Introduction Importance of Hereditary syndromes in Endocrine pathology Red flags Role of Pathologist Individual syndromes Summary

1. UPDATE IN INHERITED AND SYNDROMIC
ENDOCRINE NEOPLASMS
PROF B D RADOTRA

2. OUTLINE OF CLASS
 Introduction
 Importance of Hereditary syndromes in Endocrine
pathology
 Red flags
 Role of Pathologist
 Individual syndromes
 Summary

3. Cancer. 2015 Feb 15;121(4):589-97

4. AJSP: Reviews & Reports: September/October 2017 - Volume 22 - Issue 5 - p 246-268

5. Classic Multiple Endocrine
Neoplasia Syndromes
Hyperparathyroidism jaw
tumor syndrome
SDH related familial
paraganglioma -
pheochromocytoma
syndromes
Von Hippel-Lindau
syndrome
Neurofibromatosis Type I Carney complex
McCune Albright syndrome
Familial non-medullary
thyroid cancer syndrome
MEN4
DICER1 syndrome
Glucagon cell hyperplasia
and neoplasia syndrome

6. Multifocal neoplasia
Multiorgan
involvement
Family
history
Early onset

7. HERITABLE ENDOCRINE TUMORS ARE DIFFERENT !
Phenotypically complex and
heterogenous
Present with De-novo mutations

8. Difficult to
recognise and
classify on
clinical grounds
alone …
Don’t worry,
Pathologists are
here to solve the
mystery ..

9. Pathognomonic:
Histomorphology +
Immunohistochemistry Clues
=
Help provide further
direction

10. Genetic testing
Counselling
Targeted therapy

11. MULTIPLE ENDOCRINE NEOPLASIA TYPE I
Autosomal-dominant familial endocrine tumor syndrome caused by mutations
in the MENIN1 gene

12. MOLECULAR BASIS
Menin1 11q13
Aberrant menin protein implicated in chromatin
remodeling, transcriptional regulation, and
Wnt/β-catenin signaling pathways

13. Parathyroid
PancreasPituitary
Duodenum
Stomach
Thymus
Lung
Adrenal cortex
(Non-endocrine) Skin, CNS & Soft tissue

14. Clinical
Manifestations
Primary Hyperparathyroidism
(earliest and most common clinical manifestation)Hyperprolactinemia
Zollinger Ellison Syndrome
Hyperinsulinemic hypoglycaemia
Cushing syndrome

15. HISTOPATHOLOGIC FEATURES IN MEN1
Multiglandular parathyroid disease (multiglandular multiple microadenomas)
(Multifocal) pitNETs, often involving Pit-1 lineage adenohypophyseal cells
Multifocal gastrin-producing duodenal NETs with underlying G- and D-cell hyperplasia
Multifocal PanNETs with underlying islet dysplasia, peliosis, nesidioblastosis, and microadenomatosis
Multifocal gastric ECL cell NETs with underlying ECL-cell hyperplasia, often secondary to a gastrin-producing
duodenal NET
Thymic NET +/− underlying neuroendocrine cell hyperplasia
(Multifocal) pulmonary NETs with underlying pulmonary neuroendocrine cell hyperplasia +/− tumorlets
Adrenocortical adenoma(s) with underlying adrenocortical hyperplasia

16. Multiglandular parathyroid
disease:
• Glands lack a typical rim
of nontumorous
parathyroid parenchyma
• Genetic mutation
predisposes to the
formation of
multiglandular clonal
proliferations

17. Double ACTH and PRL pituitary
microadenomas in a patient with
hyperparathyroidism, Zollinger-Ellison
disease, Cushing disease, and
hyperprolactinemia. The PRL
microadenoma appears agranular with
Herlant tetrachrome (A). All the cells are
positive with PRL antibodies (B) and
negative with ACTH antibodies (C). The
ACTH microadenoma is composed of
basophilic cells by Herlant tetrachrome (D).
The cells are negative with PRL (E) and
positive with ACTH antibodies (F). The 2
adenomas are separated by normal
pituitary

18. Micro neuroendocrine tumor in duodenum
in background of hyperplasia
Micro neuroendocrine tumor in pancreas
Identification of ECL-cell hyperplasia in the presence of hyperplastic oxyntic
mucosa

19. Spatial arrangement –
Glucagon, Insulin,
Somatostain and
Pancreatic polypeptide
A-D – Normal
E-H – Islet cell dysplasia
I- Microadenoma,
J-Nesidioblastosis,
K-L –Peliosis

20. Glucagon is most common hormone
expressed
Ductoinsular
complexes
Pelosis of Islets
of Langerhans

21. Increase number (a)
Linear (b)
Micronodular (c)
Hyperplasia of
neuroendocrine cells and
tumerlets (<5mm) (d)

22. Angiofibroma Lipoma Collagenoma
Cutaneous manifestations seen in upto 40 to 80% of MENIN1
syndrome

23. MENIN1 IHC
Case of thymic neuroendocrine
tumor with loss of MENIN1
Case of multiple neuroendocrine
tumors in pancreas with loss of
MENIN1

24. MULTIPLE ENDOCRINE NEOPLASIA TYPE II
Autosomal-dominant familial endocrine tumor syndrome caused by activating
germline mutations in the RET proto-oncogene

25. MOLECULAR BASIS
RET (10q11.2)
Aberrant RET tyrosine kinase signaling
pathway
MEN2A – extracellular domain
MEN2B – Intracellular domain

26. Parathyroid
Medullary
Pheochromo-
cytoma
Mucosal neuromas
or
ganglioneuromas
Marfanoi
d
habitus
Medullary
Pheochro
mcytoma
MEN 2A
MEN 2B (MEN 3)

27. MEN2A
Lichen
amyloidosis
Hirschprungs
disease
Isolated familial
medullary
carcinoma

28. Clinical
Manifestations
Medullary thyroid cancer
Catecholamine excess
Primary hyperparathyroidism (MEN2A only)

29. HISTOPATHOLOGIC FEATURES IN MEN1I
(Multifocal and bilateral) MTC with underlying precursor neoplastic
C-cell hyperplasia
(Multifocal and bilateral) pheochromocytomas with underlying
medullary hyperplasia
Usually single parathyroid gland disease (parathyroid adenoma)

30. Normal C cells (c),
Multifocal and bilateral C-cell
hyperplasia (d)
Calcitonin (e)
Medullary microadnenoma

31. Normal adrenal (A) Medullary
hyperplasia (>1/3rd thickness) (B)
Micropheochromocytoma in a
background of medullary
hyperplasia

32. MULTIPLE ENDOCRINE NEOPLASIA TYPE IV (AKA
MEN X)
Autosomal-dominant familial endocrine tumor syndrome caused by inactivating
germline mutations in the CDK1B tumor suppressor gene

33. MOLECULAR BASIS
CDKN1B (12p13)
Aberrant p27/Kip1 protein
implicated in cyclin D1
signaling pathway

34. Parathyroid
PancreasPituitary
Later onset and lower
penetrance than does
MEN1

35. Clinical
Manifestations
Primary Hyperparathyroidism
Hyperprolactinemia
Zollinger Ellison Syndrome
Hyperinsulinemic hypoglycaemia
Cushing syndrome

36. HISTOPATHOLOGIC FEATURES IN MEN1V
Multiglandular parathyroid
disease
(Multifocal) pitNETs, often involving Pit-1 lineage
adenohypophyseal cells
Multifocal gastrin-producing duodenal NETs with underlying
G- and D-cell hyperplasia
Multifocal PanNETs with underlying islet dysplasia, peliosis,
nesidioblastosis, and microadenomatosis

37. p27
Wild type expression: Intense nuclear Mutant : Loss of nuclear
expression

38. HYPERPARATHYROIDISM–JAW TUMOR SYNDROME
Autosomal-dominant syndrome caused by inactivating germline mutations
CDC73/HRPT2 tumor suppressor gene

39. MOLECULAR BASIS
CDC73/HRPT2 (1p25–q31)
Aberrant parafibromin protein
implicated in the regulation of
p53 and gene transcription

40. Primary
hyperparathyroidism
(severe)
Fibro-osseous lesions of the mandible and
maxilla
Uterine leiomyomas, adenofibromas,
adenosarcoma
Pancreatic and renal lesions (cysts,
hamartomas, Wilms tumor, and carcinomas)

41. ClinicalManifestations
Primary hyperparathyroidism (severe)
-15 to 37.5% lifetime risk of parathyroid carcinoma
-15-30% parathyroid carcinomas have HJT

42. HISTOPATHOLOGIC FEATURES IN HYPERPARATHYROIDISM-JAW
TUMOR SYNDROME
Parathyroid carcinoma
Parathyroid hyperplasia, cystic adenomas to
Parathyroid carcinoma with underlying
multiglandular involvement

43. Parafibromin
Wild type expression: Intense nuclear Mutant : Loss of nuclear
expression

44. FAMILIAL PARAGANGLIOMA-PHEOCHROMOCYTOMA
SYNDROMES CAUSED BY SDH MUTATIONS
Autosomal-dominant syndrome caused by inactivating mutations in genes
encoding Succinate Dehydrogenase (SDH) Subunits

45. MOLECULAR BASIS
SDHD (11q23.1), SDHAF2 (11q12.2), SDHC
(1q23.3), SDHB (1p36.13), SDHA (5p15.33)
Deficient SDH complex resulting in
deregulated (pseudo)hypoxia
signaling pathway

46. Pheochromo
-cytoma
Paraganglio
ma
Pituitary NET
Pancreatic NET
GIST
RCC

47. ClinicalManifestations
Catecholamine excess (mainly dopamine and mixed
dopamine/norepinephrine)
~40%, paragangliomas/pheochromocytomas
demonstrate one of the highest rates of genetic
susceptibility among all tumor types
~30% to 40% of cases that metastasize
Occasional pitNET, panNET, GIST, RCC

48. HISTOPATHOLOGIC FEATURES IN FAMILIAL PARAGANGLIOMA-
PHEOCHROMOCYTOMA SYNDROMES
Synchronous or asynchronous multifocal paraganglioma-
pheochromocytoma

49. Paraganglioma with small cells with prominent clear
cytoplasm, intracytoplasmic vacuoles, and prominent
vascularity

50. SDHB
Wild type expression: Intense granular
cytoplasmic
Mutant : Loss of cytoplasmic
expression

51. VON HIPPEL-LINDAU DISEASE
Autosomal-dominant syndrome caused by inactivating mutations in VHL tumor
suppressor gene

52. MOLECULAR BASIS
vHL (3p25.3)
Inactivation of pf vHL leads to failure
of degradation of HIF, causing up-
regulation of growth factors and cyclin
D1

53. Pancreatic
NET
Paragang
lioma
Pheochr
mocytom
a
Classical
Hemangioblastoma
Visceral cyst – pancreas,
renal and liver
RCC

54. ClinicalManifestations
Catecholamine excess (mainly norepinephrine)
PanNET (usually nonfunctioning)

55. HISTOPATHOLOGIC FEATURES IN VON HIPPEL-LINDAU DISEASE
Pheochromocytoma(s) with thick vascular tumor capsule, extreme
hypervascularity and clear cell changes
Paraganglioma(s) (usually parasympathetic, noncatecholamine
releasing)
(Multifocal) PanNETs with clear cell change as well as underlying islet
dysplasia, peliosis,nesidioblastosis, and microadenomatosis

56. Paraganglioma with distinct thick vascular tumor capsule,
myxoid and hyalinized stroma rich in vasculature, and tumor
cells with variable degree of clear and amphophilic cell
cytoplasm

57. Cystic pancreatic disease
Multifocal pancreatic NETs with clear cell change

58. Tyrosine hydroxylase confirms the paraganglial origin of a clear cell
neuroendocrine neoplasm

59. Carbonic anhydrase IX
CAIX immunoexpression in multifocal clear cell NETs and cysts has been
shown to be suggestive of VHL-disease

60. -Inhibin
α-Inhibin immunoexpression in multifocal clear cell NETs has been
shown to be suggestive of VHL-disease

61. NEUROFIBROMATOSIS TYPE 1
Autosomal-dominant syndrome caused by germline mutations in the NF1 tumor
suppressor gene

62. MOLECULAR BASIS
NF1 (17q11.2)
NF1 encodes neurofibromin, a
GTPase-activating protein implicated
in the regulation of the RAS signaling
pathway

63. Duodenal
NET
Paragang
lioma
Pheochro
mocytom
a
Multiple neurofibromas
Café-au-lait macules
Axillary and inguinal
freckling
Melanocytic iris hamartomas
(Lisch nodules)
Bone dysplasia
Gliomas
Malignant peripheral nerve
sheath tumors
GISTs

64. ClinicalManifestations
Duodenal NETs +/− hyper-somatostatinemia
Catecholamine excess (mainly epinephrine)

65. HISTOPATHOLOGIC FEATURES IN NEUROFIBROMATOSIS TYPE 1
Ampullary somatostatin-producing NETs without precursor D-cell hyperplasia
Pheochromocytomas (+/− bilateral, multifocal, composite type) and rare
paragangliomas

66. Ampullary-type somatostatin expressing NETs, which are recognized by
their tubular-acinar growth, frequently associated with intraluminal
psammoma bodies

67. CARNEY COMPLEX
Autosomal-dominant syndrome caused by inactivating germline mutations in
PRKAR1A tumor suppressor gene

68. MOLECULAR BASIS
PRKAR1A (17q24.2)
Aberrant PKA/cAMP signaling
pathway

69. Adrenal
Pituitary
Thyroid
Gonads
Spotty skin
pigmentation
Myxomas
Pigmented melanocytic
schwannomas

70. ClinicalManifestations
Adrenal Cushing syndrome
Acromegaly
Thyroid nodules
Gonadal tumors

71. HISTOPATHOLOGIC FEATURES IN CARNEY COMPLEX
Primary pigmented nodular adrenocortical disease
Primary pituitary somatotroph or mammosomatotroph hyperplasia +/− pitNETs
Follicular nodular disease, follicular adenoma(s), differentiated thyroid carcinomas
Ovarian cystadenomas (females); large-cell calcifying Sertoli cell tumors (males)

72. Primary pigmented adrenocortical disease
Gross - large number of yellow to brown-black micronodules.
Micro- The pigmented eosinophilic nodules (marked by square) are round-oval and
commonly found deep within the zona reticularis or near the corticomedullary
junction

73. MCCUNE-ALBRIGHT SYNDROME
Genetic disease caused by postzygotic somatic activating mutation at the GNAS
gene.

74. MOLECULAR BASIS
GNAS (20q13.2–13.3)
Aberrant PKA/cAMP signaling
pathway

75. Thyroid
Pituitary
Adrenal
cortex
Fibrous dysplasia
Café-au-lait macules
Precocious puberty

76. ClinicalManifestations
Primary (gonadotropin-independent) gonadal
hyperfunction causing precocious puberty
Primary hyperthyroidism
Acromegaly and/or hyperprolactinemia
Cushing syndrome(during infancy or childhood)

77. HISTOPATHOLOGIC FEATURES IN MCCUNE-ALBRIGHT SYNDROME
Ovarian follicular cysts lined by granulosa cells (females)
Testicular Leydig/Sertoli cell hyperplasia and/or neoplasia (males)
Follicular adenomas with papillary hyperplasia(functioning “toxic” adenoma) +/− rare thyroid carcinoma
Pituitary (somatotoph or mammosomatotroph) hyperplasia +/− pitNETs
Childhood primary bilateral adrenocortical hyperplasia (c-BMAH) and/or PBAD

78. Cortical hyperplasia and cortical atrophy
The reddish-brown thickened cortex (arrow)
featured several “tan-to-green nodules

79. Benign follicular epithelial proliferations with intrafollicular centripedal papillary
projections reflecting their hyperfunctioning status

80. FAMILIAL NONMEDULLARY THYROID CANCER
SYNDROME
Predominant non-thyroidal (Cowden syndrome, Familial adenomatous
polyposis, Werener syndrome)

81. ClinicalManifestations
Non medullary carcinoma Thyroid cancer

82. HISTOPATHOLOGIC FEATURES IN FAMILIAL NONMEDULLARY
THYROID CANCER SYNDROME
Cowden Syndrome
• FTC and FvPTC
Familial Adenomatous Polyposis
• Cribriform-morular variant of PTC
Werner Syndrome
• PTC, FTC, and anaplastic thyroid carcinoma
Non-syndromic familial thyroid carcinoma
• Follicular nodular disease and carcinoma (mainly PTC, with more aggressive clinical features)

83. MOLECULAR BASIS
PTEN (10q23.3)
Aberrant PI3K/AKT and MAPK pathways

84. Differentiated
thyroid cancer
Multiple
hamartomas
Breast
Endometrial
Renal,
Colon tumors
Cowden
Syndrome

85. Multiple cellular thyroid
nodules in association with
differentiated thyroid
carcinoma (not shown in this
photomicrograph).
Immunohistochemical loss of
PTEN expression

86. MOLECULAR BASIS
APC (5q22)
Aberrant Wnt/β-catenin signaling pathway

87. Differentiated
thyroid cancer
Colonic adenomatous
polyps
Colorectal cancer
Familial
adenomatou
s polyposis

88. Cribriform-morular variant of
PTC
In addition to the distinct
complex cribriform
architecture and scattered
morules
IHC for β-catenin -
cytoplasmic and nuclear
expression of β-catenin

89. MOLECULAR BASIS
RECQL2/WRN (8p12)
Aberrant DNA helicase implicated in DNA repair
pathway

90. Differentiated
thyroid cancer
- PTCs, FTCs &
anaplastic
carcinomas
Loss and graying of
hair
Cataracts
Diabetes mellitus type
2
Osteoporosis
Werner
syndrome

91. Differentiated
thyroid cancer >
3 family members
Non
syndromic
familial
thyroid
carcinoma

92. DICER1 SYNDROME
Heterozygous inactivating germline mutations in the DICER1 tumor suppressor
gene

93. MOLECULAR BASIS
DICER1 (14q32.13)
Aberrant DICER1 protein implicated in
miRNA maturation pathway

94. Pituitary
blastoma
Thyroid
Pleuropulmonary blastoma
Ovarian Sertoli-Leydig cell tumor
Cystic nephroma
Nasal chondromesenchymal
hamartoma
Ciliary body medulloepithelioma
Botryoid-type embryonal
rhabdomyosarcoma of the cervix
Anaplastic sarcoma of the kidney

95. ClinicalManifestations
Cushing syndrome (typically during infancy)

96. HISTOPATHOLOGIC FEATURES IN DICER1 SYNDROME
Pituitary blastoma (pathognomonic)
Thyroid follicular nodular disease and rare carcinoma
Ovarian Sertoli-Leydig cell tumors

97. Combination of Rathke type epithelial rosettes/glands, small primitive
appearing cells & secretory cells,
Synaptophysin and chromogranin immunoreactive and expressed
ACTH in at least a subset of cells

98. GLUCAGON CELL HYPERPLASIA AND NEOPLASIA
Inactivating germline mutations in the glucagon receptor gene

99. MOLECULAR BASIS
GCGR (17q25)
Aberrant glucagon receptor signaling
pathway

100. Pancreatic NET

101. ClinicalManifestations
Hyperglucagonemia

102. HISTOPATHOLOGIC FEATURES IN GLUCAGON CELL HYPERPLASIA
AND NEOPLASIA
Alpha-cell hyperplasia-to-neoplasia sequence leading to
multifocal PanNETs and microPanNETs

103. Pancreas display multiple alpha-cell microNETs (0.05–0.5 cm) as well as NETs (>0.5
cm) arising in the background of alpha-cell hyperplasia and dysplasia
Glucagon immunohistochemistry highlights the presence of a clonal alpha-cell
proliferation

104. SUMMARY
 Era of personalized medicine, surgical pathologists play a central role in the
multidisciplinary care
 Specific genotype-phenotype correlations are harbingers of familial tumor
syndromes.
 Rapidly growing field of “molecular histopathology,” - Predict mutations
 Detailed morphologic evaluation of the tumorous and nontumorous parenchyma
 New and emerging immunohistochemical tools confirm an underlying genetic
defect
 Accurate recognition of these features is of clinical significance
 Alert to the possibility of an underlying tumor syndrome (especially in unsuspected de
novo disease),
 Confirm syndromic manifestations to facilitate a clinical diagnosis,
 Triage patients for genetic testing

105. Thank you