Educational Case: Clinical and pathologic features of primary hyperparathyroidism

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see https://www.journals.elsevier.com/academic-pathology/news/pathology-competencies-for-medical-education-pcme.¹

Primary objective

Objective CHEM 1.3: Endocrine Disease. Discuss the clinical presentation and pathophysiologic bases of other endocrine diseases including the efficient use of laboratory tests to make a definitive diagnosis and manage the disease.

Competency 3: Diagnostic Medicine and Therapeutic Pathology, Topic: Chemistry (CHEM), Learning Goal 1: Pathogenesis, Diagnosis, and Treatment of Common Disorders.

Secondary objective

Objective N3.1: Morphologic Features of Neoplasia. Describe the essential morphologic features of neoplasms and indicate how these can be used to diagnose, classify, and predict biological behavior of cancers.

Competency 1: Disease Mechanisms and Processes, Topic: Neoplasia (N), Learning Goal 3: Characteristics of Neoplasia.

Patient presentation

A 42-year-old woman presents to her primary care physician for her annual physical exam. She feels well and does not have any complaints about her health. She is not currently taking any medications or supplements, does not use tobacco or recreational drugs, and drinks 1–2 alcoholic beverages per week. She reports no recent changes in her health and no family history of disease. On physical exam, she appears generally well and is oriented to person, time, and place with appropriate affect. Her blood pressure is 122/83 mmHg, her respiratory rate is 14 bpm, her heart rate is 67 bpm, her temperature is 98.4 °F. All other components of the physical exam are within normal limits. Her physician orders a basic metabolic panel (BMP) as part of her routine health maintenance.

Diagnostic findings, Part 1

The results of the patient's BMP are displayed in Table 1.

Table 1.

Basic metabolic panel results.

Test	Reference Range	Result
Glucose, Serum	70–99 mg/dL	74 mg/dL
Sodium, Serum	136-145 mEq/L	137 mEq/L
Potassium, Serum	3.5–5.1 mEq/L	4.2 mEq/L
Chloride, Serum	98-107 mEq/L	106 mEq/L
Bicarbonate	23-29 mEq/L	25 mEq/L
Calcium, Serum	8.6–10.4 mg/dL	10.8 mg/dL
Blood Urea Nitrogen (BUN)	6–20 mg/dL	14 mg/dL
Creatinine, Serum	0.6–1.3 mg/dL	1.10 mg/dL

Questions/discussion points, Part 1

Discuss the laboratory test results

In the laboratory panel, there is an isolated elevation of the patient's serum calcium level above the normal range of 8.6–10.4 mg/dL. Her physician orders a second BMP and a serum albumin level two weeks later, which is again notable for elevated serum calcium in the context of normal albumin, confirming hypercalcemia.

Describe the normal physiological mechanisms for control of serum calcium levels and the role of parathormone (PTH)

PTH secretion is regulated by several factors, most importantly by circulating ionized calcium (Ca²⁺). The calcium-sensing receptor (CasR) is expressed in the parathyroid glands and detects changes in serum Ca²⁺. Decreases in serum Ca²⁺ lead to less binding of CasR, which results in release of stored PTH produced by chief cells in the parathyroid. PTH then acts directly on the kidneys and the bones, as well as indirectly on the gastrointestinal tract to increase serum Ca²⁺. In the kidney, PTH binds PTH receptor type 1 (PTH1R) in the thick ascending limb of the loop of Henle and distal convoluted tubule, which drives paracellular Ca²⁺ reabsorption. PTH also drives the conversion of 25-hydroxyvitamin D to 1,25-dihydroxy vitamin D, which promotes intestinal Ca²⁺ absorption. In the bones, PTH has both anabolic and catabolic effects, though its anabolic effects are thought to predominate primarily during stages of skeletal bone development. PTH exerts catabolic effects by binding PTH1R on osteoblastic lineage cells (including osteocytes), which increases production of receptor activator of nuclear factor κ-Β (RANKL). RANKL then promotes osteoclast growth and subsequent bone resorption, increasing serum calcium levels. Once serum Ca²⁺ homeostasis has been restored, inhibitory mechanisms prevent further increases in Ca²⁺. Ca²⁺ promotes PTH degradation and may also suppress PTH gene transcription.²

What is the differential diagnosis of a patient with hypercalcemia?

The differential diagnosis of a patient presenting with hypercalcemia is broad and may be due to numerous PTH or non-PTH related causes.

The largest group relates to inappropriately elevated levels of PTH. Most commonly, hypercalcemia is the result of primary hyperparathyroidism (PHPT), a condition in which secretion of PTH by the parathyroids in a previously healthy individual is dysregulated, causing increased bone resorption, and increased renal tubular calcium reabsorption, both of which contribute to hypercalcemia.³ Tertiary hyperparathyroidism is another PTH-related cause of hypercalcemia. Here, the parathyroid glands secrete PTH autonomously and independently of serum Ca²⁺ levels, typically in the setting of long-standing secondary hyperparathyroidism. Secondary hyperparathyroidism is a physiologic response to a chronically hypocalcemic state such as chronic renal failure. Chronic lithium usage can also be associated with increased PTH levels and leads to PTH-dependent hypercalcemia.

Less frequently, inherited genetic abnormalities that increase PTH secretion may be responsible for hypercalcemia. In familial hypocalciuric hypercalcemia (FHH), heterodimerization between a mutant and wild-type CasR protein impairs the parathyroid's ability to properly detect increases in serum Ca²⁺ levels. As a result, PTH secretion is not suppressed.⁴ There are also several genetic syndromes associated with PHPT, including Multiple Endocrine Neoplasia (MEN) type 1 and type 2A, as well as hyperparathyroidism-jaw tumor syndrome (HPT-JT). MEN1 is caused by an inactivation in the MEN1 gene encoding menin and predisposes patients most commonly to parathyroid hyperplasia. Parathyroid adenoma and carcinoma, pancreatic neuroendocrine tumors, and pituitary adenomas are also seen in MEN1.⁵ In MEN2A, mutations in RET predispose patients to parathyroid adenoma and hyperplasia in addition to pheochromocytoma and medullary thyroid carcinoma. In HPT-JT, patients are predisposed to developing malignant neoplasms including parathyroid carcinoma. The gene CDC73 is often inactivated or lost in these patients.⁶

The non-PTH- related causes of hypercalcemia include a heterogeneous differential. Non-parathyroid malignant neoplasms may be associated with hypercalcemia. As part of a paraneoplastic syndrome, some tumors, most commonly squamous cell carcinomas, produce parathyroid hormone-related peptide (PTHrP), a factor that shares the same receptor as PTH.^7,8 Osteolysis, frequently associated with hematologic cancers such as multiple myeloma, or metastatic tumors may also lead to hypercalcemia in the absence of elevated PTH. Another mechanism for development of non-PTH mediated hypercalcemia that may be seen in some lymphomas and in granulmatous diseases such as sarcoidosis or tuberculosis is excess production of 1-alpha-hydroxylase by macrophages, leading to excessive 1,25-dihydroxyvitamin D with increased gastrointestinal calcium reabsorption. Other non-PTH-related causes of hypercalcemia include increased levels of vitamin D via exogenous vitamin supplementation and excessive calcium ingestion termed milk-alkali syndrome. Less common non-PTH mediated causes of hypercalcemia include hyperthyroidism, vitamin A excess, adrenal insufficiency, and immobility. Thiazide diuretics increase proximal tubular calcium reabsorption and can exacerbate the hypercalcemia of PHPT or other causes. Though not an exhaustive list, these causes of hypercalcemia are summarized in Table 2.

Table 2.

PTH- and Non-PTH-related causes of hypercalcemia.

PTH-related causes of hypercalcemia:

Primary hyperparathyroidism

Genetic causes: MEN1, MEN2A, HPT-JT, FHH

Tertiary hyperparathyroidism

Non-PTH-related causes of hypercalcemia:

Hyperthyroidism

Granulomatous diseases: tuberculosis, sarcoidosis

Malignancy: PTHrP-secreting tumors, osteolysis

Drugs/supplements: thiazide diuretics, calcium supplements/antacids (milk-alkali syndrome), vitamin D

Abbreviations: PTH, parathyroid hormone; MEN1, multiple endocrine neoplasia type 1; MEN2A, multiple endocrine neoplasia type 2A, HPT-JT, hyperparathyroidism-jaw tumor syndrome; FHH, familial hypocalciuric hypercalcemia; PTHrP, parathyroid hormone-related peptide.

What laboratory tests would help the physician work up this patient's hypercalcemia?

Measuring the patient's PTH level is a crucial step in working up a patient with hypercalcemia, as it helps narrow the differential between PTH-mediated and non-PTH mediated causes of hypercalcemia. If PTH is elevated or on the high end of the normal range, the physician will place PHPT high on the differential diagnosis. Conversely, if PTH is on the low end of normal or is suppressed, non-PTH mediated causes like malignancy, medication-induced hypercalcemia, and other endocrine etiologies must be considered.

To differentiate between PHPT and FHH, a 24-h urine sample may be taken to measure the secretion of calcium and creatinine. PHPT patients will show high urinary calcium excretion, while FHH patients typically have low urinary calcium excretion. Most commonly, the renal calcium/creatinine clearance ratio (CCCR), which measures (24-h calcium/total plasma calcium)/(24-h creatinine/plasma creatinine) is used to distinguish between FHH and PHPT, with most FHH patients having a value < 0.01 and values > 0.02 being highly consistent with PHPT.⁶

When considering non-PTH-related etiologies, measuring the PTHrP level is important to assess ectopic PTHrP production. A review of the patient's current medications and supplements, as well as their pattern of use must be conducted to rule out those etiologies. A low 25-hydroxyvitamin D and elevated 1,25-dihydroxyvitamin D level may be indicative of 1-alpha-hydroxylase mediated hypercalcemia from malignancy or granulomatous disease. The conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D is catalyzed by 1-alpha-hydroxylase in the kidney. Measuring TSH and free T4 can rule out thyroid-mediated hypercalcemia.^6,8 ACTH and cortisol are useful for evaluation of adrenal insufficiency, and a vitamin A level can assess for toxicosis.

Diagnostic findings, Part 2

The results of the patient's follow-up testing are displayed in Table 3. The primary care physician also reviews the patient's medication list, and she is not taking lithium, thiazide diuretics, or any calcium-containing supplements.

Table 3.

Follow-up laboratory testing results.

Test	Reference Range	Result
PTH	20–65 pg/mL	133 pg/mL
24-h urine Ca	55–300 mg	294 mg
24-h urine Cr	800–1800 mg	1210 mg
25-hydroxyvitamin D	30–100 ng/mL	22 ng/mL
Phosphate	2.5–4.5 mg/dL	2.6 mg/dL
TSH	0.45–4.5 mIU/mL	3.2 mIU/mL
T4, free	0.82–1.77 ng/dL	1.4 ng/dL

Abbreviations: PTH, parathyroid hormone; Ca, calcium; Cr, creatinine; TSH, thyroid stimulating hormone.

Questions/discussion points, Part 2

Interpret the laboratory findings and correlate with the patient presentation to suggest a likely diagnosis for this patient

There is an elevated PTH, ruling out non-PTH-related etiologies of disease. The 24-h urine calcium level is on the high end of normal and the 24-h urine creatinine level is within the normal range. The 25-hydroxyvitamin D level is low. The phosphate level is on the low end of the normal range. The TSH and free T4 levels are normal, ruling out hyperthyroidism.

Based on the presentation and diagnostic findings, this patient has PHPT. This patient presented for her annual physical exam feeling well but had an incidental finding of hypercalcemia on laboratory testing, which is more likely to be seen in PHPT than other causes of elevated calcium. A diagnosis of PHPT is highly suggested based on findings of elevated PTH and hypercalcemia. The patient's other laboratory testing also supports this diagnosis. The 24-h urine calcium excretion is on the high end of the normal range, which is not typically seen in FHH. The patient's 24-h urine calcium and urine creatinine levels may be used to calculate this patient's CCCR. Based on the values from Table 2, Table 3, her CCCR is 0.0247 [(294mg/10.8 mg/dL)/(1210mg/1.10mg/dL)], which is > 0.02 and consistent with PHPT. Patients with PHPT typically have low phosphorus, as PTH stimulates renal excretion of phosphorus. Low 25-hydroxyvitamin D levels may be attributed to increased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D in the kidney because PTH stimulates 1-alpha-hydroxylase.⁶

What are the clinical features of PHPT?

The clinical presentation of PHPT may vary depending on the accessibility and implementation of biochemical screenings as part of health maintenance. When biochemical screenings are accessible and widely implemented, PHPT presents as an incidental finding in an otherwise asymptomatic patient, with hypercalcemia and elevated PTH as the biochemical findings.^3,9 When serum calcium screening is not accessible or implemented, symptomatic presentation of PHPT is more common. Typically, this manifests as renal and bone disease. Patients with PHPT are at greater risk for nephrolithiasis, nephrocalcinosis, and reduced creatinine clearance signifying renal dysfunction.^3,9,10 Osteoporosis is a risk for patients with PHPT, particularly patients with older age and lower body weight. Increased bone resorption and decreased bone mineral density can present in PHPT patients as osteitis fibrosa cystica, a rare disease characterized by pathologic radiographic findings including fracture, resorption of bone at the distal phalanges, and bone cysts.^3,9 A wide variety of other findings have been associated with PHPT including cardiovascular findings like hypertension and left ventricular hypertrophy, neurologic findings like inability to concentrate and fatigue, and gastrointestinal findings including peptic ulcer disease and pancreatitis.^3,6,9,10

Diagnostic findings, Part 3

The diagnosis of PHPT is made and though the patient is asymptomatic, her primary care physician recommends parathyroidectomy to cure the disease. This is in line with the current guidelines for management of asymptomatic primary hyperparathyroidism that will subsequently be discussed. She is referred for imaging of her parathyroids as part of preoperative planning. She undergoes four-dimensional parathyroid computed tomography (4DCT) to determine parathyroid localization.¹¹ The study shows a teardrop-shaped nodule abutting the lateral esophageal wall deep and inferior to the lower pole of the thyroid, consistent with a left superior parathyroid gland lesion (Fig. 1).

Fig. 1.

4DCT of parathyroid gland. Axial and coronal 4DCT images of the neck display a left hypodense 8.9 × 4.9 × 22.8mm teardrop-shaped nodule (arrow), located along the tracheoesophageal groove and abutting the lateral esophageal wall, deep and inferior to the lower pole of the thyroid demonstrating arterial phase enhancement. In other series that are not shown, the nodule has delayed phase washout, consistent with a parathyroid adenoma.

The patient undergoes minimally invasive parathyroidectomy. Her baseline PTH is measured before the surgical procedure. A series of intraoperative PTH measurements is taken at 5, 10, and 15 minutes after resection of the gland, at which point the PTH measurement has dropped to less than 50% of the baseline reading and is within the normal range, confirming that the parathyroid tissue responsible for inappropriate secretion of PTH has been resected.¹¹

The parathyroid gland is sent to Pathology. It weighs 600 mg.

Question/discussion point, Part 3

Describe the gross and histologic appearance of a normal parathyroid gland

The normal parathyroid glands grossly are small, flattened, ovoid structures that range from pink to brown in color and typically weigh approximately 30 mg each. The normal parathyroid is surrounded by a thin fibrous capsule. Histologically, the gland itself is composed of a mixture of adipose tissue, chief cells that regulate the secretion of PTH, and oxyphil cells whose function is not fully elucidated.¹² Chief cells are typically small, round cells with clear cytoplasm and indistinct borders, while oxyphil cells have prominent eosinophilic cytoplasm (Fig. 2).

Fig. 2.

Histological appearance of the normal parathyroid gland. The gland is composed of endocrine cells and interspersed adipocytes. The inset demonstrates the endocrine cells in greater detail. The predominant cells are the chief cells, a uniform population of rounded cells with clear cytoplasm, indistinct borders and small, central nuclei. Chief cells secrete PTH. The oxyphil cells (arrows) are larger cells with eosinophilic cytoplasm whose function is not clear. (Hematoxylin and eosin stain; magnification, 200x; inset, 400x).

Describe the gross and histologic appearance of the resected parathyroid gland as seen in Fig. 3

Fig. 3.

The patient's resected parathyroid gland. A. Gross appearance: The gland is well circumscribed, tan-pink, and soft. Its smooth surface is covered by a delicate capsule (except superiorly, where there has been some procedural disruption). The weight is 600 mg (far heavier than the normal 30 mg!). B. Microscopic appearance: The lesion is composed of homogeneous sheets of cells that can be identified in the inset as being chief cells; adipose tissue is not observed. The normal parathyroid gland tissue (arrows) has been pushed to the side; note that it contains adipocytes. (Hematoxylin and eosin stain; magnification, 40x; inset, 200x). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

The resected parathyroid gland sent to Pathology is smooth and tan-pink in color (Fig. 3A). Histologically, the gland is largely replaced by sheets of chief cells. The edge of the lesion is smooth and has pushed the minimal amount of normal parathyroid gland tissue to the side (Fig. 3B).

What is this patient's diagnosis – based on clinical and pathological features?

These morphological features in conjunction with the clinical findings are consistent with parathyroid adenoma, a benign neoplasm typically involving a single parathyroid gland. Parathyroid adenoma is the most common pathologic cause of PHPT, causing approximately 85% of PHPT cases.^5,10

Grossly, the weight of parathyroid adenomas can be highly variable, though frequently they weigh at least 300 mg, approximately 10 times greater than the weight of a normal parathyroid. In this case the tumor weighed 600 mg! In the presence of an adenoma, the other parathyroid glands are typically normal in size or even somewhat smaller due to feedback inhibition from elevated serum calcium levels. This was demonstrated on pre-operative imaging. The typical parathyroid adenoma is comprised of proliferating chief cells, usually without nuclear atypia, mitotic figures, or pleomorphism. Adipocytes, seen in the normal parathyroid gland, are not usually found within the adenoma. Often, a rim of normal parathyroid tissue can be seen adjacent to the adenoma (as seen in this case). Less frequently, an adenoma may be comprised of oxyphil cells rather than chief cells.^5,12

Discuss the other pathologic diagnoses, along with their morphological appearance, that can cause PHPT

Less commonly, PHPT can be caused by parathyroid hyperplasia or parathyroid carcinoma.

In parathyroid hyperplasia, which is responsible for approximately 10–15% of cases of PHPT, there is more diffuse abnormal proliferation of cells, accompanied by enlargement of all four parathyroid glands. The combined weight of all four parathyroids is typically about 1–3 g. The most common histological appearance is symmetric expansion via proliferation of chief cells in a solid pattern.¹³

Parathyroid carcinoma is a rare cause of PHPT, responsible for approximately 1% of cases.¹⁰ Grossly, parathyroid carcinomas may be extremely large, weighing up to 12 g⁵ (Fig. 4).¹⁴ But carcinoma cannot be definitively diagnosed in the primary specimen unless invasion into adjacent tissue structures, perineural or lymphovascular invasion, or distant metastasis is identified.^5,12 Distinguishing by microscopic criteria between parathyroid adenoma and carcinoma is challenging due to similarities on histology and a lack of immunohistochemical tools to differentiate between these entities. Atypical forms of adenomas may present with fibrosis, focal nuclear atypia, focal tumor necrosis, and a high mitotic rate suggestive of carcinoma. But as in the gross, definitive diagnosis relies on tissue or vascular invasion or metastasis (Fig. 5A and B).¹⁵

Fig. 4.

Gross appearance of parathyroid carcinoma. This surgical specimen shows a large tumor arising in the parathyroid gland. It exhibits an irregular border with invasion into the surrounding soft tissue. These gross findings are consistent with carcinoma. Fig. 4 is reproduced under Creative Commons License CC BY-NC 3.0 (https://creativecommons.org/licenses/by-nc/3.0/) from Fig. 2A in Parathyroid Carcinoma Presenting as a Hyperparathyroid Crisis by Tan et al. in The Korean Journal of Internal Medicine.¹⁴

Fig. 5.

Microscopic appearance of parathyroid carcinoma. A. The tumor is composed of sheets of chief cells that exhibit slight nuclear atypia and occasional mitotic figures (arrow) (Hematoxylin and eosin; magnification, × 400). (Note that these histological findings, which also may be seen in atypical parathyroid adenomas, do not confirm a diagnosis of carcinoma.) B. This lower power view at the periphery of the tumor, however, shows an island of tumor within a vein (arrow). Vascular invasion is a feature of malignancy. Fig. 5A and B are reproduced under Creative Commons License CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) from Fig. 2A and B in CDC73 Intragenic Deletion in Familial Primary Hyperparathyroidism Associated with Parathyroid Carcinoma by Korpi-Hyövälti et al. in The Journal of Clinical Endocrinology and Metabolism.¹⁵

When is surgical intervention indicated for PHPT?

Parathyroidectomy is a definitive cure for PHPT and is recommended for any patients with symptomatic disease, including renal manifestations and bone loss. However, asymptomatic patients are also candidates for surgery. Current guidelines recommend parathyroidectomy for any patient with asymptomatic disease who is less than 50 years of age, has serum calcium measuring greater than 1 mg/dL above the normal limit, reduced bone density in the osteoporotic range, nephrolithiasis, creatinine clearance of less than 60 cc/min, or marked hypercalciuria (>400 mg/day). Even without meeting these criteria, patients with PHPT may elect to undergo parathyroid surgery rather than receive medical management.¹¹ For this patient, the primary care physician recommended a referral for surgery because she is less than 50 years old.

Teaching points

• •Serum calcium levels are tightly controlled by PTH and its effects on kidneys, bones, and gastrointestinal tract. Serum calcium levels in turn normally induce stimulatory or inhibitory effects on PTH secretion.
• •PTH level is a crucial laboratory value to differentiate between parathyroid- and non-parathyroid-mediated etiologies of hypercalcemia.
• •The laboratory diagnosis of PHPT typically includes hypercalcemia in the setting of an elevated PTH level.
• •In the U.S most cases of PHPT are found on routine laboratory testing of asymptomatic individuals.
• •Symptomatic PHPT often has renal and skeletal sequelae including impaired renal function, nephrolithiasis, osteoporosis, and bone pain or fractures.
• •Parathyroid adenomas cause the most cases of PHPT, and typically present as a single gland replaced by a well-circumscribed benign neoplasm with uniform chief cells in the absence of stromal fat.
• •Parathyroid hyperplasia is a less common cause of PHPT that presents with increased parathyroid gland mass due to parenchymal proliferation within all four glands.
• •Parathyroid carcinoma is rarely the pathologic cause of PHPT but can only be definitively diagnosed if there is invasion into tissue beyond the parathyroid gland, perineural or lymphovascular invasion, or metastatic disease.

Funding

The article processing fee for this article was funded by an Open Access Award given by the Society of ‘67, which supports the mission of the Association of Pathology Chairs to produce the next generation of outstanding investigators and educational scholars in the field of pathology. This award helps to promote the publication of high-quality original scholarship in Academic Pathology by authors at an early stage of academic development.

Declaration of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.