ENDOCRINE PATHOLOGY

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CHAPTER 4 ENDOCRINE PATHOLOGY

Congenital adrenal hyperplasia
Adrenal ‘cysts’
Heterotopic tissue in adrenals
Adrenal cortical adenoma / carcinoma
Phaeochromocytoma

Predisposing conditions associated with phaeochromocytoma and other endocrine tumors

Multiple endocrine neoplasia type 2 (men2)
Multiple endocrine neoplasia type 1 (men1)
Hyperparathyroidism–jaw tumor syndrome
Von hippel–lindau syndrome
Neurofibromatosis (nf) type 1
Carney syndrome

CONGENITAL ADRENAL HYPERPLASIA

• Most 21-hydroxylase deficiency

image present with virilization

• Diffuse bilateral cortical enlargement

image esp zone reticularis

ADRENAL ‘CYSTS’

• Pseudocysts due to previous hemorrhage
• Endothelial lined vascular / lymphatic cyst
• Cystic degeneration of adrenal tumor including NTs
• True epithelial lined cysts

image Beckwith–Wiedemann syndrome

• V rare ectopic bronchogenic adrenal cysts

HETEROTOPIC TISSUE IN ADRENALS

• Well reported including:

image liver
image thyroid
image ovary

ADRENAL CORTICAL ADENOMA / CARCINOMA

Epidemiology

• Mainly older adults
• Well reported smaller peak in frequency in early childhood:

image most are sporadic
image may be associated with Li–Fraumeni or Beckwith–Wiedemann syndrome

• Children have overall better prognosis than adults

Clinical features

• Mass effect
• Excess hormone production

image androgens – virilization
image glucocorticoids – Cushing’s syndrome
image mineralocorticoids – hypertension

• 30–50% metastases
• May invade renal vein and IVC
• Stage important predictor of outcome

Histopathological features (Figs 4.1–4.7)

• Sheets and trabeculae of cells morphologically resembling normal adrenal cortex

image clear and eosinophilic cytoplasm

– variable nuclear atypia and mitotic rate

• Main features suggesting malignant behavior (carcinoma vs adenoma):

image diameter >5cm
image fibrous bands
image necrosis
image capsular invasion
image vascular invasion
image greater mitotic rate

image

Fig. 4.1

image

Figs 4.1–4.2 Photographs of a resected adrenocortical carcinoma, measuring more than 10cm in maximum extent, the cut surface showing a solid tan yellow appearance with areas of necrosis.

image

Fig. 4.3

image

Fig. 4.4

image

Fig. 4.5

image

Fig. 4.6

image

Figs 4.3–4.7 Photomicrographs of a case of adrenocortical carcinoma in a child, demonstrating focal necrosis and marked nuclear pleomorphism. There was also capsular and vascular invasion and local recurrence appeared soon after surgery.

Immunohistochemical staining

• Alpha inhibin+
• SF1+
• Chromogranin negative (cf medullary tumors)
• May be only weakly positive for cytokeratin and EMA
• CEA negative

Differential diagnoses and pitfalls

• Smaller lesions difficult to predict clinical behavior from histological features
• May be related to germ-line point mutation of p53 even with no positive family history, acting in a tissue-specific manner (Ribeiro et al 2001)

PHAEOCHROMOCYTOMA

• Tumor of chromaffin cells of adrenal medulla

image paraganglioma if affecting other sites

• Benign (90%)
• Malignant (10%: strictly defined by metastases)

Epidemiology

• Mainly sporadic
• >10% associated with NF-1, MEN2, VHL and/or familial cases

image these more likely to present at younger age

Genetics

• Many abnormalities reported including RET defects but currently non-diagnostic

Clinical features

• Mass effect
• Catecholamine secretion effect

image especially episodic hypertension

Histopathological features (Figs 4.8–4.10)

• Solid tumor with areas of hemorrhage / necrosis
• Nested architecture (zellballen) with surrounding sustentacular cells

image uniform polygonal cell (sometimes spindled)
image granular cytoplasm
image variable nuclear pleomorphism

• Scattered melanin containing cells and ganglion cells may be present
• Features suggestive of malignancy (no universally agreed or diagnostic criteria except for metastases or widespread local invasion):

image metastatic disease
image capsular invasion
image vascular invasion
image local extension into periadrenal tissue
image necrosis
image increased cellularity
image pleomorphism
image spindle cell phenotype
image atypical and increased mitoses
image loss of S100 sustentacular cells
image increased proliferation index

image

Fig. 4.8

image

Fig. 4.9

image

Figs 4.8–4.10 Photomicrographs of a case of phaeochromocytoma, demonstrating a solid tumor with nested architecture (zellballen) of uniform polygonal cells with surrounding sustentacular cells, and variable nuclear pleomorphism.

Immunohistochemical staining

• Nest cells

image chromogranin+
image EMA−

• S100+ sustentacular cells around nests

Differential diagnoses and pitfalls

• Some phaeochromocytomas may resemble adrenal cortical tumors on routine light microscopy

image immunostaining and additional investigations may be required for definitive diagnosis

• Composite phaechromocytoma also has features of ganglioneuroma or other neuroblastic or nerve sheath tumor

image usually affects adults
image relatively increased frequency in NF1 / MEN2

• Compared to sporadic cases, in MEN 2, phaeochromocytomas:

image may be preceded by diffuse medullary adrenal hyperplasia

– nodules <1cm diameter

image more commonly bilateral and multiple
image <5% malignant
image histologically identical

• Familial paraganglioma-phaeochromocytoma syndromes due to mutations in SDHB, SDHV and SDHD are also now recognized (Astuti et al 2001, Cascon et al 2002)

image may present with tumors in childhood or adolescence
image histologically similar to sporadic cases but more commonly

– bilateral
– multicentric

• Even apparently isolated familial phaeochromocytoma may be associated with germline VHL gene mutations (Crossey et al 1995, Frenzel et al 2001)

Extra-adrenal paraganglioma

• Similar histological features to phaechromocytoma but occurring at a wide range of other sites of paraganglia
• Usually adults

image up to 50% familial

• Less clinical manifestations of increased catecholamines
• Mass effects

PREDISPOSING CONDITIONS ASSOCIATED WITH PHAEOCHROMOCYTOMA AND OTHER ENDOCRINE TUMORS

MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 (MEN2)

• Autosomal dominant activating germline mutations of RET gene 10q11.2

image specific codon mutations within RET correlate with disease phenotype and severity (Lakhani et al 2007)

• Three clinical syndromes:

image familial medullary thyroid carcinoma (FMTC)
image MEN2a (MTC, phaeochromocytoma, hyperparathyroidism)
image MEN2b (MTC, phaeochromocytoma, neuromas, ganglioneuromatosis)

• Compared to sporadic cases, in MEN 2, phaeochromocytomas:

image may be preceded by diffuse medullary adrenal hyperplasia

– nodules <1cm diameter

image more commonly bilateral and multiple
image <5% malignant
image histologically identical

• Parathyroid hyperplasia

image all glands enlarged and hypercellular
image variation in size
image mainly cytologically bland chief cells
image histologically identical to sporadic cases

• Rarely MEN2 is also associated with Hirschsprung’s disease
• In view of risk of medullary carcinoma of thyroid, prophylactic thyroidectomy is performed in childhood:

image <6 years in MEN2a
image <2 years in MEN2b

• Also screening for phaechromocytoma from age 6

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN1)

• Autosomal dominant (Menin gene)
• Multifocal endocrine tumors
• Most often present in late adolescence to adulthood

image 50% have hyperparathyroidism by 20 years

• Parathyroid, pancreas, pituitary, adrenal and other
• Germline MEN1 11q13 mutations in 10%
• Gastrinoma / Zollinger–Ellison syndrome in around 50%

HYPERPARATHYROIDISM–JAW TUMOR SYNDROME

• Hyperparathyroidism in late adolescence / early adulthood

image due to parathyroid adenomas / carcinomas

• In association with ossifying fibroma of the maxilla / mandible and renal cysts and tumors (including Wilms’ tumor)
• Autosomal dominant

image HRPT2 gene

VON HIPPEL–LINDAU SYNDROME

• Predilection for multiple tumors due to dominant but age dependent penetrance of VHL gene mutations: 3p25

image phaeochromocytoma
image multifocal and extra-adrenal paragangliomas
image clear cell RCC
image cerebellar hemangioblastoma
image retinal angiomas
image pancreatic cysts / tumors
image endolymphatic sac tumors
image capillary hemangioblastomas

• Most tumors occur during adulthood but phaeochromocytomas occur in childhood

image especially with VHL2

– vascular tumor capsule
– myxoid or hyalinized stroma
– clear cells
– no atypia
– no associated diffuse adrenal medullary hyperplasia

· cf MEN2

image retinal angiomas may also occur in childhood

NEUROFIBROMATOSIS (NF) TYPE 1

• 90% of NF
• Around 1 in 3000
• Autosomal dominant mutations in NF1 17q11.2

image many lesions present at birth or early childhood

• Features include:

image café-au-lait macules of skin
image neurofibromata (Figs 4.11–4.13)

– especially plexiform
image MPNST

– most high grade

image axillary / inguinal freckling
image optic glioma / other CNS gliomas
image Lisch nodules
image bony lesions

– pseudoarthrosis
– scoliosis
– sphenoid wing dysplasia

• Family history NF1
• Other less common features (mainly affect adults):

image carcinoid tumor
image phaeochromocytoma
image renal artery stenosis

image

Fig. 4.11

image

Fig. 4.12

image

Figs 4.11–4.13 Photomicrographs of a case of plexiform and diffuse neurofibroma in a child with NF1, demonstrating expanded nerve trunks and surrounding diffuse proliferation of bland tapered spindle cells.

CARNEY SYNDROME

• Multiple tumors and mucocutaneous pigmented lesions

image develop during childhood

– myxomas

· skin/mucosa
· heart (any chamber)
· breast

• Primary pigmented adrenocortical disease
• Gonadal (testis) large cell calcifying sertoli cell tumors
• Psammomatous melanotic schwanomma

REFERENCES

Astuti D, Douglas F, Lennard TW, et al. Germline SDHD mutation in familial phaeochromocytoma. Lancet. 2001;357:1181-1182.

Cascon A, Ruiz-Llorente S, Cebrian A, et al. Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma. Eur J Hum Genet. 2002;10:457-461.

Crossey PA, Eng C, Ginalska-Malinowska M, et al. Molecular genetic diagnosis of von Hippel–Lindau disease in familial phaeochromocytoma. J Med Genet. 1995;32(11):885-886.

Frenzel S, Apel TW, Heidemann PH, Zerres K, Neumann HP, Dörr HG. Phaeochromocytoma associated with a de novo VHL mutation as form fruste of von Hippel–Lindau disease. Eur J Pediatr. 2001;160:421-424.

Lakhani VT, You YN, Wells SA. The multiple endocrine neoplasia syndromes. Annu Rev Med. 2007;58:253-265.

Ribeiro RC, Sandrini F, Figueiredo B, et al. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA. 2001;98:9330-9335.

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