Parathyroid Cancer: Symptoms, Types, Causes and Treatment

Parathyroid cancer is one of the rarest cancers, but its impact can be profound due to severe hormonal and metabolic disturbances. Unlike more common parathyroid conditions, this cancer often presents with striking symptoms and poses unique diagnostic and therapeutic challenges. In this comprehensive overview, we’ll explore the key features of parathyroid cancer—its symptoms, types, causes, and the current treatment landscape—offering a clear and engaging guide to understanding this rare but serious disease.

Symptoms of Parathyroid Cancer

Parathyroid cancer symptoms can be severe and wide-ranging, primarily due to excessive secretion of parathyroid hormone (PTH), which drives dangerously high calcium levels in the blood. This hormonal imbalance leads to a spectrum of problems affecting multiple organs and systems in the body.

Most patients with parathyroid cancer experience pronounced symptoms at presentation, often far more dramatic than those seen in benign parathyroid disorders. Recognizing these symptoms early is crucial for timely intervention.

Symptom	Description	Frequency/Significance	Source(s)
Hypercalcemia	Very high blood calcium, sometimes a crisis	Most patients, can be life-threatening	1 3 5 6 7 13
Bone complications	Bone pain, fractures, osteoporosis, 'brown tumors'	~30% develop skeletal issues	1 3 6 7
Kidney issues	Kidney stones, nephrocalcinosis, polyuria	~30% develop renal problems	1 3 6 7
Neuropsychiatric	Mood changes, depression, neuropathy	Common; may be severe	1 3 6
GI symptoms	Nausea, vomiting, abdominal pain, ulcers, pancreatitis	Frequently observed	1 3 6
General symptoms	Fatigue, weight loss, palpable neck mass	Often present	1 5 7

Table 1: Key Symptoms

Overview of Symptomatology

Parathyroid cancer’s hallmark is the dramatic elevation in blood calcium (hypercalcemia), driven by excessive PTH. This leads to a cascade of systemic effects:

• Bone Involvement: The continuous leaching of calcium from bones causes pain, fractures, osteoporosis, and sometimes the formation of “brown tumors,” which are areas of bone weakened by overactive cells 1 3 6 7.
• Kidney Complications: The kidneys work overtime to clear excess calcium, resulting in kidney stones, calcification within the kidneys (nephrocalcinosis), and increased urination (polyuria) 1 3 6 7.
• Neuropsychiatric Effects: Patients may experience mood disturbances, depression, and, in severe cases, neurological impairment such as neuropathy 1 3 6.
• Gastrointestinal Distress: Nausea, vomiting, abdominal pain, pancreatitis, and even peptic ulcers are seen due to high calcium levels and PTH activity 1 3 6.
• General/Systemic Symptoms: Fatigue, unexplained weight loss, and a palpable mass in the neck are common. In advanced cases, a hard lump may be felt at the site of the tumor, and symptoms escalate rapidly if a hypercalcemic crisis develops 1 5 7.

Recognizing Severe Presentations

Approximately 90% of parathyroid cancers are hormonally active, meaning that symptoms of hypercalcemia are not only common but often severe and the primary reason for seeking medical attention 13. In rare cases, patients may present with complications such as hungry bone syndrome (a rapid drop in calcium after tumor removal), chondrocalcinosis (calcium deposits in cartilage), or even portal vein thrombosis 3.

Prognostic Implications

The severity and range of symptoms often correlate with disease burden. Most deaths in parathyroid cancer are not from tumor spread but from the complications of uncontrolled hypercalcemia, highlighting the importance of early detection and management 6 7 13.

Types of Parathyroid Cancer

Despite its rarity, parathyroid cancer is not a uniform disease. Contemporary research and clinical practice recognize several types and subtypes, mainly differentiated by their clinical presentation, pathology, and risk of aggressive behavior.

Type	Defining Features	Risk/Prognosis	Source(s)
Functional PC	Secretes excess PTH, causes hypercalcemia	Most common, severe symptoms	3 7 11 13
Non-functional PC	Does not secrete PTH	Rare, often discovered late	7
Sporadic	Occurs without genetic link	Majority of cases	3 6 7
Hereditary/Syndromic	Linked to CDC73 mutations, HPT-JT, MEN1/2	Higher risk in syndromes	3 6 7 9
Atypical Parathyroid Tumor (APT)	Intermediate features, not frankly malignant	Lower recurrence and mortality	2

Table 2: Types and Subtypes

Functional vs. Non-Functional Tumors

• Functional Parathyroid Carcinomas: Over 90% of parathyroid cancers are functional, meaning they secrete high levels of PTH, leading to hypercalcemia and its associated symptoms 3 7 11 13.
• Non-Functional Tumors: Rarely, tumors do not produce excess hormone and may be discovered incidentally or at a more advanced stage due to mass effect rather than metabolic symptoms 7.

Sporadic vs. Hereditary Forms

• Sporadic Cases: Most parathyroid cancers arise sporadically, without a family history or identifiable syndrome 3 6 7.
• Hereditary/Syndromic Cases: A subset is linked to inherited syndromes such as hyperparathyroidism-jaw tumor syndrome (HPT-JT), multiple endocrine neoplasia types 1 and 2A (MEN1, MEN2A), or germline CDC73/HRPT2 mutations. These patients (and their relatives) have a higher lifetime risk of developing parathyroid cancer 3 6 7 9.

Atypical Parathyroid Tumors (APT)

• APT: These are tumors with some but not all features of cancer; they have intermediate behavior. APTs have lower recurrence and mortality rates compared to frank carcinoma but can resemble cancer in size and hormone levels. The latest World Health Organization (WHO) classification recognizes APT as a separate entity, which aids diagnosis and treatment planning 2.

Risk Stratification Based on Pathology

Parathyroid cancers can also be classified based on their invasive properties:

• Low-risk: Tumors limited to the capsule or soft tissue.
• High-risk: Tumors with vascular invasion, organ invasion, lymph node involvement, or distant metastasis. High-risk features predict a greater chance of recurrence and poorer survival 4 14.

Causes of Parathyroid Cancer

Understanding what drives parathyroid cancer is a topic of ongoing research. While most cases arise without a clear cause, recent advances have highlighted several genetic and molecular factors that play a pivotal role in the development of this rare disease.

Cause/Factor	Role/Details	Heritability or Frequency	Source(s)
CDC73/HRPT2 mutations	Tumor suppressor gene; parafibromin loss	Germline in 15–30%, somatic in up to 70%	5 6 9 10 11
Syndromic associations	HPT-JT syndrome, MEN1/2A	Rare, but high risk	3 6 7 9
Epigenetic changes	Aberrant methylation, microRNA patterns	Distinct signature in PC	11
Sporadic occurrence	No identifiable cause	Most cases	3 6 7
Other risk factors	Age >40, male sex, Caucasian race, large tumor size	Associated with worse prognosis, not causation	8

Table 3: Causes and Risk Factors

Genetic Mutations: CDC73/HRPT2

• Major Genetic Driver: The inactivation of the CDC73 (also called HRPT2) gene is the most significant known risk factor. This gene encodes parafibromin, a protein that suppresses tumor formation. Loss or mutation of this gene disrupts normal cellular regulation, leading to tumor development 5 6 9 10 11.
  • Germline mutations (inherited) are found in about 15–30% of cases, while somatic mutations (acquired) occur in up to 70% 5 6 9.
  • High-impact mutations, especially those affecting the C-terminal domain of parafibromin, dramatically increase the risk of parathyroid carcinoma 10.
• Familial Syndromes: Patients with inherited CDC73/HRPT2 mutations may develop parathyroid cancer as part of broader syndromes, like HPT-JT, or as isolated familial cases. Screening relatives of affected patients is crucial for early detection 6 9.

Syndromic Associations

• Hyperparathyroidism-Jaw Tumor (HPT-JT) Syndrome: This rare syndrome carries a high risk of parathyroid cancer and is almost always associated with CDC73 mutations 3 6 7 9.
• Multiple Endocrine Neoplasia (MEN): Types 1 and 2A may rarely feature parathyroid cancer, though the risk is lower than in HPT-JT 3 6 7.

Epigenetic and Molecular Changes

Distinct patterns of DNA methylation and microRNA expression further distinguish parathyroid cancer from benign tumors. These epigenetic signatures may one day offer new diagnostic tools and therapeutic targets 11.

Non-Genetic Factors

• Sporadic Cases: The majority of parathyroid cancers arise without a clear inherited or environmental cause 3 6 7.
• Demographic and Tumor Factors: Older age, male sex, Caucasian race, tumor size >4 cm, and poor tumor differentiation are associated with worse outcomes but are not direct causes 8.

Treatment of Parathyroid Cancer

Treating parathyroid cancer is challenging due to its rarity, high recurrence rate, and resistance to most non-surgical therapies. However, advances in surgical techniques and supportive care have improved outcomes for many patients.

Treatment	Purpose/Approach	Effectiveness/Notes	Source(s)
En bloc surgical resection	Remove tumor with clear margins	Only curative option, best done at first surgery	3 5 6 7 8 12 13 14 15 16
Reoperation/debulking	Address recurrences or inoperable tumor	Palliative; rarely curative	6 7 13 16
Medical therapy	Control hypercalcemia (calcimimetics, bisphosphonates)	Essential for inoperable disease; symptom relief	9 13 16
Radiation therapy	Adjuvant or for residual disease	Usually ineffective; limited role	5 15 16
Chemotherapy	Rare, experimental	Largely ineffective	5 7 13 16
Surveillance	Lifelong monitoring for recurrence	Essential due to high relapse risk	6 12 13

Table 4: Treatment Options

Surgery: The Mainstay of Cure

• En Bloc Resection: Complete surgical removal of the tumor, ideally at the initial operation, is the only curative treatment. This involves excising the tumor with surrounding tissues and sometimes local lymph nodes to ensure no cancerous cells are left behind 3 5 6 7 8 12 13 14 15 16.
• Importance of Early, Radical Surgery: The outcome is best when the cancer is removed entirely during the first surgery. Delayed or incomplete resection increases the risk of local recurrence and worsens the prognosis 7 13 14.
• Reoperation and Debulking: High recurrence rates (up to 50%) mean many patients need additional surgeries. These are often palliative, aiming to reduce tumor burden and control hormone levels rather than cure 6 7 13 16.

Medical Management

• Hypercalcemia Control: For inoperable or metastatic cases, managing calcium levels becomes the priority:
  • Calcimimetics (e.g., cinacalcet): Lower blood calcium by mimicking calcium’s action on the parathyroid gland 9 13 16.
  • Bisphosphonates: Help reduce bone resorption and lower calcium 9.
  • Hydration and Diuretics: Used acutely to reduce dangerously high calcium 1 3.
• These treatments provide symptom relief but do not alter the course of the cancer.

Other Therapies

• Radiation Therapy: Has not consistently improved survival or disease-free intervals but may be used selectively, especially for residual disease after surgery 5 15 16.
• Chemotherapy: No standard regimen has proven effective. Use is generally limited to rare, aggressive, or inoperable cases 5 7 13 16.

Long-Term Follow-Up

• Surveillance: Due to the high risk of recurrence, patients require lifelong monitoring of calcium, PTH levels, and imaging as needed 6 12 13.
• Genetic Counseling: All patients should be considered for genetic testing (especially for CDC73/HRPT2 mutations), and at-risk family members should be screened 6 9.

Conclusion

Parathyroid cancer, while rare, is a formidable disease due to its aggressive hormonal effects, diagnostic challenges, and high risk of recurrence. A multidisciplinary approach, centered around early and radical surgical intervention, offers the best hope for cure. Ongoing surveillance and supportive care are crucial for managing persistent or recurrent disease.

Key Takeaways:

• Symptoms are usually severe, dominated by hypercalcemia and its systemic complications.
• Types include functional (most common) and non-functional tumors; most cases are sporadic, but hereditary forms exist.
• Causes are primarily genetic, with CDC73/HRPT2 mutations playing a central role; syndromic associations include HPT-JT and MEN.
• Treatment relies on complete surgical removal; medical management of hypercalcemia is essential for symptom control in advanced or inoperable cases.

Early recognition, prompt surgical intervention, and lifelong follow-up are the cornerstones of managing parathyroid cancer. Research into the molecular underpinnings of this disease continues to offer hope for improved diagnosis and therapy in the future.