Pathologie Prof. Dr. med. Katharina Glatz Adrenal Gland and Paraganglia Benign and malignant lesions 2016-02-02
Pathologie Prof. Dr. med. Katharina Glatz
Adrenal Gland and Paraganglia Benign and malignant lesions
2016-02-02
Catecholamines
Aldosterone
Cortisol
Androgens
Normal weight: 4-4.2g
♀ both: 13g
♂ both: 14.5g
Hyperplasia: both >15g
Weight Size of the organ Size of tumor
Mark the margins! > 50g: 1 block/10g > 100g: 1 block/20g > 400g: 1 block/40g > 1000g: 1 block/100g Prefer the periphery Include necrosis
Der Pathologe 2015, 3: 301-309. Saeger W.
Myelolipomatous Metaplasia
Myelolipomatous Metaplasia: Adrenal cortex Adrenocortical nodules Adrenocortical adenomas Myelolipoma: Tumor consisting mainly of fatty tissue with inclusion of foci of bone marrow cells. No adrenocortical cells DD: adrenocortical adenoma with widespread myelolipomatous metaplasia
Adrenocortical Hyperplasia
Noduli Adenoma
Diameter mostly <1cm mostly >1cm
Multiplicity frequent
Histology like zona
fasciculata or
reticularis
own pattern, often
irregular
Cells monomorphous partly pleomorphic
Adjacent cortex regular often compressed
Remmele, 3. edition. Urogenitale und Endokrine Organe, Gelenke und Skelett. p. 744-765
• 0.5-2 / million / year
• Children (50-80% Li Fraumeni) & 4.-5. decade (5% Li Fraumeni, MEN-1, FAP, 3% Lynch syndrome)
• Abdominal pain steroid hormones (Cushing, virilization)
• Prognosis (5y OS <50% / M1 <15%) • R0
• TNM
• Ki-67
Adrenocortical Carcinoma
Adrenocortical Tumors Pitfalls
300 ACC Consulting Cases
269 ACC
14 Adenoma
7 UMP
5 Soft tissue tumors
3 Angiorsarcomas
1 PECOMA
1 SFT 3 Pheochr.
2 Metastases
Lung
Breast
Human Pathol 2015, 46:1799-1807. Papotti M et al. Pitfalls in the diagnosis of adrenocortical tumors: a lesson from 300 consultation cases
Adrenal Tumors
Human Pathol 2015, 46:1799-1807. Papotti M et al. Pitfalls in the diagnosis of adrenocortical tumors: a lesson from 300 consultation cases
Primary tumor or metastatic lesion? Adrenal cortex or adrenal medulla? Endocrine or nonendocrine tumor?
Adenoma or carcinoma?
Primary Tumor or Metastasis
Undifferentiated metastases may mimick ACC Absence of a tumor capsule suggests metastasis
Stain for adrenocortical markers: • Melan A • -Inhibin • Calretinin • Vimentin • SF-1 (steroidogenic factor 1, nuclear, most specific) Of note: • Pancytokeratin mostly negative in adrenal tumors • Estrogen receptor may be positive
Stain for specific markers depending on suspected primary site e.g. TTF-1, GATA-3
Nonendocrine Adrenal Tumor
Hemorrhagic adrenal mass Lung masses Markedly atypical epithelioid cells Irregular anastomosing vessels Intracytoplasmic vacuoles
Think of angiosarcoma: CD34, CD31, FLI1, ERG
• ACC may be associated with hypertension
• Many similarities
– Incidentalomas of similar size (4-5 cm)
– Unspecific imaging findings
– Similar macroscopy (encapsulation, hemorrhage)
– Similar microscopy (solid, diffuse, compact or nested growth of large pleomorphic cells)
ACC or Pheochromocytoma
Human Pathol 2015, 46:1799-1807. Papotti M et al. Pitfalls in the diagnosis of adrenocortical tumors: a lesson from 300 consultation cases
ACC or Pheochromocytoma
Human Pathol 2015, 46: 1799-1807. Papotti M et al. Der Pathologe 2015, 3: 301-309. Saeger W.
Adrenocortical Carcinoma Pheochromocytoma
Melan A +
Steroidogenic factor 1 +
Pan-keratin +/-
Inhibin +
Chromogranin A –
Her-2/neu -
Melan A -
Steroidogenic factor 1 -
Pan-keratin –
Inhibin -
Chromogranin A +
Her-2/neu + (granular)
Of note: Synaptophysin is positive in both ACC and PHC
• For conventional and myxoid tumors:
– Modified Weiss (Aubert) Am J Surg Pathol 2002; 26:1612-1619
– Van Slooten Cancer 1985; 55:766-773
– Helsinki score Hum Pathol 2015; 46:404-410
• For pure oncocytic tumors:
– Lin-Weiss-Bisceglia system Int J Surg Pathol 2004; 12:231-243
• For pediatric tumors:
– Wieneke Am J Surg Pathol 2003; 27:867-881
Benign or Malignant ?
• Consistently useful criteria:
– Mitotic rate
– Ki-67 cutoff 4% for adenoma vs. carcinoma sens 71% spez 97%
– Vascular or capsular invasion
– Size
• >8cm: 50% malignant
• <4cm: 5% malignant
Benign or Malignant
Ki-67
J Clin Endocrinol Metab. 2015 Mar;100(3):841-9. Epub 2015 Jan 5. Beuschlein F et al.
Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection.
Months since R0 resection Months since R0 resection
This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.
Adrenal Medulla and Paraganglia
Pheochromocytoma Paraganglioma
Neuroblastoma Paraganglioma «Glomus tumors»
Diagnostic Histopathology 2012, 18(6): 234-244. Moonim MT
Adrenal Medulla and Paraganglia
3% Head&neck 10% Thorax 85% Abdominal 46% Superior paraaortic 20% Inferior paraaortic 10% Bladder
2% Pelvis
Adrenal paraganglioma: Phaeochromocytoma
Extra-adrenal Paraganglioma
10% Myth
Germline mutations up to 32.1% in adults up to 40% in children
> 10% malignant > 10% extraadrenal > 10% children Sporadic tumors usually solitary Familial disease >50% bilateral
> 30% familial
• Malignancy:
– 13% of pheochromocytomas
– 20% of paragangliomas
– 37.5% of SDHB mutation carriers
Benign or Malignant ?
Ki-67 >2.5%: 0% of 99 benign tumors 50% of 37 malignant tumors high specificity for malignancy but low sensitivity
J Pathol 2000;191:175-180
© 2002 Lippincott Williams & Wilkins, Inc. Ver??ffentlicht von Lippincott Williams & Wilkins, Inc. 8
TABLE 1.
Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) to Separate Benign From Malignant Neoplasms: A Clinicopathologic and Immunophenotypic Study of 100 Cases. Thompson, Lester American Journal of Surgical Pathology. 26(5):551-566, May 2002.
TABLE 1. Pheochromocytoma of the Adrenal Gland Scoring Scale (PASS)HPF = high-power field.
PASS > 4: potential for biologically aggressive behavior PASS < 4: likely to behave in a benign manner
PASS Score 100 tumors 50 histologically benign 50 histologically malignant
Endocr Relat Cancer 2014 May 6;21(3):405-14.
GAPP Score Phaeochromocytoma Study Group Japan 2014. 163 tumors including 40 metastatic Gapp score non metastatic: 2.08 0.17 Gapp score metastatic: 5.33 0.43
Figure 1 Representative images of histological features.
Noriko Kimura et al. Endocr Relat Cancer 2014;21:405-414
© 2014 Society for Endocrinology
Regular zellballen Regular zellballen
Irregular large
zellballen Pseudorosettes
Comedo-type necrosis
But...
Observer variation in the application of the PASS Score. Am J Surg Pathol. 2009 Apr;33(4):599-608. Wu D et al. Significant interobserver and intraobserver variation among a group of pathologists with expertise in endocrine pathology. We consequently suggest that PASS requires further refinement and validation. We cannot currently recommend its use for clinical prognostication.
Pheochromocytomas and Paragangliomas: An Update on Recent Molecular Genetic Advances and Criteria for Malignancy. Adv Anat Pathol. 2015 Sep;22(5):283-93. Guo Z, Lloyd RV. Although this approach (GAPP scoring) looks promising, it will require independent validation in other laboratories
Molecular Genetic Testing
Clinical presentation of paraganglioma/pheochromocytoma Int J Endocrinol 2014: 794187 Curr Opin Oncol 2016, 28:5-10
Family History and/or syndromic phenotype
Unilateral/bilateral pheochromocytoma
Abdominal/thoracic paraganglioma
Head&neck paraganglioma
Malignant tumor
Analyze gene according to clinical
phenotype: VHL RET SDHB SDHD
NF1 HIF2A
VHL RET
SDHB SDHD TME127
MAX
SDHB SDHD VHL RET
SDHD SDHB VHL
SDHC SDHAF2
SDHB SDHD VHL NF1 MAX
Stain all paragangliomas/ pheochromocytomas for SDHB
Immunohistochemistry
Chromogranin A Melan A/Inhibin Cytokeratin
Ki67 SDHB SSTR2A Human Pathol 2015, 46:390-396
Increased SSTR2A and SSTR3 expression in SDH-deficient pheochromocytomas and paragangliomas.
Adv Anat Pathol 2015, 22:283-293