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