The vast majority of PC are functional tumors secreting parathyroid hormone [1] [2]. Because cancer cells have become independent of feedback mechanisms, parathyroid hormone levels increase beyond the physiological range and propel the mobilization of calcium from bone. At the same time, the renal excretion of calcium is inhibited, and PC patients develop hypercalcemia. This condition may manifest in a variety of symptoms:

• Symptoms characteristic of renal disease, such as flank pain, renal colics, hematuria, polyuria, and polydipsia, are most commonly observed. Further diagnostics may then reveal nephrocalcinosis, nephrolithiasis, or nephrogenic diabetes insipidus.
• Epigastric instead of flank pain may be related to the presence of gastric and duodenal ulcers. They are usually accompanied by nausea and vomitus and are induced by the calcium-dependent increase of gastric acid production. Pancreatitis may also occur.
• On the other hand, the prolonged elevation of parathyroid hormone levels induces structural changes in osseous tissues. Bone pain, skeletal deformities, and pathological fractures may result from the ongoing replacement of bone with fibrous tissue. This condition is known as osteitis fibrosa cystica. Osteopenia and osteoporosis may also be observed in PC patients.
• Finally, hypercalcemia may affect the function of the central nervous system and induce psychiatric disorders such as anxiety and depression, or memory impairment. More severe neurological symptoms may arise upon the decompensation of hypercalcemia, triggering a hypercalcemic crisis. This condition is otherwise known as parathyroid toxicosis and refers to a medical emergency characterized by an altered mental state and reduced consciousness. Patients with parathyroid toxicosis may additionally present renal failure with oliguria or anuria.

Beyond the symptoms of hypercalcemia, PC may present as a mass lesion interfering with the function of surrounding tissues. The tumor itself is usually indolent, but it may exert pressure on the recurrent laryngeal nerve and provoke hoarseness [1]. Dysphagia and dyspnea are more commonly observed in patients with non-functional PC, where tumors may grow to considerable sizes before being detected.

Finally, the presence of metastases in regional lymph nodes or distant organs, usually the lungs, liver, or bone, may cause symptoms related to organ failure and/or pressure on adjacent structures [2] [3].

• Weight Loss

  A 29-year-old man presented to his primary care physician with nausea, severe weight loss and muscle weakness. He had a hard, fixed neck swelling. He was severely hypercalcaemic with 10-fold increased parathyroid hormone (PTH) concentrations. [ncbi.nlm.nih.gov]

  Case Presentation A 15 year old male presented with decreased appetite and weight loss. Calcium was 14.7mg/dl. Additional history included musculoskeletal pain and headaches. No supplements. [austinpublishinggroup.com]

  Diseased states of the thyroid gland may result in either too much thyroid hormone (hyperthyroidism) or too little thyroid hormone (hypothyroidism) causing generalized symptoms, weight loss or gain and rarely can be life-threatening if untreated. [nyhni.org]

  This was associated with fatigue, anorexia, muscle weakness and progressive weight loss about of 30%. She took analgesics and tolerated her condition. About 3 months prior to admission, she could no longer ambulate due to severe bone pains. [asean-endocrinejournal.org]

  These can be symptoms: Feeling weak or tired Upset stomach and vomiting Stomach or back pain Poor appetite Weight loss Thirst Lots of peeing Trouble pooping Not thinking clearly A lump in the neck (rare) Bone pain Hoarse voice Trouble swallowing Kidney [webmd.com]

• Thyroid Nodule

  Fine-needle aspiration cytology (FNAC) may fail to distinguish a parathyroid tumor from a benign thyroid nodule because at FNAC, parathyroid and thyroid lesions have some morphological similarities. [ncbi.nlm.nih.gov]

• Goiter

  Neck ultrasonography demonstrated multinodular goiter with predominant 34 mm nodule in left thyroid lobe. Additional 16 mm nodule was found beneath the left lobe. [ncbi.nlm.nih.gov]

  The medical term for an abnormally large thyroid gland is goiter. Some goiters are diffuse, meaning that the whole gland is large. Other goiters are nodular, meaning that the gland is large and has one or more nodules (bumps) in it. [cancer.org]

  US demonstrated a multinodular goiter and a 3×2.5-cm mass in contact with the lower pole of the right lobe of the thyroid gland. [spandidos-publications.com]

  gross Thyroid, nodular goiter, low power microscopic Thyroid, Graves disease, low power microscopic Thyroid, Graves disease, high power microscopic Thyroid, follicular adenoma, gross Thyroid, follicular adenoma, gross Thyroid, follicular adenoma, microscopic [library.med.utah.edu]

• Fever

  Fever as initial symptom of hypernephroid tumor of the kidney. Arch. Surg. 1940; 41: 385 Shipman K.H. Downing S.W. Bradford H.A. Hypernephroma presenting as fever of unknown origin associated with elevated alkaline phosphatase levels. J. [goldjournal.net]

  Case Report A 46-year-old farmer was first seen in the Christie Clinic in September 1946 because of urinary frequency, dysuria, and fever. [pubs.rsna.org]

  Contact your healthcare team if you experience: Fever of > 100.5 and/or with signs of an infection like chills, incisional redness, tenderness and/or drainage. Lightheadedness. Shortness of breath/difficulty breathing. Nausea/Vomiting. [oncolink.org]

  Lung: a chronic or bloody cough, fever, chills, and shortness of breath can indicate a bronchial adenoma. [encyclopedia.com]

  It was not associated with fever and urinary symptoms, and was not radiating from loin to groin. There was no history of passage of stones in the urine. [sjmms.net]

• Anemia

  […] parathyroid hormone levels (iPTH) of 2,800 pg/mL (reference values 10-65 pg/mL), in addition to evidence of renal failure, with serum creatinine values of 3.4 mg/dL, creatinine clearance of 16.7 mL/min (Cockcroft-Gault), and normochromic normocytic anemia [scielo.br]

   Fanconi’s anemia  Bloom syndrome  Ataxia  Telegiactasis Autosomal recessive disorder with increased chromosomal fragility are associated with oral cavity & pharyngeal carcinoma.  Li- Fraumeni syndrome : autosomal dominant condition mutation of [slideshare.net]

  Fever, anemia, and hyperhepatoglobinemia. Ann. Intern. Med. 1968; 68: 613 Wagle D.G. Scal D.R. Renal cell carcinoma - a review of 256 cases. J. Surg. Oncol. 1970; 2: 23 Arnold D. [goldjournal.net]

  Recurrent severe pancreatitis, anemia and peptic ulcer disease can also occur. Among our 3 patients, 2 were symptomatic. One patient experienced fatigue, ankle and knee pain and the other fatigue, polyuria and polydipsia. [jcancer.org]

• Nausea

  A 29-year-old man presented to his primary care physician with nausea, severe weight loss and muscle weakness. He had a hard, fixed neck swelling. He was severely hypercalcaemic with 10-fold increased parathyroid hormone (PTH) concentrations. [ncbi.nlm.nih.gov]

  They include: Bone pain Constipation Fatigue Fractures Frequent thirst Frequent urination Kidney stones Muscle weakness Nausea and vomiting Poor appetite Parathyroid cancer is very hard to diagnose. [nlm.nih.gov]

  Possible Causes and Tests Some possible causes of parathyroid cancer: Radiation (treatment with X-rays or other kinds of energy) to the neck Familial Isolated Hyperparathyroidism -- a condition that can cause kidney stones, nausea, vomiting, high blood [webmd.com]

  These might include: mental changes such as depression, lethargy, or confusion nausea vomiting pain in your muscles or abdomen Sometimes, doctors aren’t sure what causes a tumor to appear on one of your glands. [healthline.com]

• Dyspepsia

  There were no other symptoms such as weakness, fatigue, nausea, vomiting, constipation, dyspepsia, headache, polyuria, or abdominal pain. [wjso.biomedcentral.com]

  The most frequent complaints are weakness, fatigue, anorexia, nausea, vomiting, loss of weight, dyspepsia, constipation, headaches, polydipsia and polyuria. [jcancer.org]

  = 28 % n = 7 % n = 13 % Bone pain 20 71.4 3 42.9 11 84.6 NS Fatigue 22 78.6 3 42.9 10 76.9 NS Kidney stones 11 39.3 0 0 3 23.1 NS Anorexia 7 25 2 28.6 2 15.4 NS Weight loss 6 21.4 0 0 2 15.4 NS Hoarseness 3 10.7 0 0 0 0 NS Abdominal symptoms (pain, dyspepsia [acsjournals.onlinelibrary.wiley.com]

  […] clinical presentations in recent series have changed from those dominated by severe bone and kidney disease to those characterized by lack of symptoms or by fatigue, weakness, depression and gastrointestinal symptoms, including constipation, nausea and dyspepsia [nature.com]

• Acute Abdomen

  Hypernephroma presenting as an acute abdomen. Surgery. 1971; 70: 656 Botting A.J. Harrison Jr., E.G. Black B.M. [goldjournal.net]

• Heart Disease

  Free radicals may play a part in cancer, heart disease, stroke, and other diseases of aging. [cancer.gov]

• Jaundice

  Pheochromocytoma Elevated blood pressure Damp and sticky skin Unusual anxiety Heart palpitations Nausea, headaches, fever Neuroendocrine Carcinoma: Hyper or hypoglycemia Unusual weight changes Unusual anxiety Unexplained lumps Jaundice Unexplained bleeding [medstarcancer.org]

  Symptoms include jaundice, abdominal pain, nausea, vomiting, and weight loss. [cancer.gov]

• Hepatomegaly

  […] polyadenitis = inflamation of many glands THYRO- thyroid thyroaplasia = defective growth of the thyroid -CRINE to secrete endocrine = endo (within) crine (secrete) -TROPHY growth hypertrophy = excessive growth of an organ or part -MEGALY enlargement hepatomegaly [cancerindex.org]

• Aggressive Behavior

  Vascular invasion seems to predict aggressive behavior [9,43]. In addition, in the present study, all tumors characterized by necrosis recurred. [tandfonline.com]

• Neck Mass

  The overt hyperparathyroid bone or renal disease with palpable neck mass, as well as severe hypercalcemia with extremely high parathyroid hormone, are clinical parameters raising the suspicionforparathyroid carcinoma. [ncbi.nlm.nih.gov]

• Asthenia

  We describe the case of a 62-year-old woman with a 2-year history of asthenia and mental depression. Her past medical history was significant for osteoporosis. [ncbi.nlm.nih.gov]

  A 25-year-old male patient with a family history of osteogenesis imperfecta initially complained of fragility fractures in the wrist and ankle, and also reported asthenia, weakness, the loss of 12kg in three weeks, and generalized bone pain. [elsevier.es]

  We report the case of a 59-year old woman with a personal history of arterial hypertension and of recurrent renal lithiasis, presenting with diffuse bone pain associated with asthenia. [scienceopen.com]

  An 88-year old male patient presented with severe anaemia, asthenia and melaena in the previous days. [giornalechirurgia.it]

  Examples are special grips for holding utensils, computer screen monitors to help a person with low vision read more easily, computers controlled by talking, telephones that make the sound louder, and lifters to help a person rise out of a chair. asthenia [cancer.gov]

None of the symptoms described in the previous paragraph is pathognomonic for PC [4]. They may be observed in any condition involving the development of hypercalcemia or neck masses. Additional measures have to be taken to identify the parathyroid glands as the source of the disease and to distinguish PC from other, more common pathologies of these organs.

Laboratory analyses of blood samples are likely to reveal markedly increased levels of parathyroid hormone and severe hypercalcemia. It has been suggested that higher levels are reached in PC patients than in those with parathyroid adenoma, but the sensitivity and specificity of this criterion have not yet been tested in larger studies. Additionally, alkaline phosphatase concentrations may be elevated as well as levels of human chorionic gonadotropin in serum and urine [1] [2] [5].

Parathyroid tumors are usually depicted first using ultrasound. In this context, hypoechoic, inhomogeneous mass lesions with poorly demarcated borders should raise suspicion as to malignancies. PC tend to become larger, reach diameters of about 3 cm, show increased vascularization and possibly calcifications. They may have a capsule. Invasive growth is another feature associated with malignant neoplasms rather than parathyroid adenoma [1]. Additional techniques, such as scintigraphy or magnetic resonance imaging, may be used to corroborate these findings, to identify ectopic parathyroid tissue as well as metastases [6]. 18F-fluorodeoxyglucose positron emission tomography has recently been employed to clarify equivocal findings [2].

In any case, the diagnosis of PC should be based on the histopathological analysis of tissue samples [7]. These may be obtained by fine-needle aspiration or biopsy, or during the surgical resection of the unknown lesion. The latter is to be preferred in order to prevent the spread of cancer cells. PC are often described as solid and hard tumors of greyish to white color. They may have cystic parts and be surrounded by a dense fibrous capsule that firmly adheres to surrounding structures [1]. In 1972, Schantz and Castleman listed "a trabecular pattern, mitotic figures, thick fibrous bands, and capsular and blood vessel invasion" as the principle histological features that distinguish PC from adenoma, and these criteria are still applied today [3]. Immunohistochemical and genetic studies may be carried out to gain additional information. In this context, tissue samples may be tested for the expression of HRPT2, which is significantly reduced in the majority of PC [5]. 5-hydroxymethylcytosine has been proposed as an epigenetic marker of parathyroid neoplasms. It has found to be universally absent in PC while parathyroid adenoma stained positive [8]. Notwithstanding, further research is required to identify markers that allow for the reliable distinction between parathyroid adenoma and PC, to assess their sensibility and sensitivity [5].

• Nephrolithiasis

  PRTC presents as a palpable painless mass in the neck and causes severe hypercalcemia and related symptoms, non-specific gastrointestinal manifestations, as well as renal and bone complications related to primary hyperparathyroidism (nephrolithiasis, [orpha.net]

  Complications included nephrolithiasis in 14 of 25 patients (56%), bone disease in 20 of 22 patients (91%) and both in 8 of 15 patients (53%). All patients underwent primary surgical resection of parathyroid carcinoma. [scienceopen.com]

  These patients may be asymptomatic or have varied symptoms including peptic ulcerations, osseous brown tumors, nephrolithiasis and altered sensorium. [sonoworld.com]

  Clinical symptoms arise from parathyroid hormone increase and they can also consist of fatigue, weakness, weight loss, anorexia besides bone pain and renal symptoms such as nephrolithiasis (kidney stones and renal colic). [arquivosdeorl.org.br]

• Anterior Mediastinal Mass

  A routine chest film demonstrated a huge anterior mediastinal mass extending well into the right hemithorax (Fig. 1). [pubs.rsna.org]

Due to the rarity of PC, there is no general consensus on management and follow-up. Most experts agree that radical surgery is the initial treatment of choice for PC, where en bloc resection of the tumor should be combined with the excision of the ipsilateral thyroid lobe. Cervical lymph node dissection is recommended if metastatic spread has been proven but should be avoided in patients with localized disease [7]. Following the resection of PC, hypocalcemia and hypophosphatemia are to be expected and should be counteracted with calcium and activated vitamin D therapy [4] [5]. Of note, PC is considered to be refractory to radiation and chemotherapy, although this perception is based on small case studies [2].

In cases of advanced, inoperable PC, the maintenance of calcium homeostasis takes a pivotal role in disease management. Saline infusion and loop diuretics are generally used to this end but may be insufficient to lower serum calcium levels. Cinacalcet may then be employed to increase the sensitivity of the calcium-sensing receptors of parathyroid cells, thereby inhibiting the secretion of parathyroid hormone. Bone resorption by osteoclasts may also be diminished by mitramycin, plicamycin, gallium nitrate, bisphosphonates, calcitonin, or denosumab [4] [5].

Five-year survival rates for PC amount to 82%, ten-year survival rates have been estimated at 66%. Median survival has been reported to be 14 years [9]. Recurrence is a rather common, unfavorable prognostic factor: Despite all efforts, it occurs in more than half of all cases. Repeated surgeries should be carried out after detailed localization studies and may aim at cure or debulking in preparation for palliative therapy. Mortality is mostly due to intractable hypercalcemia.

The triggers of PC development remain largely unknown. Genetic factors are likely to play an important role and may indeed predispose to the disease. Patients with hyperparathyroidism-jaw tumor syndrome, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2A, or familial isolated hyperparathyroidism are at higher risks of PC than the general population. Notwithstanding, PC is not a common feature in either of those cases. Its prevalence is far exceeded by that of parathyroid adenoma even if the molecular biological background favors the development of endocrine tumors. Prior radiotherapy of the neck has been identified as another risk factor for PC, as well as chronic renal failure, prolonged secondary and subsequent tertiary hyperparathyroidism [2]. These conditions may constitute an ongoing stimulation for growth.

PC is a very rare malignancy. About 1,000 cases have been reported in literature since the disease has first been described in 1904, and it has been estimated to account for 0.005% of all cancers [1]. What's more, PC is identified in only 1% of patients presenting with primary hyperparathyroidism [8].

Men and women are affected equally and are typically diagnosed during their fifth or sixth decade of life. Parathyroid adenoma, by contrast, tends to develop later in life and is more commonly diagnosed in females [2].

The identification of genes associated with endocrine tumor syndromes as listed above has allowed for the generation of hypotheses regarding the molecular basis of parathyroid cancerogenesis. One of these genes has been named HRPT2. It is also known as parafibromin or CDC73 and has initially been related to hyperparathyroidism-jaw tumor syndrome [10]. The gene has been characterized as a tumor suppressor involved in transcriptional and post-transcriptional control, and possibly in cell cycle progression. Similarly, the MEN1 gene, whose mutations underlie multiple endocrine neoplasia type 1, has been identified as a tumor suppressor affecting transcriptional regulation. Mutations of HRPT2 and MEN1 have later been detected in subsets of families affected by familial isolated hyperparathyroidism and, with regards to parafibromin, have been stated to account for up to 70% of sporadic PC [4] [11]. These findings suggest dysfunctional transcriptional regulation as a common origin of PC development, and this condition may render parathyroid cells susceptible to the accumulation of additional genetic alterations. In detail, mutations of known oncogenes such as mTOR, KMT2D, CDKN2C, THRAP3, PIK3CA, and EZH2 may subsequently be acquired. They have repeatedly been determined in PC, albeit none of them is specific for PC [4].

PC occurring in the setting of genetic syndromes should prompt a thorough familial workup. First-degree relatives of PC patients carrying mutations of HRPT2 should be encouraged to undergo genetic testing, and those who are actually diagnosed with endocrine tumor syndromes should be recommended to participate in surveillance programs. Beyond that, no specific recommendations can be given to prevent the development of malignant tumors of the parathyroid glands.

PC is generally referred to as the rarest endocrinological malignancy. Unfortunately, its rarity implies a lack of reliable data regarding diagnostic criteria and the efficacy of distinct therapeutic approaches. What's more, PC is generally diagnosed after the resection of degenerated parathyroid tissue, but the surgical approach is one of the most important prognostic factors. When PC is suspected before surgery, a radical procedure can be performed, leaving wide disease-free margins. The particularly cautious handling of parathyroid malignancies further helps to diminish the risk of local recurrence and improves the outcome. Thus, awareness needs to be raised among endocrinologists and oncologists for this rare entity. The risks of more aggressive surgery should be carefully weighed against the chances for cure, and in this context, a series of parameters should be considered before making the diagnosis of parathyroid adenoma or carcinoma.

The parathyroid glands are small endocrine glands located in close proximity to the thyroid in the anterior neck. Despite their tiny size, they play a pivotal role in the maintenance of calcium homeostasis. They secrete parathyroid hormone, which promotes the mobilization of calcium and phosphate from bone. It also augments the excretion of phosphate but prevents the renal loss of calcium.

Similar to other tissues, the parathyroid glands may undergo degenerative changes, and patients may develop parathyroid tumors. In the vast majority of cases, parathyroid tumors are benign adenomas. Parathyroid cancer, otherwise known as parathyroid carcinoma, is a very rare entity. People with genetic syndromes such as hyperparathyroidism-jaw tumor syndrome, multiple endocrine neoplasia, or familial isolated hyperparathyroidism are at increased risks of parathyroid cancer, but it may also develop in the absence of a genetic predisposition.

The development of parathyroid carcinoma is associated with an increase of parathyroid size, but few patients present with palpable neck masses. The majority of affected people suffer from hypercalcemia, the main consequence of excess parathyroid hormone secretion. Serum calcium levels may augment significantly and induce kidney stones and renal failure, bone pain and susceptibility to fractures, anxiety and depression, among others. The presence of such symptoms combined with laboratory and imaging findings may raise suspicion as to parathyroid carcinoma.

In any case, this suspicion needs to be confirmed after the surgical resection of the tumor. Surgery thus serves a double purpose: It is the therapeutic approach of choice, the one that implies best chances for cure, and it yields tissue samples to verify the original diagnosis. Follow-ups are scheduled according to the results of histopathological analyses and may be required throughout life.

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3. Schantz A, Castleman B. Parathyroid carcinoma. A study of 70 cases. Cancer. 1973; 31(3):600-605.
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10. Carpten JD, Robbins CM, Villablanca A, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet. 2002; 32(4):676-680.
11. Villablanca A, Calender A, Forsberg L, et al. Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP). J Med Genet. 2004; 41(3):e32.