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PRIMARY HYPERPARATHYROIDISM: A CURRENT PERSPECTIVE

Ronald A. DeLellis, M.D. Professor of Pathology, The Warren Alpert Medical School of Brown University and Pathologist-in-Chief, Rhode Island Hospital and The Miriam Hospital Providence, Rhode Island

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

INDIAN RHINOCEROS

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PROF. R OWEN: ANATOMY OF THE INDIAN RHINOCEROS

Chief Complaint: Anorexia in July, 1849 when it was under the influence of the rut* Course: Vomiting, progressive deterioration. g p g Died November, 1849 Autopsy: Fractured 7th rib with extension into the lung. Ankylosis of dorsal vertebrae (5-7) * Periodic sexual excitement of certain mammals, esp. to males, often specific to those male ruminants in whom it occurs once per year

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

"Our able and active Secretary has reminded Our me that at the time when the large male elephant was exhibited with the rhinoceros in a contiguous paddock, the latter used to submit to the be poked on the back by the elephant who elephant, would lift his head over the pailings and press down with his tusks upon the thick hide of the rhinoceros; and that the rhinoceros had been observed to have been thus forced down until his belly touched the ground"

(Proceedings of the Royal Society)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

SIR RICHARD OWEN

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

IVAR VIKTOR SANDSTRÖM (1852-89) (1852 89)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

NORMAL PARATHYROIDS

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

HISTORICAL ASPECTS

1891 1925 1926 Relationship of parathyroid glands to cysticbone disease (von Recklinghausen) First successful removal of parathyroid tumor in Vienna (Prof. F. Mandl) Albert J First successful removal of parathyroid tumor in US (Drs. Churchill and Cope) ( p ) Capt. Charles Martell

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

CAPTAIN MARTELL

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

BONE CHANGES (Primary Hyperparathyroidism)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

HYPERPARATHYROIDISM

"renal stones, painful bones (osteitis fibrosa cystica), abdominal moans (gastric ulcer, pancreatitis), psychic overtones (depression) and fatigue overtones" t "

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PRIMARY HYPERPARATHYROIDISM

·E Excessive and d i d dysregulated secretion of l t d ti f PTH from one or more enlarged parathyroid glands i th absence of a th id l d in the b f known stimulus for PTH secretion (e.g. renal failure) l f il ) · M bili ti of calcium f Mobilization f l i from b bone, renal conservation of calcium and increased GI resorption of calcium i d ti f l i

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

AGE SPECIFIC INCIDENCE RATES OF HYPERPARATHYROIDISM

160 New Ca ases/100,000 120 80 40 0 <39 40-59 40 59 >60 Age (Years)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

1965-74 1974-76

Pop pulation

PRIMARY HYPERPARATHYROIDISM

100

Renal Asymptomatic

% Patien nts

50

Bone

0 '48 '61' '69

Year at Diagnosis

'71

'74

'78

'80

'83

'90

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PRIMARY HYPERPARATHYROIDISM

% Adenoma Carcinoma Chief cell hyperplasia Clear cell hyperplasia 85 2-3 12 (rare)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

BENJAMIN CASTLEMAN, M.D.

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA: Castleman (1952 AFIP Atl ) C tl Atlas)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA (IPX for PTH)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

ADENOMA ASSOCIATED PARATHYROID

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

OIL RED O

ADENOMA ASSOCIATED SSOC PARATHYROID GLAND

ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA (MITOSIS)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA

Mitoses 0 < 1/10 HPF >1/10 HPF / 0 % Cases 29 59 12

Snover and Foucar, 1981

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA ( (FOLLICULAR) )

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA (CLEAR CELL)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID ADENOMA (Oncocytic Type)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

ONCOCYTIC ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

LIPOADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

MOLECULAR FEATURES OF PARATHYROID ADENOMAS

· M Monoclonal proliferations l l lif ti · Pericentromeric inversion of chromosome 11 with breakpoints at 11q13 and 11p15 results in PTH-PRAD1 rearrangement leading to overexpression of cyclin D1 · LOH at MEN1 locus of 11q13 is present in 25-40% of adenomas with somatic homozygous mutations of MEN1 gene in 50% of these cases

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

EVOLUTION OF PARATHYROID SURGERY

· Conventional open parathyroidectomy · Open minimal access parathyroidectomy · Endoscopic parathyroidectomy

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

SESTAMIBI IODINE SUBTRACTION SCAN DEMONSTRATING R LOWER PARATHYROID ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

INTRAOPERATIVE PTH ASSAY (SINGLE ADENOMA) (S G A O A) 100

% PTH FALL L

50

90%

0

5m ion on cis i cis 10

90%

Pr e-

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

Ex

In

m

100

% PTH FALL

INTRAOPERATIVE PTH ASSAY (DOUBLE ADENOMAS)

*

50

30% 60%

0

5m 5m io n on m 2 10 i si cis n# 10 m

in c

Ex

e-

Pr

* Second enlarged gland

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

Pr

e-

ex

ci s

io

PARATHYROID CARCINOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID CARCINOMA

· Low malignant p g potential with tendency y for local recurrence · 50% cured by en bloc resection · Mean time to recurrence approximately 33 months · Late development of metastases (lymphatic and hematogenous) in 35% of cases f

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

METASTATIC PARATHYROID CARCINOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID CARCINOMA

% Thick fibrous bands Mitotic Activity Capsular invasion Vascular i V l invasion i 90 80 65 15

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID CARCINOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID CARCINOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID CARCINOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID CARCINOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID CARCINOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID CARCINOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID CARCINOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

Rb Protein (% Positive)

Adenoma Carcinoma Cryns et al (1994) Vargas et al (1997) Farnebo et al (1999) 100 100 25 12.5 82 73

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

FAMILIAL HYPERPARTHYROID SYNDROMES

Syndrome

Multiple endocrine neoplasia 1 p p Multiple endocrine neoplasia 2 Hyperparathyroidism-jaw t H th idi j tumor syndrome Familial isolated hyperparathyroidism Familial hypocalciuric hypercalcemia Neonatal severe hyperparathyroidism Autosomal dominant mild hyperparathyroidism h th idi

Gene

MEN1 RET HRPT2 MEN1, HRPT2, CaSR CaSR CaSR CaSR

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

HEREDITARY HYPERPARATHYROIDISM ­ JAW TUMOR SYNDROME (HPT-JT)

· Autosomal dominant · Primary HPT, ossifying fibromas HPT (mandible, maxilla ), renal cysts, Wilms' tumor · Multiple parathyroid adenomas (cystic) and carcinoma ( i ) d i g ( q q ) · Mutations of HRPT gene (1q25-q-32) which encodes parafibromin

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARATHYROID CARCINOMA

· Carcinomas from 10 of 15 patients had HRPT mutations · 3 patients with apparent sporadic parathyroid carcinomas had germline HRPT mutations and might represent a phenotypic variant of the syndrome

Shattuck et al (2003)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

HRPT2 GENE/ PARAFIBROMIN

· C i t of 17 exons Consists f · Maps to 1q32.1 p q · Tumor suppressor gene · Encodes parafibromin (531aa), a transcription factor associated with the PAF complex · Functions are mediated by transcriptional g growth factors regulation of g

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARAFIBROMIN IN PARATHYROID TUMORS*

Carcinoma Equivocal (Atypical adenoma) Adenoma Adenoma (HPT JT (HPT-JT associated) Total Cases C 96 21 215 13 Neg. 84 10 4 11 Pos. 12 11 211 2

*Based *B d on Tan et al (2004), Cetani et al (2004), Juhlin et al T t l (2004) C t i t l (2004) J hli t l (2007), Cetani et al (2007)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARAFIBROMIN (ADENOMA)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PARAFIBROMIN (CARCINOMA)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

ATYPICAL ADENOMA

A tumor of unknown behavior that exhibits some of the characteristics of parathyroid carcinoma but f i i which lacks evidence of invasion (soft tissue, perineural spaces, blood vessels) or metastasis

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

ATYPICAL PARATHYROID ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

ATYPICAL ADENOMA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

MOLECULAR ANALYSIS

[p27(+), Bcl-2(+), Ki-67(-), mdm2(+)]

% Adenoma Atypical adenoma Carcinoma

Stojadinovic et al, 2003

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

76 29 0

PRIMARY CHIEF CELL HYPERPLASIA

An increase in parenchymal mass involving multiple parathyroid glands in the absence of a known stimulus for PTH hypersecretion

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PRIMARY CHIEF CELL HYPERPLASIA

Type Sporadic Familial % 75 25

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

MEN SYNDROMES

Type T MEN1 MEN2A MEN2B %PT >90 90 30-40 Rare

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

MEN 1 MUTATIONS

· Found in 80-90% of index cases of MEN1 · Remainder represent mutations in untested parts of the MEN1 gene or large deletions that are not detectable by PCR

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

MEN 1 TUMORS

Type yp Parathyroid Enteropancreatic E t ti Pituitary y Carcinoid Adrenal Ad l Thyroid No. (%) ( ) 129 (99) 86 (66) 61 (47) ( ) 21 (16) 21 (16) 16 (12)

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

PRIMARY CHIEF CELL HYPERPLASIA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

NODULAR CHIEF CELL HYPERPLASIA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

NODULAR CHIEF CELL HYPERPLASIA

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

SUMMARY

· P i Primary hyperparathyroidism (P HPT) is one h th idi (P-HPT) i of the most common of all endocrine disorders · Studies of heritable HPT syndromes have provided i i ht i t th molecular id d insights into the l l mechanisms underlying sporadic parathyroid proliferative lesions · S t ibi scanning and the rapid Sestamibi i d th id intraoperative PTH assay have revolutionized the management of patients with P HPT P-HPT

©2009, Ronald A. DeLellis, M.D. and the New England Society of Pathologists, Inc.

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