pleural thickening or mediastinal adenopathy.
- 74. Diagnosis? Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia
- 75. Case 2 • A 26-year-old female presented with wheezing episodes, cough and mild dyspnea. • After a chest x-ray revealed normal findings, she was commenced on bronchodilators and inhaled corticosteroids. • Two years later, the symptoms were not entirely relieved and she had developed hemoptysis.
- 83. Case 3 • A 15-year-old healthy girl presented with cough and dyspnea for 3 days duration. • Her past medical history showed reactive airway and asthma since last year.
- 86. Case 3 • A rigid bronchoscopy was performed which showed a small polyp like mucosal projection in left main bronchus, measuring 1×0.5 cm. • The mass was excised by bronchoscopy. • The specimen in the pathology department received as a small nodule of about 1 cm with grey color and soft consistency.
- 91. Case 4 • A 55-year-old male patient was admitted because of a large mass lesion that was detected incidentally by a chest radiograph. • He had smoked 30 cigarettes per day for 35 years.
- 96. Diagnosis? Large cell neuroendocrine carcinoma
- 97. Case 5 • A 74‐year‐old man with a history of 20 pack‐years smoking and 18 years of type 2 diabetes mellitus (T2DM) suffered general weakness and worsening hyperglycemia for a month. • The patient’s adrenocorticotropic hormone level was 299.10 PG/Ml (7.2–63.3 PG/mL) and serum cortisol level was >63.44 μg/dL (4.4– 19.9 μg/dL), which indicated cushings syndrome.
- 104. Diagnosis? Small cell lung carcinoma
- 105. SUMMARY • Careful counting of mitoses is essential as it is the most important histologic criteria for separating typical from atypical carcinoid and the carcinoids from the high-grade SCLC and LCNEC. • IHC can be very helpful in diagnosing pulmonary neuroendocrine tumors. • The role of Ki-67 is mainly to separate the high-grade SCLC and LCNEC from the carcinoid tumors, especially in small biopsies with crushed and/or necrotic tumor cells
- 106. REFERENCE • Practical Pulmonary Pathology – Leslie and Wick – 1st Edition • WHO Classification of Tumors – Pathology and Genetics – Tumors of the Lung, Pleura, Thymus and Heart • Ackerman’s Surgical Pathology • Robbins- 9th Edition • Sternberg • Fletcher • Articles
Notas do Editor
- With larger lesions bulging into the lumen but not breaking the subepithelial basement membrane
- With larger lesions bulging into the lumen but not breaking the subepithelial basement membrane
- Those neoplasms associated with cartilaginous airways are considered to be central Others without that relationship are considered to be peripheral
- Top - Yellow white mass in peripheral pul parenchyma; Bottom– Endobronchial mass ( far left) with intact overlying mucosa representing a central Grade 1 NEC of lung. This lesion caused a bronchial luminal obstruction with attendant post obstructive pneumonia
- Bottom right – pseudo glandular pattern
- Left – mixed medullary insular pattern right – insular pattern
- Aggregate of small regular cells with stippled neuroendocrine nuclear chromatin pattern (pap)
- Dyscohesive cells with plasmacytoid configuration – causing potential confusion with hematopoietic proliferations
- Peripheral spindle cell pattern..right – spindle cells in fnac
- CK: Distinct Punctuate or Globoid Paranuclear/Perinuclear “ dot”-like immunoreactivity with Keratin
- Left – CD 99 ( MIC2 protein); Right – TTF-1
- Typically positive in the majority of well-differentiated NE tumors of lung, with much lesser reactivity in high-grade carcinomas.
- Argyrophil reactivity of NEC with the Churukian-Schenck method
- Dense-core cytoplasmic granules, (neurosecretory) varying in size from 30 to 300 nm Rounded structures consisting of a central dense core, a peripheral lucent halo and a single delimiting outer membrane Numerous cytoplasmic dense-core (NS) granules; Can also be demonstrated in specimens retrieved from paraffin blocks
- Notable mitotic activity and areas of spontaneous necrosis
- Tumor cells are > 3X the size of mature lymphocytes Nuclei in LCNEC are more pleomorphic than those of SCLC Extensive zonal/geographic necrosis producing a jig-saw puzzle pattern Presence of nucleoli helps to differentiate it easily from SCLC
- large cells with moderate to abundant quantity of pink cytoplasm. The nuclei have vesicular chromatin and prominent nucleoli – an important point of distinction from small cell carcinoma. Mitotic activity is increased (usually > 30 mitoses/2 sq.mm).
- Cohesive acinar and rosette-like structure (Pap, HP) If no light microscopic features exist to support diagnosis of LCNEC, then IHC and EM should not be used to make the diagnosis
- Azzopardi Phenomenon : Accretion of basophilic nucleic acid material around intratumoral blood vessels
- Azzopardi Phenomenon – Accretion of densely basophilic smudgy nuclei acid material adjacent to intratumoral blood vessels. Chromatin Diffusion secondary to necrosis may spread to the wall of the blood vessels, which may appear strongly hematoxyphilix
- Divergent glandular differentiation
- [SMALL CELL CARCINOMA, LUNG]. One of the commonest morphologic features of small cell carcinoma, as opposed to many similar malignancies, is the nuclear “crushed” artifact (arrow) caused by section preparation. This crushed artifact is a very helpful diagnostic morphologic feature especially on frozen sections because small lymphocytes in a node (arrowhead) generally do not show such crushing artifact. Note the cell size difference between a small cell carcinoma and small lymphocytes.
- [SMALL CELL CARCINOMA, LUNG]. Another typical morphologic feature of small cell carcinoma is the finely distributed nature of chromatin (salt and pepper) and absence of prominent nucleoli. The presence of prominent nucleoli should suggest another diagnosis and not a small cell carcinoma. Note also the presence of single apoptotic nuclei. Apoptosis and necrosis are fairly common in these tumors and a helpful diagnostic morphologic feature.
- [SMALL CELL CARCINOMA, LUNG]. Mitoses (arrows) are very common in small cell carcinoma and in fact a diagnosis of small cell carcinoma must not be made in the absence of mitoses. Mitoses are coupled with apoptosis and areas of necrosis.
- Conceptually, neuroendocrine cells are closest to “stem” cells in the lung, as evidenced by embryological data Empirical information (still being gathered) suggests that CAs of lung with occult NE differentiation may behave more aggressively than histologically-similar lesions without NE features, when matched by grade & stage
- Preoperative CT scans. The preoperative CT scans clearly demonstrate the main tumor in the upper lobe of the right lung.
- Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) refers to proliferation of pulmonary neuroendocrine cells within the walls of airways. The image shows one such focus. Differential diagnosis: Reactive proliferation of pulmonary neuroendocrine cells vs DIPNECH: Proliferation of pulmonary neuroendocrine cells may be seen in the setting of inflammatory or fibrotic lesions in the lungs. These conditions can be distinguished from DIPNECH by the presence of the underlying condition and the absence of carcinoid tumors.
- Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) refers to proliferation of pulmonary neuroendocrine cells within the walls of airways. It forms nodular or papillary cellular aggregates that may protrude into the bronchial lumen causing mucus plugging, airway obstruction, air-trapping, and bronchiectasis. Usually, there is chronic inflammatory infiltrate nearby along with peribronchiolar fibrosis. The cells are round to oval in shape with moderate amount of eosinophilic cytoplasm and uniform nuclei with salt and pepper chromatin.
- A picture of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, staining for synaptophysin.
- left perihilar shadow in the chest radiograph
- high resolution computed tomography was performed showing a nodule in the left primary bronchus causing its partial obstruction
- Carcinoids show a variety of growth patterns commonly seen in neuroendocrine tumors, including nesting (shown here), trabecular (most common), rosettes, papillary, pseudoglandular, follicular, and solid patterns. Peripheral tumors frequently show spindle cell pattern. Multiple patterns are usually seen in an individual case. The background stroma is highly vascular but may show hyalinization, calcification, mucin, amyloid, bone or cartilage formation. The nesting pattern seen here resembles paraganglioma. The presence of S-100 positive cells may further add to confusion in such cases.
- Chromogranin A positive
- Synaptophysin positive
- The main distinguishing histologic feature of atypical carcinoids is increased mitotic activity (2-10 mitoses per 10HPF or 2 sq.mm) and/or the presence of necrosis. The necrosis is usually punctate (as shown in this image) but may be more extensive.
- Chest CT scan revealed a 75×55×40 mm nodule in right lower lobe of the lung
- At low magnification, large cell neuroendocrine carcinoma has more eosinophilic appearance than small cell carcinoma due to abundant cytoplasm. The tumor cells are arranged in solid sheets, organoid nests with peripheral palisading, or anastomosing trabeculae. Multiple rosettes forming cribriform structures and large areas of geographic necrosis are other commonly seen features.
- In large cell neuroendocrine carcinomas, the tumor cells are arranged in solid sheets, organoid nests with peripheral palisading, or anastomosing trabeculae. Multiple rosettes forming cribriform structures and large areas of geographic necrosis are other commonly seen features.
- Large cell neuroendocrine carcinomas (LCNEC) have large cells with moderate to abundant quantity of pink cytoplasm. The nuclei have vesicular chromatin and prominent nucleoli – an important point of distinction from small cell carcinoma. Mitotic activity is increased (usually > 30 mitoses/2 sq.mm).
- Right lower lobe mass conforms to malignant features with mediastinal and right hilar lymph node metastasis.
- Multiple occupied lesions in the liver, considered metastases
- CD56/NCAM positive