adrenal cortex and medulla benign and malignant tumors.pptx

adrenal gland, benign, malignant, cortex

1. Adrenal tumors Presenter: Dr Sahana S N Moderator: Dr Neetha Y, Dr Shashikala P

2. Zona reticularis Adrenal medulla Venous channels

3. Noradrenaline Adrenaline Cytoplasm of the medullary cells contains dense core granules (Narrow clear halo) (Wider clear halo)

4. Adrenal medullary tumors Phaeochromocytoma Composite Phaeochromocytoma Extra adrenal paraganglioma Composite paraganglioma

5. Phaeochromocytoma

6. Definition A tumour of chromaffin cells that arises in the adrenal medulla. Synonyms: Chromaffinoma

7. Epidemiology Age: 40-50 years. Male: Female ratio is 1:1 61% of phaeochromocytomas are incidentalomas 10% Rule: 10% are familial 10% are malignant 10% are extra-adrenal ( paragangliomas ) 10% are not associated with hypertension

8. Clinical features Caused by excess catecholamine production & release Classic triad of headache, tachycar­dia/palpitations, sweating

9. Biochemical investigations: Plasma free metanephrines or urinary fractionated metanephrines - reflect intratumoural O-methylation of catecholamines leaked from storage vesicles in tumour cells A ssociated with multiple endocrine neo­ plasia type 2 (MEN2) or neurofibromato ­ sis type 1: produces epinephrine, resulting in increased concentrations of metanephrine .

10. Isolated increases in normetanephrine and nor epinephrine suggest von Hippel-Lindau syndrome Additional or isolated produc­tion of the dopamine metabolite 3-meth­oxytyramine points to the presence of SDHB, SDHD, or SDHC mutation and also associated with potentially metastat­ic tumours

11. Hyperenhancing bilateral adrenal masses I¹²³-MIBG SPECT image: Intense uptake of tracer in adrenal masses

12. Macroscopy Circumscribed Unencapsulated C/S: pinkish-grey to tan, may undergo slight yellowing after exposure to air or during formalin fixation Haemorrhage, cen­ tral degenerative changes , fibrosis , cystic change

13. Tumour diameter is usually about 3-5 cm, can be > 10 cm or < 1 cm Search for additional medullary nodules & dif­fuse medullary hyperplasia- indicates hereditary disease Confirm the origin of the tumour within (rather than adjacent to) the adrenal gland Stored catecholamine granules of adrenal medullary cells are oxidized to a brown colour

14. Tumour may extend to the adrenal cap­sule, or a pseudocapsule may be pres­e nt Border with adjacent cortex: sharp or irregular Attenuated cortex , comma shaped residual adrenal is seen below

15. Architecture: alveolar ( Zellballen ) pattern , consisting of nests of polygonal tumour cells separated by peripheral capillaries Architectural variation: trabecular & dif­fuse growth patterns, prominent vascularity Haemorrhage, hae­mosiderin deposition, sclerosis Microscopy :

16. Cytoplasm with punctate granularity barely resolvable by light microscopy. Tumor cell with nuclear pseudo-inclusion.

17. Cytologically , phae­ochromocytoma cells can closely resem­ble normal chromaffin cells, or may be smaller or larger; Larger cells have vesicular nuclei with prominent nucleoli. Cytoplasm: Granular, Basophilic to amphophilic . Nuclear pseudoinclusions & in­tracytoplasmic hyaline globules(diastase-resistant positive periodic acid-Schiff(PAS)reaction) Nuclear pleomorphism & cellular pleomorphism are sometimes conspicu­ous, but mitoses are usually rare

18. Risk factors: Invasion (vascular, adrenal, capsular, periadrenal soft tissue) Architectural variation ( irregular , enlarged, conflu­ent cell nests; diffuse growth )

19. Cytological variation( spindling , small cells, high cell density, cellular monotony, extreme pleomorphism ) Necrosis (focal or conflu­ent, comedo necrosis in cell nests) Proliferative activity(increased mitotic count, atypical mitoses & increased Ki-67 proliferation index)

20. Genetic profile At least 30% of tumours develop in patients having germline mutations in hereditary susceptibility genes Occult germline mutations are present in 11-24% of patients with sporadic phaeo chromocytoma or paraganglioma Genetic testing for at least the most frequent germline mutations be considered for all patients, regardless of family history

21. Complete resection is the only cure He­reditary SDHB mutations , which are as­sociated with the highest risk of metasta­sis Survival times tend to be < 5 years when metastasis involves the liver or lung & longer when metastasis involves bone

22. Composite phaeochromocytoma Definition: A tumour consisting of phaeochromo­cytoma combined with a developmen­tally related neurogenic tumour such as ganglioneuroma , ganglioneuroblastoma , neuroblastoma , or peripheral nerve sheath tumour.

23. Epidemiology 3-9% of all phaeochromocytomas Ganglioneuroma is present in 70-80% of composite cases, ganglioneuroblastoma in 10-20% Me­ dian patient age is 40-50 years Male: Female ratio is 1:1

24. Clinical features Generally same as with phaeochro­m ocytomas Metastasize by lymphatic & haema­togenous routes to lymph nodes, lung, bone, liver & may seed the omen­tum & diaphragm When metastases occur, they usually arise from tumours containing ganglioneuroblastoma , neuroblastoma or malignant peripheral nerve sheath tumour

25. Macroscopy : Patchy, firm, pale areas corre­sponding to ganglioneuroma or to necrotic & haemorrhagic areas of gangli ­ oneuroblastoma or neuroblastoma Composite phaeochromocytoma (dark-grey areas) with ganglioneuroma (pale-grey areas). The heterogeneous gross appearance provides an important clue to the composite nature of the tumour.

26. Neoplastic chromaffin cells (at right), ganglion cells (at left), neurons (at right) & an intervening Schwann cell-rich stroma . Microscopy Scattered neuron-like cells can be pres­ent in typical phaeochromocytomas & are not sufficient S tromal fea tures : bundles of spin­dle-shaped Schwann cells and axon-like processes, patchy areas with unusually prominent sustentacular cells , or hyalini ­ zation

27. IHC staining patterns help to identify neuroblastom a­ tous foci to distinguish imma ­ ture neurons from neoplastic chromaffin cells of the same size

28. Schwann cells & sustentacular cells stain for S100, axon-like processes stain for NFPs. S100

29. Phaeochromocytoma cells (secretory granules) stain strongly for chromogranin A & syn ­ aptophysin Neurons (sparse granules)weak or focal staining; linear or punctate pattern corresponding to cell processes Chromogranin A

30. Genetic profile Reduced expression of neurofibromin has been reported in Schwann cells & sustentacular cells of composite phaeo­c hromocytomas

31. Extra-adrenal paragangliomas Paragangliomas are non-epithelial tumours originating from neural crest­ derived paraganglion cells situated in the region of the autonomic nervous system ganglia and accompanying nerves P araganglion system can be divided into adrenal medulla & the extra­ adrenal paraganglion system. Extra adrenal paraganglion system is subdivided into the para sympathetic and sympathetic paragan­glia .

32. Parasympathetic paraganglia are primarily located in the head & neck and are less frequently located in the thorax and pelvis. The sympathetic paraganglia are primarily located along the sympathetic nerve chains bordering the vertebrae in the abdomen and pelvis

33. Sympathetic paraganglioma Sympathetic paraganglioma is a neu ­ ral crest-derived neoplasm arising from extra-adrenal paraganglia distributed along the prevertebral & paravertebral sympathetic chains & the sympathetic nerve fibres innervating the retroperito ­ neum , thorax & pelvis.

34. Epidemiology 10-15% of all phaeochro ­ mocytoma / paraganglioma cases 40-50 years, male: female ratio is 1:1 Compared with adult cases, paediatric cases are more frequently familial, bilateral, multifocal & malignant Risk of metastasis: 2.5-50%

35. Clinical features Signs & symptoms are caused by excess catecholamine production & release Sympathetic paragangliomas : elevated norepinephrine only, or norepinephrine and dopamine, but not elevated epinephrine Because phenylethanolamine N- methyltrans ­ ferase , the enzyme required for convert­ing norepinephrine to epinephrine, is not expressed in paragangliomas as it is in the adrenal medulla

36. Direct invasion into other organs is rare; retroperitoneal paragangliomas invading the duodenum have been reported Most common sites of metastasis are local lymph nodes, bone, liver, & lung; rare sites include the peritoneum, pleura, ovary & testis

37. Macroscopy Well-circumscribed, solid, soft, tan tu­mours . Haemorrhagic or cystic degener­ation may be seen in larger tumours . Tumours may firmly adhere to and occa­sionally invade adjacent tissues such as vessels & nerves

38. Microscopy Similar to phaeochromo ­ cytoma . Architectural variations include irregular combined large & small zell­ ballen & pseudorosette patterns Pseudorosette pattern is suggestive of SDHB mutation-associated tumours

39. Tumour cells have abundant cytoplasm, monomorphic, hyperchromic nuclei

40. IHC Neuroendocrine markers (e g. chro ­ mogranin A, synaptophysin & CD56)are almost always positive in paragangli ­ omas . Focally positive for keratin, Ki 67 proliferation index is usually low

41. Grading System for Adrenal Phae­ochromocytoma & Paraganglioma (GAPP) developed in Japan, classifies Phaeochromocytomas & paragan­gliomas into a three-tiered Grading sys­tem reflecting a continuum of metastatic risk on the basis of histological features, Ki-67 immunohistochemistry, hor­mone data

42. Parameter Score Pattern: Zellballen Large and irregular-sized nest Pseudorosette forming 1 1 Cellularity: Low Moderate High 1 2 Coagulation necrosis: Presence Absence 2 Vascular/capsular invasion: Presence Absence 2 Ki-67 immunoreactivity : >3% or 50 cells/MPF >1% or 20 cells/MPF Few cells 2 1 Types of catecholamine: Norepinephrine Epinephrine Non functioning 1 Total 10 GAPP PASS Parameter Score Large nests or diffuse growth 2  Central or confluent tumor necrosis 2  High cellularity 2  Cellular monotony 2   Tumor cell spindling 2  Mitotic figures >3/10 HPF 2  Atypical mitotic figure(s) 2  Extension into adipose tissue 2  Vascular invasion 1  Capsular invasion 1  Profound nuclear pleomorphism 1  Nuclear hyperchromasia 1 Total 20 well differentiated: 0 - 2; moderately differentiated: 3 - 6; poorly differentiated: 7 - 10

43. Composite paraganglioma A tumour consisting of paraganglioma combined with a developmentally related neurogenic tumour such as ganglioneu­roma , ganglioneuroblastoma , neuroblas­toma , or peripheral nerve sheath tumour.

44. Epidemiology Extreme­ly rare tumours Reported in pa­tients aged 15 months to 81 years with a slight female predomi nance

45. Clinical features Clinically silent or associated with catecholamine related signs

46. Macroscopy Same as those of composite phaeochromocytomas

47. Microscopy Histopathology is same as that of composite phaeochromocytoma , except in cauda equina paragangliomas , which can show extensive expression of keratins

48. References: WHO Classification of Tumors of Endocrine Organs. 5 th ed. International Agency for Research on Cancer. 2022.P182-207. Rosai & Ackerman’s Surgical Pathology. 1 st South Asia Ed. Elsevier. 2018. P1190-212. Fletcher CDM. Diagnostic histopathology of tumors. 4 th Ed. Elsevier. 2013. P1394-318,2064-80. Mills SE, Greenson JK, Hornick JL, Longacre TA, Reuter VE. Diagnostic surgical pathology. 7 th Ed. Wolters Kulwel Health. 2015. P624-704. Robbins & Cotran . Pathologic Basis of Disease.10 th ed. Elsevier. 2021. P1114-31.

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