Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Primary hyperparathyroidism (PHPT):
  • Is caused by an increased secretion of parathyroid hormone (PTH) by the parathyroid gland(s):
    • Which leads to an elevated serum calcium level
• The overproduction of parathyroid hormone (PTH):
  • Termed hyperparathyroidism (HPT), can be categorized as:
    • Primary
    • Secondary
    • Tertiary
• Primary hyperparathyroidism (PHPT);
  • Arises from an unregulated overproduction of PTH from an abnormal parathyroid gland
• Increased PTH levels may also occur as a compensatory response to hypocalcemic states resulting from:
  • Chronic renal failure or gastrointestinal (GI) malabsorption of calcium:
    • This secondary HPT can be reversed by the correction of the underlying problem:
      • For example kidney transplantation for chronic renal failure
• However, chronically stimulated parathyroid glands:
  • May occasionally become autonomous:
    • Resulting in the persistence or recurrence of the hypercalcemia after successful renal transplantation:
      • Resulting in tertiary HPT
• PHPT is defined as:
  • Hypercalcemia or widely fluctuating levels of serum calcium resulting from:
    • The inappropriate or autogenous secretion of PTH:
      • By one or more parathyroid glands:
        • In the absence of a known or recognized stimulus
• The most common cause of hypercalcemia in the outpatient setting is:
  • Primary hyperparathyroidism (PHPT):
    • With approximately 100,000 new cases per year reported in the United States
• Since the advent of routine laboratory testing:
  • The prevalence of the disease has increased from:
    • 0.1% to 0.4%:
      • One to seven cases per 1000 adults
• In a study by Yeh et al:
  • The incidence of PHPT fluctuated between:
    • 36.3 and 120.2 cases per 100,000 women-years
    • 13.4 and 35.6 in 100,000 men-years
• PHPT may present at any age:
  • With the vast majority of cases occurring in patients older than 45 years of age
  • The mean age at diagnosis has remained between:
    • 52 and 56 years
• Women have consistently made up the preponderance of cases:
  • With a female-to-male ratio of:
    • 3:1 to 4:1
  • Based on a population based study from Rochester Minnesota:
    • The higher incidence of this could be secondary (hypothetically) to:
      • Estrogen deficiency after menopause:
        • That reveals underlying HPT
• The precise origin of PHPT is unknown:
  • Although exposure to low-dose therapeutic ionizing radiation and familial predisposition account for some cases:
    • Irradiation for acne could have accounted for a 2 to 3-fold increase in the incidence of this disease at some point in time, and a 4-fold increase was noted in survivors of the atomic bomb
  • Schneider et al., in their study of 2555 patients followed for 50 years, even low doses of radiation exposure during the teenage years:
    • Was associated with a slight risk of developing PHPT
    • In this study a dose response was documented in people receiving external-beam radiotherapy for benign diseases before their 16th birthday
    • The latency period for the development of PHPT after radiation exposure:
      • Is longer than that for the development of thyroid tumors, with most cases occurring 30 to 40 years after exposure
  • Patients who have been radiated have similar clinical manifestations and serum calcium levels when compared to patients without a history of radiation exposure:
    • However, the former tend to have higher PTH levels and a higher incidence of concomitant thyroid neoplasms
• Certain medications have been implicated in the development of hypercalcemia:
  • Lithium therapy has been known to:
    • Shift the set point for PTH secretion in parathyroid cells:
      • Thereby resulting in elevated PTH levels and mild hypercalcemia
  • Lithium stimulates the growth of abnormal parathyroid glands in vitro and also in susceptible patients in vivo
  • Unusual metabolic features associated with lithium use include:
    • Low urinary calcium excretion
    • Normal cyclic AMP excretion
    • Lack of calcic nephrolithiasis
  • The mechanism probably results from:
    • Lithium linking with the calcium sensing receptor on the parathyroid glands resulting in PTH secretion
• Elevated serum calcium levels have been associated with thiazide diuretic:
  • The overall annual age- and sex-adjusted (to 2000 U.S. whites) incidence was:
    • 7.7 (95% CI, 5.9 to 9.5) per 100,000 individuals
  • The average 24-hour plasma calcium concentrations are increased with thiazide diuretic use:
    • But the mean 24-hour PTH levels remain unchanged in subjects with normal baseline PTH levels and no evidence of hypercalciuria
  • Thiazides diuretics have several metabolic effects that may contribute to increased calcium levels:
    • A decrease in urine calcium excretion is the most likely cause:
      • But in some cases diuretic use has been associates with a metabolic alkalosis:
        • That could also increase the total serum calcium levels through a pH-dependent increase in protein-bound calcium
    • Although plasma 1,25 (OH) vitamin D levels are unchanged:
      • Increased intestinal calcium absorption in response to thiazide diurectic use:
        • Has been noted and could also contribute to an increase in serum calcium
    • One last possible explanation for the elevated serum calcium levels associated with thiazide diuretic use is:
      • Hemoconcentration associated with dieresis
• Numerous genetic abnormalities have been identified in the development of PHPT, including:
  • Anomalies in tumor suppressor genes and proto-oncogenes
  • Specific DNA mutations in a parathyroid cell:
    • May confer a proliferative advantage over normal neighboring cells:
      • Thus allowing for clonal growth:
        • Large populations of these altered cells containing the same mutation within hyper functioning parathyroid tissue:
          • Suggest that such glands are a result of clonal expansion
  • The majority of PHPT cases are:
    • Sporadic
  • Nonetheless, PHPT also occurs within the spectrum of a number of inherited disorders such as:
    • Multiple endocrine neoplasia syndromes (MEN):
      • MEN type 1 (Wermer Syndrome)
      • MEN type 2A (Sipple Syndrome)
    • Isolated familial HPT
    • Familial HPT with jaw-tumor syndrome
  • All of these are inherited in an:
    • Autosomal dominant fashion
• The earliest and most common presentation of MEN type 1 (Wermer Syndrome):
  • Is PHPT:
    • Develops in approximately 80% to 100% of patients by age 40 years
  • These patients also are predisposed to the development of:
    • Pancreatic neuroendocrine tumors
    • Pituitary adenomas
    • Less frequently:
      • Skin angiomas
      • Lipomas
      • Adrenocortical tumors
      • Neuroendocrine tumors of the:
        • Thymus
        • Bronchus
        • Stomach
    • MEN type 1 has been shown to result from:
      • A germline mutation in a tumor suppressor gene:
        • Called MEN1 gene:
          • Located on chromosome 11q12-13 that encodes Menin:
            • A protein that is postulated to interact with the transcription factors JunD and nuclear factor-κB in the nucleus, in addition to replication protein A and other proteins
    • Pre-symptomatic screening for mutation carriers for MEN type 1:
      • Is difficult because generally MEN1 mutations result in a nonfunctional protein and are scattered throughout the translated nine exons of the gene
    • MEN1 mutations also have been found in kindred’s initially suspected to represent isolated familial HPT
    • Screening for mutation carriers for MEN type 1 has a very high detection rate greater than 94%, and is used in Sweden for patients with:
      • PHPT with a first-degree relative with a major endocrine tumor, age of onset is less than 30 years and / or if multiple pancreatic tumors / parathyroid hyperplasia is detected
• Approximately 20% of patients with MEN type 2A (Sipple Syndrome):
  • Develop PHPT:
    • Which is usually less severe
  • MEN type 2A is caused by:
    • A germline mutation of the RET proto-oncogene:
      • Located on chromosome 10
  • Genotype and phenotype correlations have been noted in this syndrome:
    • In that individuals with mutations at codon 634:
      • Are more likely to develop PHPT
• Patients with the familial HPT with jaw-tumor syndrome:
  • Have an increased predisposition to:
    • Parathyroid carcinoma
  • This syndrome maps to a tumor suppressor locus HRPT2 (parafibromin):
    • On chromosome 1
• Sporadic parathyroid adenomas and some hyperplastic parathyroid glands:
  • Have loss of heterozygosity (LOH) at 11q13:
    • The site of the MEN1 gene in approximately 25% to 40% of the cases
• Over expression of PRAD1:
  • Which encodes cyclin D1:
    • A cell cycle control protein:
      • Is found approximately 18% of parathyroid adenomas
  • This was proven to result from a rearrangement on chromosome 11:
    • That places the PRAD1 gene:
      • Under the control of the PTH promoter
• Other chromosomal regions deleted in parathyroid adenomas and possibly reflecting loss of tumor suppressor genes include:
  • 1p
  • 6q
  • 15q
• Amplified regions suggesting oncogenes have been identified at:
  • 16p
  • 19p
• RET mutations:
  • Are unusual in sporadic parathyroid tumors
• Sporadic parathyroid cancers are characterized by:
  • Uniform loss of the tumor suppressor gene RB:
    • Which is involved in cell cycle regulation
  • 60% have HRPT2 (CDC73) mutations located in chromosome 1:
    • Encodes the protein Parafibromin
  • These alterations are rare in benign parathyroid tumors;
    • May have implications for diagnosis
  • The p53 tumor suppressor gene:
    • Is also inactivated in a subset (30%) of parathyroid carcinomas
• Single gland adenoma:
  • Is the most common cause (75% to 90%) of PHPT
• Lower pole adenomas (in relation to the thyroid):
  • Are more common than are upper pole adenomas
• Sizes range from 1 cm to 3 cm:
  • The normal parathyroid gland measures approximately 6 mm X 4 mm X 2 mm
• The weight of parathyroid adenomas vary between:
  • 553.7 mg +/- 520.5 mg (range, 66-2536):
    • The normal weight of a parathyroid gland is:
      • Approximately 40 mg to 50 mg
• Ectopic glands can be present:
  • 4% to 16% of cases
• PHPT is caused by multiple adenomas or hyperplasia in:
  • 15% to 25% of the cases
• Parathyroid carcinoma as the cause of PHPT:
  • Is extremely rare in most parts of the world (~1%)
• Multi-gland adenoma arises in a significant number of patients:
  • Double adenomas are seen in approximately:
    • 2% to 12% of the cases
  • Triple adenomas:
    • In less than 1% the cases
  • Four adenomas or parathyroid gland hyperplasia:
    • In less than 3% to 15% of the cases
• Most parathyroid adenomas:
  • Consist of parathyroid chief cells
  • They are usually encapsulated
  • In 50% of the cases they are surrounded by normal parathyroid tissue
  • Some adenomas, nevertheless, are composed of oxyphil cells:
    • These adenomas are usually larger than chief cell adenomas
• Parathyroid adenomas are sometimes located within the thymus:
  • They express a parathyroid-specific gene:
    • GCMB
  • Contrasting with the normal thymus:
    • Which does not neither express PTH nor GCMB
• In a study by Ruda et al:
  • 225 patients with PHPT:
    • Parathyroid hyperplasia accounted for approximately 6% of cases
• In parathyroid hyperplasia all four glands are enlarged:
  • With the lower glands typically being larger than the upper time
  • The glands are usually composed of:
    • Chief cells
  • Clear cell hyperplasia is very rare and is the only one in which the upper parathyroid glands are larger than the lower ones

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #Hyperparathyroidism #PrimaryHyperparathyroidism #CancerSurgeon #EndocrineSurgery #Teacher #Surgeon #HeadandNeckSurgeon #SurgicalOncologist #ParathyroidAdenoma #Hypercalcemia #ElevatedCalciumLevels #Miami #MountSinaiMedicalCenter #MSMC #Mexico #Hialeah

• Axillary pCR in ER⁺ / HER2⁻ Breast Cancer after neoadjuvant chemotherapy (NACT):
  • Neoadjuvant chemotherapy is commonly used to downstage axillary disease in node-positive breast cancer:
    • However, ER – positive, HER2 – negative tumors:
      • Especially luminal A subtype:
        • Are less responsive to chemotherapy compared to triple-negative or HER2-positive tumors

• Interpretation and Considerations:
  • Luminal A tumors (low Ki-67):
    • Typically show < 10% pCR
  • Luminal B tumors (higher proliferative index):
    • Achieve up to 20% to 25% axillary pCR
  • Hormone receptor positivity:
    • Correlates inversely with chemotherapy response
  • Axillary response:
    • May exceed breast pCR in some ER+ / HER2− patients:
      • Isolated nodal clearance
  • Ki-67 and genomic assays (e.g., Oncotype DX, MammaPrint):
    • May predict likelihood of response
• Clinical Implications:
  • Lower pCR in ER+ / HER2-:
    • Supports careful use of NACT primarily for:
      • Tumor downsizing in borderline resectable disease
      • Downstaging axilla to avoid ALND:
        • If cN1 → ypN0
      • Surgical planning should consider likelihood of residual disease:
        • Particularly in low-proliferative tumors
  • Role for post-NACT axillary imaging and sentinel lymph node biopsy remains critical in this group

• Key References:
  • Cortazar P, et al. Lancet. 2014;384(9938):164–72. PMID: 25456301
  • Mamtani A, et al. Ann Surg Oncol. 2016;23(10):3374–81. PMID: 26643802
  • Barrio AV, et al. Ann Surg Oncol. 2021;28(11):6090–6097. PMID: 34047660
  • Boughey JC, et al. J Am Coll Surg. 2014;219(4):740–746. PMID: 25456736
  • Kuehn T, et al. Lancet Oncol. 2013;14(7):609–18. PMID: 23836191
  • Tolaney SM, et al. Nat Commun. 2020;11(1):5485. PMID: 33199856

👉All patients with primary hyperparathyroidism may be considered for parathyroid surgery, guidelines also include osteoporosis, kidney stones, and very high blood calcium levels as strong indications for surgery

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #HeadandNeckSurgeon #MountSinaiMedicalCenter #MSMC #Miami #Mexico #EndocrineSurgery

• Definition of problem:
  • Primary hyperparathyroidism (PHPT):
    • Is the unregulated overproduction of parathyroid hormone (PTH) resulting in abnormal calcium homeostasis
• Frequency:
  • Primary hyperparathyroidism is more common in women:
    • The incidence being:
      • 66 per 100,000 person-years in females
      • 25 per 100,000 person-years in males
  • In a large study of 3.5 million enrollees in Kaiser Permanente of Southern California:
    • The incidence fluctuated over time but was not seen to decrease substantially​
    • On the contrary, the prevalence of primary hyperparathyroidism saw a substantial increase in this population
  • The mean age at diagnosis has remained between:
    • 52 and 56 years
• Etiology:
  • In approximately 85% to 90% of cases:
    • Primary hyperparathyroidism is caused by:
      • A single adenoma
  • In 15% of cases:
    • Multiple glands are involved:
      • Multiple adenomas:
        • Doble adenomas
        • Triple adenomas
      • Hyperplasia (4 glands)
  • Rarely, primary hyperparathyroidism is caused by parathyroid carcinoma
  • The etiology of adenomas or hyperplasia:
    • Remains unknown in most cases
  • Familial cases can occur as either part of the:
    • Multiple endocrine neoplasia syndromes (MEN 1 or MEN 2a)
    • Hyperparathyroid-jaw tumor (HPT-JT) syndrome
    • Familial isolated hyperparathyroidism (FIHPT)
    • Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism also belong to this category
  • The molecular genetic basis of MEN 1 (Wermer Syndrome):
    • Is an inactivating mutation of the MEN1 gene:
      • Located on chromosome band 11q13
  • MEN 2a is caused by a:
    • Germline mutation of the Ret proto-oncogene on chromosome 10. 
  • Germline mutation of HRPT2 localized on chromosome arm 1q:
    • Is responsible for HPT-JT
• While FIHPT is genetically heterogeneous

#Arrangoiz #ParathyroidSurgeon #ParathyroidSurgeon #HeadandNeckSurgeon #EndocrineSurgery #Hyperparathyroidism #MSMC #MountSinaiMedicalCenter #Mexico #Miami

• The exact cause of PHPT is unknown:
  • Although exposure to low-dose therapeutic ionizing radiation and familial predisposition account for some cases
  • Various diets and intermittent exposure to sunshine may also be related
  • Other causes include:
    • Renal leak of calcium
    • Declining renal function:
      • With age
    • Alteration in the sensitivity of parathyroid gland:
      • To be suppression by calcium
• The latency period for development of PHPT after radiation exposure:
  • Is longer than that for the development of thyroid tumors:
    • With most cases occurring 30 to 40 years after exposure
  • Patients who have been exposed to radiation:
    • Have similar clinical presentations and calcium levels when compared to patients without a history of radiation exposure:
      • However, the former tend to have higher PTH levels and a higher incidence of concomitant thyroid neoplasms
• Lithium therapy:
  • Has been known to shift the set point for PTH secretion in parathyroid cells:
    • Thereby resulting in elevated PTH levels and mild hypercalcemia
  • Lithium stimulates the growth of abnormal parathyroid glands in vitro and also in susceptible patients in vivo
• PHPT results from the enlargement of a single gland or parathyroid adenoma:
  • In approximately 80% to 95% of cases
  • Multiple gland disease in seen in 15% to 20% of the cases:
    • Doble adenomas 6% to 9% of cases:
      • This entity is less common in younger patients but is more prevalent in older patients
    • Triple adenomas < 0.3% of cases
    • Four gland hyperplasia 3% of cases
  • Parathyroid carcinoma:
    • In 1% of patients
• It should be emphasized that when more than one abnormal parathyroid gland is identified preoperatively or intraoperatively:
  • The patient has hyperplasia (all glands abnormal) until proven otherwise
• Genetics of PHPT:
  • Most cases of PHPT are sporadic:
    • However, PHPT also occurs within the spectrum of a number of inherited disorders such as:
      • MEN1 (Wermers Syndrome)
      • MEN2A (Sipple Syndrome)
      • Isolated familial HPT
      • Familial HPT with jaw-tumor syndrome
    • All of these syndromes are inherited in an autosomal dominant fashion
  • MEN type 1 Wermers Syndrome:
    • PHPT is the earliest and most common manifestation of MEN1:
      • It develops in 80% to 100% of patients by age 40 years old
    • These patients also are prone to:
      • Pancreatic neuroendocrine tumors:
        • About 50% of patients develop gastrinomas:
          • Which often are multiple and metastatic at diagnosis
        • Insulinomas develop in 10% to 15% of cases
        • Whereas many patients have nonfunctional pancreatic endocrine tumors
      • Pituitary adenomas:
        • Prolactinomas occur in 10% to 50% of MEN1 patients and constitute the most common pituitary lesion
      • Less commonly, to:
        • Adrenocortical tumors
        • Lipomas
        • Skin angiomas
        • Carcinoid tumors of the bronchus, thymus, or stomach
    • MEN1 has been shown to result from germline mutations in the MEN1 gene:
      • A tumor suppressor gene:
        • Located on chromosome 11q12-13:
          • That encodes menin:
            • A protein that is postulated to interact with the transcription factors JunD and nuclear factor-κB in the nucleus, in addition to replication protein A and other proteins
      • Most MEN1 mutations result in a nonfunctional protein and are scattered throughout the translated nine exons of the gene:
        • This makes presymptomatic screening for mutation carriers difficult
      • MEN1 mutations also have been found in kindreds initially suspected to represent isolated familial HPT
  • MEN type 2A Sippple Syndrome:
    • HPT develops in about 20% of patients with MEN2A:
      • It is generally is less severe
    • MEN2A is caused by germline mutations of the RET proto-oncogene:
      • Located on chromosome 10
    • In contrast to MEN1:
      • Genotype-phenotype correlations have been noted in this syndrome:
        • In that individuals with mutations at codon 634 are more likely to develop HPT
  • Patients with the familial HPT with jaw-tumor syndrome:
    • Have an increased predisposition to parathyroid carcinoma
    • This syndrome maps to a tumor suppressor locus HRPT2 (CDC73 or parafibromin):
      • On chromosome 1
  • Patients belonging to isolated HPT kindreds:
    • Also appear to demonstrate linkage to HRPT2
  • Approximately 25% to 40% of sporadic parathyroid adenomas and some hyperplastic parathyroid glands:
    • Have loss of heterozygosity (LOH) at 11q13:
      • The site of the MEN1 gene
  • The parathyroid adenoma 1 oncogene (PRAD1):
    • Which encodes cyclin D1:
      • A cell cycle control protein:
        • Is overexpressed in about 18% of parathyroid adenomas
    • This was demonstrated to result from a rearrangement on chromosome 11 that places the PRAD1 gene:
      • Under the control of the PTH promoter
  • Other chromosomal regions deleted in parathyroid adenomas and possibly reflecting loss of tumor suppressor genes include:
    • 1p, 6q, and 15q
    • RET mutations are rare in sporadic parathyroid tumors
    • Sporadic parathyroid cancers:
      • Are characterized by uniform loss of the tumor suppressor gene RB:
        • Which is involved in cell cycle regulation
      • 60% have HRPT2 (CDC73) mutations
        • These alterations are rare in benign parathyroid tumors and may have implications for diagnosis
  • Whereas amplified regions suggesting oncogenes have been identified at 16p and 19p
  • The p53 tumor suppressor gene is also inactivated in a subset (30%) of parathyroid carcinomas

• Guidelines for the management of asymptomatic primary hyperparathyroidism (PHPT):
  • Were updated in 2013 by the Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism
• Indications for surgery include the following:
  • Serum calcium :
    • 1 mg/dL above the upper limit of the reference range
  • Bone mineral density T-score:
    • At or below -2.5 SD (in perimenopausal or postmenopausal women and in men aged 50 years or older):
      • At the lumbar spine, total hip, femoral neck, or distal 1/3 radius
  • Vertebral fracture:
    • As evidenced via radiography or vertebral fracture assessment (VFA)
  • Creatinine clearance of:
    • Less than 60 ml/min
  • Twenty-four–hour urinary calcium excretion:
    • Greater than 400 mg/day and increased stone risk as assessed through biochemical stone risk analysis
  • Presence of nephrolithiasis or nephrocalcinosis as determined using radiography, ultrasonography, or CT scanning
  • Age younger than 50 years

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• No study has yet identified a reliable predictor:
  • For determining which patients with sporadic hyperparathyroidism:
    • Will have multigland disease:
      • The exception is in familial, secondary, and tertiary hyperparathyroidism:
        • Because of the nearly uniform incidence of four-gland hyperplasia:
          • All these patients are managed with bilateral neck exploration:
            • And either total parathyroidectomy with autotransplantation or three-and-a-half gland parathyroidectomy
• Although some surgeons believe that patients with higher preoperative PTH or calcium levels (or both):
  • Are more likely to have multi-gland disease:
    • This has not been proved to be true in clinical studies

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• Numerous genetic abnormalities have been identified in the development of PHPT, including:
  • Anomalies in tumor suppressor genes
  • Proto-oncogenes
• Specific DNA mutations in a parathyroid cell:
  • May confer a proliferative advantage over normal neighboring cells:
    • Thus allowing for clonal growth:
      • Large populations of these altered cells containing the same mutation within hyperfunctioning parathyroid tissue:
        • Suggest that such glands are a result of clonal expansion
• The majority of PHPT cases are:
  • Sporadic
• Nonetheless, PHPT also occurs within the spectrum of a number of inherited disorders such as:
  • Multiple endocrine neoplasia syndromes (MEN):
    • MEN type 1 (Wermer Syndrome)
    • MEN type 2A (Sipple Syndrome)
    • Isolated familial HPT
    • Familial HPT with jaw-tumor syndrome
      • All of these syndromes are inherited in an:
        • Autosomal dominant fashion
• MEN type 1 (Wermer Syndrome):
  • The earliest and most common presentation of MEN type 1 is:
    • PHPT:
      • Develops in approximately 80% to 100% of patients:
        • By age 40 years
  • These patients also are predisposed to the development of:
    • Pancreatic neuroendocrine tumors
    • Pituitary adenomas
    • Less frequently:
      • Skin angiomas
      • Lipomas
      • Adrenocortical tumors
      • Neuroendocrine tumors of the:
        • Thymus
        • Bronchus
        • Stomach
  • MEN type 1 has been shown to result from:
    • A germline mutation in a tumor suppressor gene:
      • Called MEN1 gene:
        • Located on chromosome 11q12-13:
          • That encodes Menin:
            • A protein that is postulated to interact with the transcription factors JunD and nuclear factor-κB in the nucleus, in addition to replication protein A and other proteins
  • Pre-symptomatic screening for mutation carriers for MEN type 1 is difficult:
    • Because generally MEN1 mutations result in a nonfunctional protein and are scattered throughout the translated nine exons of the gene
  • MEN1 mutations also have been found in kindred’s initially suspected to represent isolated familial HPT
  • Screening for mutation carriers for MEN type 1:
    • Has a very high detection rate:
      • Greater than 94%
    • In Sweden it is used for patients with PHPT with a first-degree relative with a:
      • Major endocrine tumor
      • Age of onset is less than 30 years and/or
      • If multiple pancreatic tumors / parathyroid hyperplasia is detected
• MEN type 2A (Sipple Syndrome):
  • Approximately 20% of patients with MEN type 2A develop PHPT:
    • Which is usually less severe
  • MEN type 2A is caused by a:
    • Germline mutation of the RET proto-oncogene:
      • Located on chromosome 10
    • Genotype and phenotype correlations have been noted in this syndrome:
      • In that individuals with mutations at:
        • Codon 634 are more likely to develop PHPT
• Patients with the familial HPT with jaw-tumor syndrome:
  • Have an increased predisposition to:
    • Parathyroid carcinoma
  • This syndrome maps to a tumor suppressor locus:
    • HRPT2 (parafibromin):
      • On chromosome 1
• Sporadic parathyroid adenomas and some hyperplastic parathyroid glands:
  • Have loss of heterozygosity (LOH) at 11q13:
    • The site of the MEN1 gene:
      • In approximately 25% to 40% of the cases
• Over expression of PRAD1:
  • Which encodes cyclin D1:
    • A cell cycle control protein:
      • Is found approximately 18% of parathyroid adenomas
  • This was proven to result from a rearrangement on chromosome 11:
    • That places the PRAD1 gene under the control of the PTH promoter
• Other chromosomal regions deleted in parathyroid adenomas and possibly reflecting loss of tumor suppressor genes include:
  • 1p, 6q, and 15q
• Amplified regions suggesting oncogenes have been identified at:
  • 16p and 19p
• RET mutations:
  • Are unusual in sporadic parathyroid tumors
• Sporadic parathyroid cancers:
  • Are characterized by uniform loss of the:
    • Tumor suppressor gene RB
      • Which is involved in cell cycle regulation
  • 60% have HRPT2 (CDC73) mutations
  • These alterations are rare in benign parathyroid tumors:
    • May have implications for diagnosis
  • The p53 tumor suppressor gene is also inactivated in a subset (30%) of parathyroid carcinomas

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #PHPT #HeadandNeckSurgeon #CASO #CenterforAdvancedSurgicalOncology #EndocrineSurgery

• Hyperparathyroidism can be diagnosed during pregnancy and should be closely monitored to prevent complications associated with hypercalcemia.
• Mild hypercalcemia in gestational PHPT is generally not associated with an increased risk of obstetrical complications.
• https://academic.oup.com/jcem/article/100/5/2115/2829737

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• During the fifth to sixth week of intrauterine development:
  • The embryonic pharynx is marked:
    • Externally by:
      • Four branchial clefts of ectoderm origin
    • Internally by:
      • Five branchial pouches of endoderm origin
• The branchial apparatus:
  • Is made up by the branchial clefts and branchial pouches:
    • Together with the branchial arches of mesoderm origin:
      • Found in between them
  • This apparatus undergoes normal involution:
    • Leaving behind some derivatives which include the thyroid gland, parathyroid glands, thymus, ultimobranchial body, Eustachian tube, middle ear, and external auditory canal
• The parathyroid glands:
  • Develop as epithelial thickenings of the dorsal endoderm of the third and fourth branchial pouches
• The superior parathyroid glands:
  • Are derived from the fourth branchial pouch:
    • Which also gives rise to the thyroid gland
• The inferior parathyroid glands:
  • Are derived from the third branchial pouch:
    • Which also gives rise to the thymus
• The parathyroid glands:
  • Remain intimately connected with their respective branchial pouch derivatives
• The normal anatomic location of the superior parathyroid glands:
  • Is more constant than the inferior parathyroid glands:
    • With 80% of the superior glands being found near the posterior aspect of the thyroid gland at the junction of the upper and middle portion of the thyroid lobes:
      • At the level of the cricoid cartilage:
        • Each gland with its own capsule of connective tissue
  • Roughly one percent of the superior parathyroid glands;
    • May be found in the paraesophageal or retroesophageal space
  • Enlarged superior glands may descend in the tracheoesophageal groove and come to lie below the inferior parathyroid glands
  • Truly ectopic superior parathyroid glands:
    • Are extremely rare:
      • But may be localized to the middle or posterior mediastinum or in the aortopulmonary window 
• During intrauterine development, the thymus and the inferior parathyroid glands migrate caudally in the neck:
  • The most common location for the inferior parathyroid glands:
    • Is within a distance of 1 cm from a point centered where the inferior thyroid artery and the recurrent laryngeal nerve (RLN) cross
  • Approximately 15% to 50% of the inferior glands:
    • Are found in the thymus
  • The position of the inferior parathyroid glands:
    • However, tends to be more variable:
      • Due to their longer migratory route
  • Undescended inferior glands:
    • May be found near the skull base, angle of the mandible, or above the superior parathyroid glands along with an undescended thymus
• The frequency of intrathyroidal glands:
  • Is approximately 2% 
• There are normally two pairs of parathyroid glands (inferior and superior)
  • The parathyroid gland:
    • Is oval or bean-shaped (Figure)
    • It typically measures 6 mm × 4 mm × 2 mm
    • Weighs 40 mg to 60 mg

• Most people have four parathyroid glands:
  • Akerström et al, in a series of 503 autopsies:
    • Identified four parathyroid glands in 84% of the cases
    • Supernumerary glands were found in:
      • 13% of the cases:
        • Most commonly in the thymus
      • In the literature, the incidence of supernumerary glands:
        • Is anywhere between 3% and 13%
  • Only in three percent of the cases less than four parathyroid glands are identified
• The superior glands usually are dorsal to the RLN at the level of the cricoid cartilage:
  • Whereas the inferior parathyroid glands are located ventral to the nerve