This document provides an overview of the endocrine system, focusing on the histology and pathology of key endocrine organs, including the parathyroid glands, pancreas, adrenal glands, and pituitary gland. Key lesions discussed include parathyroid adenomas, chief cell hyperplasia, pancreatic islet cell tumors, adrenal cortical lesions, and multiple endocrine neoplasia. The roles of these organs in hormone production and regulation are also reviewed.

1. ENDOCRINE SYSTEM
November 29, 2017
Aida Isabel G. Mendoza MD DPSP

2. Course Objectives:
• Review the different
functions of selected
organs in endocrine
system
• Identify and describe
the histologic features
of different neoplastic
lesions of selected
organs in endocrine
system
• Correlate the lesions
clinically

3. Outline
• Parathyroid Gland
• Endocrine
Pancreas
• Adrenal Gland
• Pituitary Gland

4. PARATHYROID GLANDS
1. Chief cell – with variable amount of glycogen
particles and secretory droplets
- Secretes parathormone (PTH) and PTH-
related protein
- (+) anti PTH E11* strong in normal
2. Oxyphil cell – with a deeply granular and
eosinophilic cytoplasm
- many mitochondria but few secretory granules
- Appear as nodules
3. Water-clear cells
4. Transitional oxyphil and transitional water- clear
cells – more common in hyperfunctioning glands

5. PARATHYROID GLANDS
NORMAL HISTOLOGY
Before puberty: Gland is composed of chief
cells (no fat)
At puberty: oxyphil cells and fat (tiny droplets)
appear (until age 40)
Adult parathyroid – 40% fat but variable,
parenchyma is always constant
Some parathyroids (50%) contain follicles and
cysts with colloid-like material (thyroid vs
parathyroid*)
+ glycogen-parathyroid
+ CaOx (bifringent in polarized light)-thyroid

6. PARATHYROID GLANDS

7. PARATHYROID GLANDS
NORMAL PHYSIOLOGY
- Mediate their endocrine function through the
production of PTH
Physiologic actions of PTH
1. Increased renal excretion of phosphate
2. Increased renal tubular absorption of
calcium
3. Increased intestinal absorption of calcium
4. Direct effects in bone – increased
osteoclastic activity

8. PARATHYROID GLAND ADENOMA
o M<F, ave. age: 4TH decade
o Majority are Solitary (75% involve one of the
inferior glands)
o Other glands have a normal or atrophic
appearance
o Usually oval with slight lobulation, and
surrounded by a thin capsule
o With a rim of compressed non-neoplastic
tissue
o PTH staining is weaker in the adenoma than
in the residual normal gland

9. PARATHYROID GLAND ADENOMA

10. PARATHYROID GLAND ADENOMA

11. PARATHYROID GLANDS
ADENOMA VARIANTS
1. Oxyphil adenoma – non-functioning
2. Lipoadenoma – functioning

12. PARATHYROID GLANDS
CHIEF CELL HYPERPLASIA
1. Primary chief cell hyperplasia – constant
finding in patients with MEN I and IIA
- All glands are enlarged (superior larger
than inferior)
- Diffuse or nodular
*Parathyromatosis

13. PARATHYROID GLANDS
CHIEF CELL HYPERPLASIA
Primary chief cell hyperplasia
Treatment = surgery with transplantation in
the forearm

14. PARATHYROID GLANDS
CHIEF CELL HYPERPLASIA
2. Secondary chief cell hyperplasia – secondary
to impairment of renal function or chronic
malabsorption
- higher number of oxyphil cells compared to
primary form

15. PARATHYROID GLANDS
WATER-CLEAR CELL HYPERPLASIA
 No familial incidence and not associated
with MEN
 Extreme enlargement of all parathyroid
tissue (>100g)
 Strangely, this disorder disappeared in
recent times (unknown reason)
 Superior larger than inferior
 Have a typical brown color
 With pseudopods

16. PARATHYROID GLANDS
WATER-CLEAR CELL HYPERPLASIA

17. PARATHYROID GLANDS
CARCINOMA
 Presents with hyperparathyroidism
 Clinical features: very high serum calcium or
PTH, palpable cervical mass, vocal cord
paralysis, recurrence of hyperparathyroidism a
short time after surgery
 Gross: hard, surrounded by a dense fibrous
reaction, and adherent to adjacent structures

18. PARATHYROID GLANDS
CARCINOMA

19. HYPERPARATHYROIDISM – persistent
production of PTH
1. PRIMARY HYPERPARATHYROIDISM
 there is no evidence of previous
parathyroid stimulation by chronic renal or
intestinal disease
 caused by adenoma (>80%), chief cell
hyperplasia, carcinoma, or water-clear
cell hyperplasia
 Hypercalcemia, hypercalciuria,
hypophosphatemia

20. HYPERPARATHYROIDISM
PRIMARY HYPERPARATHYROIDISM
a) Osseous manifestations – always
generalized
- osteitis fibrosa cystica or
Recklinghausen’s disease or brown
tumor*
- G: with alternation of solid and cystic
areas
- M: combination of osteoblastic and
osteoclastic activity

21. PRIMARY HYPERPARATHYROIDISM
a) Osseous manifestations
- expansile, multilocular masses
- osteitis fibrosa cystica or
Recklinghausen’s disease or
brown tumor
Jaw-preferred location

22. HYPERPARATHYROIDISM
PRIMARY HYPERPARATHYROIDISM
b) Renal manifestations – renal stones,
nephrocalcinosis, polyuria, polydipsia and
impairment of renal function
- still progress after the removal of the
parathyroid lesion
c) Other manifestations – hypertension,
peptic ulcer, pancreatitis, mental
disturbances
*Parathyroid crisis - fatal

23. HYPERPARATHYROIDISM
2. SECONDARY HYPERPARATHYROIDISM
- occurs as a consequence of renal disease
or intestinal malabsorption
- with Vitamin D resistance*
- with mild bone changes
- cutaneous calciphylaxis*
- chief cell hyperplasia-parathyroid
manifestation

24. HYPERPARATHYROIDISM
3. TERTIARY HYPERPARATHYROIDISM
- secondary to chronic renal disease or
intestinal malabsorption, in which one or more
of the stimulated parathyroid glands seem to
become autonomous
- nonsuppressible, autonomous, or refractory
hyperparathyroidism, reversible
- microscopic…chief cell hyperplasia but more
nodular

25. THERAPY OF HYPERPARATHYROIDISM
Primary chief cell hyperplasia – subtotal
parathyroidectomy*
Primary and secondary chief cell hyperplasia –
total parathyroidectomy with
autotransplantation into the forearm muscle
Adenoma – local excision of the tumor*
Carcinoma – excision of the tumor and
surrounding soft tissues and thyroid
lobectomy

26. PANCREAS
Endocrine tumors of the pancreas – islet cell
tumors, pancreatic endocrine neoplasm
 most common location: body and tail
 G: more cellular, more pink
 Do not have a well-defined capsule
 M: small cuboidal cells with centrally
located nuclei and finely granular
cytoplasm
 May be non-functioning or functioning (esp
malignant)

27. ENDOCRINE PANCREAS
IMMUNOHISTOCHEMISTRY
(+) epithelial markers
(+) panendocrine markers
Special stain for islet cell – Silver technique
PATTERNS OF GROWTH
I A solid
II B gyriform – beta or alpha cells
III C glandular – G or VIP cell
IV D nondescript

28. ENDOCRINE PANCREAS
1. BETA CELL TUMORS – insulinomas (if functional)
- most common
- majority are benign
- usually solitary (90%), with gyriform pattern
Whipple triad-characteristic of the tumor
a) Mental confusion, weakness, fatigue,
convulsions
b) FBS <50mg%
c) Relief of symptoms by the administration of
glucose
Treatment: surgical (subtotal pancreatectomy)

29. ENDOCRINE PANCREAS
2. ALPHA CELL TUMORS
A) Glucagonomas – solitary and large
- high incidence of malignancy
- non descript pattern
- IHC: few cells positive for glucagon
B) Not associated with the glucagonoma
syndrome - multiple and small
- gyriform pattern
- nearly always benign
- strongly immunoreactive for glucagon

30. ENDOCRINE PANCREAS
ALPHA CELL TUMORS
A) Glucagonomas – solitary and large
- high incidence of malignancy

31. ALPHA CELL TUMORS

32. ENDOCRINE PANCREAS
ALPHA CELL TUMORS
Components of Glucagonoma Sndrome
a) abnormal glucose tolerance test
b) normocytic normochromic anemia
c) skin rash – necrolytic migratory erythema
- heals with hyperpigmentation
d) sore red tongue, angular stomatitis, DVT,
overwhelming infections

33. ENDOCRINE PANCREAS
3. G-CELL TUMORS – gastrinomas
- produce the Zollinger-Ellison syndrome
(gastric hyperacidity with gastric, duodenal
or jejunal ulcers)
- pancreas > duodenum > antrum
a) Sporadic – solitary, clinically malignant,
pancreas (assoc with ZES)
b) Familial – component of MEN I
- multicentric, less likely to be clinically
malignant, duodenum
Treatment: total excision of tumor and/or
removal of target organ

34. ENDOCRINE PANCREAS
4. VIP-PRODUCING TUMORS – associated with
diarrhea or cholera-like syndrome
5. DELTA CELL TUMORS – clinically silent because
somatostatin is an inhibitory hormone
S/Sx: Somatostatinoma syndrome (diabetes,
cholecystolithiasis, steatorrhea, indigestion,
hypochloridia)
6. CARCINOID TUMORS – arise from
Kulchitsky’s (serotonin-producing) cells

35. ENDOCRINE PANCREAS
MALIGNANCY
- Behavior: Correlate with size, extrapancreatic
spread, vascular invasion, mitotic activity, degree
of Ki-67 immunostaining, glandular/solid pattern,
METASTATIC TUMORS – usually from the large
bowel and kidney

39. MULTIPLE ENDOCRINE NEOPLASIA
 Autosomal dominant
 Hyperplastic or neoplastic proliferation of >1
endocrine gland
MEN type I (Werner’s syndrome) 3Ps
• Mutation of MEN 1 gene (chrom. 11)
• Pituitary adenomas, pancreatic tumor (G-cell
tumor, 50%), Chief cell hyperplasia of the
parathyroids
• S/Sx; acromegaly or hypopituitarism, Zollinger-
Ellison syndrome, hyperparathyroidism

40. MULTIPLE ENDOCRINE NEOPLASIA
MEN II
 Mutation of RET proto-oncogene
 Medullary thyroid carcinoma
a) MEN IIA
b) MEN IIB
c) Familial medullary thyroid carcinoma

41. MULTIPLE ENDOCRINE NEOPLASIA II
a) MEN IIA (Sipple syndrome)
 medullary thyroid carcinoma (multiple &or bil)
 pheochromocytoma of adrenal (bil)
 C-cell hyperplasia
 Chief cell hyperplasia of parathyroid
b) MEN IIB (Gorlin’s syndrome)
 medullary carcinoma of the thyroid
 pheochromocytoma of adrenal
 Mucosal neuromas (most constant feature)
 Skeletal abnormalities (marfanoid habitus)
c) Familial medullary thyroid carcinoma
 In at least 4 family members
 Combined with pancreatic endocrine tumors,
paraganglioma, etc

43. ADRENAL GLAND
 Located in the retroperitoneum, superomedial to
the kidneys, combined wt < 6 g.
 Composite of 2 endocrine organs
a) Medulla – from the neuroectoderm
- pheochromocyte / medullary cell /
chromaffin cell (may be epinephrine or
norepinephrine-containing)
- sustentacular cell
b) Cortex – from the mesoderm
- under the influence of ACTH
1. zona glomerulosa – mineralocorticoids
2. zona fasciculata – glucocorticoids
3. zona reticularis – sex hormones

45. LESIONS OF ADRENAL CORTEX
 HETEROTOPIA – MC site is the retroperitoneal fat
 CONGENITAL HYPERPLASIA – autosomal
recessive, inborn error of metabolism
- Responsible for adrenogenital syndrome
developing within the first year of life
- Defect in an enzyme required to synthesize
cortisol from cholesterol
- 95% absence of 21-hydroxylase (virilization)
- Deficiency of 11β-hydroxylase (virilization and
hypertension)
- Pathology: Diffuse cortical hyperplasia esp. the
zona reticularis
- Treatment: Replacement with cortisol and surgical
correction of the external sex organ

46. LESIONS OF ADRENAL CORTEX
 ACQUIRED HYPERPLASIA – bilateral
- Diffuse or a nodular enlargement of the adrenal
gland (>6g)
 Diffuse: Due to ACTH hyperproduction by the
pituitary gland or ACTH-producing neoplasm in
the lung, ACTH dependent
 Nodular : ACTH independent or adrenal
dependent
- Pathology: increased thickness of the zona
fasciculata and reticularis

47. LESIONS OF ADRENAL CORTEX
ACQUIRED HYPERPLASIA – bilateral
- Diffuse or a nodular enlargement of the adrenal
gland (>6g)

48. ADRENOCORTICAL TUMORS
• Adenomas and carcinomas
• Usually in adults (50 years old ave), M=F
• Asymptomatic or with signs related to hormonal
dysfunction
• Highly necrotic carcinomas may result in fever
• Palpable=malignant
• Gross: solitary
• Adenomas-small
• Carcinoma-> 10 g
• Diagnosis: Computed tomography
• Treatment: Surgical excision

49. ADRENOCORTICAL TUMORS
1. Adenomas - <5cm, encapsulated, yellow
homogenous
- IHC: (+) LMWK
- treated by excision
2. Carcinoma - >10g, variegated, with necrosis and
hemorrhage
- mitotic rate >5 per 50 HPF
- absence of clear cells
- with capsular invasion
- spreads to the retroperitoneum and
infiltrates the kidney
- overexpression of p53
- IHC: strongly (+) for vimentin

50. ADRENOCORTICAL TUMORS
 Adenoma
 Carcinoma

51. ADRENAL CORTEX
FUNCTIONAL MANIFESTATIONS
 Non-functioning lesions – usually carcinomas
- due to deletion in some of the enzymes
for cortisol synthesis
 Primary aldosteronism – Conn’s syndrome
- results in loss of potassium, retention of
sodium, hypertension, suppressed renin
levels, muscle weakness
- 70% is due to adenoma
- spironolactone bodies are seen in patients
treated with spironolactone

52. Primary aldosteronism - spironolactone bodies

53. ADRENAL CORTEX
FUNCTIONAL MANIFESTATIONS
 Cushing syndrome
- due to hyperproduction of cortisol
- only 20% has primary adrenal cause (80%F)
- may be diffuse/nodular hyperplasia (bilat),
adenoma or carcinoma (both unilat)
- majority of the cases of diffuse cortical
hyperplasia are the result of pituitary
hyperfunction (Cushing disease)
- Other ACTH –producing neoplasms: small cell
ca of the lung, endocrine tumors of the
foregut, pheochromocytoma, certain ovarian
tumors

54. ADRENAL CORTEX
FUNCTIONAL MANIFESTATIONS
 Adrenogenital syndrome
- excess androgens bring about changes towards
adult musculinity in male or female children and
toward masculinity in female adults.
- excess of dehydroisoandrosterone
CAH- MC cause of childhood virilization
- hyperplasia > carcinoma > adenoma
If with neoplasm presentcarcinoma
Malignant  70% virilization in adult woman
 100% adult male with fem

55. ADRENAL MEDULLA
Paraganglion system – numerous collections of
neuroepithelial cells scattered throughout the body,
having numerous cytoplasmic neurosecretory
granules containing catecholamines
- appear as chief cells arranged in well-defined nests
(“Zelballen”) encircled by a thin layer of S-100
protein-positive sustentacular cells
a) adrenal medulla
b) parasympathetic system
and sympathetic system

56. ADRENAL MEDULLA
Paraganglia

57. ADRENAL MEDULLA TUMORS
2 Categories
1. Embryonal neural (sympathetic) – children
 Neuroblastoma
 Ganglioneuroblastoma
 Ganglioneuroma
2. Adult neuroendocrine tumors and tumor-like
conditions
 Pheochromocytoma
 Adrenal medullary hyperplasia

58. ADRENAL MEDULLA TUMORS
NEUROBLASTOMA
• 80% are detected in children <4 years
• Usually present as an abdominal mass first
noted by the parents
• G: large, soft and relatively well
circumscribed with areas of calcification,
hemorrhage and necrosis
• Homer Wrights rosettes are seen in ¼ to 1/3
of cases (tumor cells arranged around a
central area filled with a fibrillary material*
without a central lumen)

59. ADRENAL MEDULLA TUMORS
NEUROBLASTOMA
• IHC: neuron-specific enolase,
neurofilaments
• Genetic events: loss of a region on chrom.
1 and amplification of N-myc
• Metastasize to liver (Pepper syndrome),
skeletal system (Hutchinson syndrome)
• Poor prognosis: <2 y/o, high Ki-67 scores,
presence of CD44
• Treatment: surgical excision,
chemotherapy and bone marrow
transplantation

60. ADRENAL MEDULLA TUMORS
NEUROBLASTOMA

61. ADRENAL MEDULLA TUMORS
NEUROBLASTOMA

62. ADRENAL MEDULLA TUMORS
GANGLIONEUROBLASTOMA
• Malignant ganglioneuroma
• young children
• most are located in the retroperitoneum
rather than the adrenal gland
• Better prognosis than neuroblastoma

63. ADRENAL MEDULLA TUMORS
GANGLIONEUROMA
• Benign
• Seen in older age group
• Most common neoplasm of the sympathetic
nervous system in adults
• be multiple and/or associated with other
independent types of neural/neuroendocrine
neoplasms,
• MC location is the posterior mediastinum
and retroperitoneum
• Catecholamine synthesis is a constant
feature

64. ADRENAL MEDULLA TUMORS
GANGLIONEUROMA

65. ADRENAL MEDULLA LESIONS
ADRENAL MEDULLARY HYPERPLASIA
Usually occur as a component of MEN 2b
PHEOCHROMOCYTOMA
• Paraganglia of the adrenal medulla
• 10% tumor (extra-adrenal, children, bilateral,
malignant)
• Triad of sweating attacks, tachycardia and
headaches
• Secrete epinephrine and norepinephrine
(paragangliomas secrete norepinephrine)
• Confirmation of Dx: measuring urinary
catecholamines or their catabolites

66. ADRENAL MEDULLA LESIONS
PHEOCHROMOCYTOMA
• Takes on a dark brown appearance when
immersed in dichromate solution *
(chromaffin reaction)
• Triad:3P
• G: encapsulated, soft
• M: tumor cells are arranged in well-defined
nests (“Zellballen”) bound by a delicate
fibrovascular stroma
- with sustentacular cells at the
periphery, (+) for S-100

67. ADRENAL MEDULLA LESIONS
PHEOCHROMOCYTOMA
Chromaffin reaction

68. ADRENAL MEDULLA LESIONS
PHEOCHROMOCYTOMA
• Malignant tumors metastasize to the skeletal
system, particularly the ribs and spine
• Treatment: surgical excision

69. PITUITARY ADENOMA
• Arise from the adenohypophysis
• Usually benign
• 70% are functioning
• Some present with insidious symptoms of
hypopituitarism
• Suprasellar extension produce neurologic signs
• Pituitary apoplexy (abrupt onset of headache,
ocular deficits and altered consciousness)
• Dx: MRI

70. PITUITARY ADENOMA
1. PRL adenoma – MC
 Usually present with the galactorrhea-
amenorrhea syndrome (Chiari-Frommel
syndrome or Forbes-Albright syndrome)
 Dx: serum PRL >200 ng/mL
 M: chromophobic or slightly acidophilic
 Treatment: dopamine agonists
(bromocriptine)

71. PITUITARY ADENOMA
2. GH cell adenoma
 May result in gigantism or acromegaly
3. Mixed GH-cell-PRL-cell adenoma
 Mammosomatotroph adenoma
 Associated with acromegaly and slight
hyperprolactinemia

72. PITUITARY ADENOMA
GH cell adenoma
- 2nd MC type
- May result in gigantism
or acromegaly
- Densely vs sparsely
granulated GH
adenomas

73. PITUITARY ADENOMA
4. ACTH cell adenoma
 Corticotroph adenoma
 Patients have Cushing’s disease, Nelson
syndrome, Pituitary apoplexy, or non-
functioning
 Usually basophilic
 PAS-positive due to proopiomelanocortin
 With perinuclear microfilaments – an important
diagnostic feature (Crooke’s hyalinization)

74. PITUITARY ADENOMA
ACTH cell adenoma
Crooke’s hyalinization

75. PITUITARY ADENOMA
5. Glycoprotein hormone-producing adenomas –
gonadotrophs and thyrotrophs
 Results in excessive production of the alpha-
unit*
6. Plurihormonal adenoma – tend to be large at
presentation and have a more aggressive clinical
course
7. Null cell adenoma – no evidence of hormone
production
- manifest with progressive loss of vision and
hypopituitarism (mass effect)

79. PITUITARY ADENOMA
TREATMENT
 Surgical excision (transsphenoidal)
 radiation
 Medical – bromocriptine, ocreotide

80. PITUITARY GLAND
OTHER LESIONS
LYMPHOCYTIC HYPOPHYSITIS
o Primary or secondary
o rare autoimmune endocrine disease
o With polymorphic lymphoplasmacytic infiltration
associated with destruction of the anterior
pituitary cells
o Tx: Corticosteroid

81. PITUITARY GLAND
OTHER LESIONS
RATHKE’S CLEFT CYST
o Cyst of the hypophyseal cleft
o Become clinically apparent with
compression of the hypothalamus and
optic chiasm
o M: cysts are lined by
predominantly columnar
ciliated cells
o Tx: surgical excision and
o drainage
o MRI findings of an anteriorly
o displaced pituitary stalk, a
o ‘posterior ledge sign’

82. PITUITARY GLAND
OTHER LESIONS
RATHKE’S CLEFT CYST

83. PITUITARY GLAND
SELLAR/SUPRASELLAR LESIONS
CRANIOPHARYNGIOMA
o Constitutes 3% of brain tumors
o Sx: hydrocephalus, pressure on the optic
chiasm and optic tracts
1. Adamantinomatous form – with peripheral
palisaded nuclei, ghost cells, focal calcification,
wet keratin
- children
2. Papillary craniopharyngioma – adults
- with papillary, nonkeratinizing stratified
squamous epithelium

84. PITUITARY GLAND OTHER LESIONS
CRANIOPHARYNGIOMA

85. PITUITARY GLAND
OTHER LESIONS
PITUICYTOMA
o Arise from the pituicyte, a specialized glial cell
found in posterior pituitary
o Sx: headache, visual field defect