Abstract
Background: Parathyroid carcinoma is a rare malignancy that accounts for 0.5% to 5% of all cases of primary hyperparathyroidism. It may occur sporadically or as a part of a genetic syndrome. Diagnosis is challenging due to the lack of clinical and pathological features that may definitively distinguish malignant from benign disease.
Methods: From January 2013 to December 2017, from a population of 358 patients affected by parathyroid diseases, 3 patients were managed for PC in our Academic Department of General Surgery. We retrospectively analysed our experience and performed a literature review.
Results: Case 1: A 62-year-old man was admitted for left-sided palpable neck mass confirmed by US and CT scan, associated to hypercalcemia and elevated PTH. FNA was suspect for parathyroid carcinoma. At surgery, a large cystic parathyroid mass was excised in bloc with total thyroidectomy and a central neck dissection was performed. Pathology confirmed parathyroid carcinoma, and MEN1 was post-operatively diagnosed. Case 2: A 48-year-old woman with hypothyroidism was referred to our Department for a US-detected solid nodule on the posterior margin of the right lobe of thyroid, cytologically suspect for follicular thyroid lesion. The patient underwent total thyroidectomy. Histopathology revealed parathyroid cancer. Case 3: A 47 year-old man was admitted for hypercalcaemic crisis in the context of PHPT and renal failure. A nodule suggestive for parathyroid adenoma was detected on the posterior margin of the inferior right thyroid lobe on US and removed by mini-invasive approach. Pathology revealed parathyroid cancer and re-surgery consisted in hemythyroidectomy and central neck dissection.
Conclusion: Despite parathyroid cancer is an extremely rare endocrine malignan¬cy it should be suspected in patients with primary hyperparathyroidism when severe hypercalcemia is associated to cervical mass, renal and skeletal disease. Parathyroid surgery remains the mainstay of treatment. Radical tumour resection and surgery by an experienced endocrine surgeon represent the crucial prognostic factors.
KEYWORDS: Parathyroid Carcinoma, Parathyroidectomy, Endocrine Surgery, Hyperparparathyroidism, Hypercalcemia, MEN 1, Diagnosis.
Background
Parathyroid carcinoma (PC) is a rare malignancy that was first described in 1904 by de Quervain [1] as a metastat¬ic non-functioning carcinoma [2-4]. Since then, less than 1,000 recorded cases have been reported in literature [3-6]. It accounts for between 0.5% and 5% of all cases of primary hyperparathyroidism (PHPT) [6-12]. Further, it is the least commonly seen endocrine cancer worldwide, and has an estimated prevalence of 0.005% of all cancers [8, 13]. The pathogenesis of PC is unknown. It may occur sporadically or as a part of a genetic syndrome as hyperparathyroidism jaw tumour syndrome (HPT-JT), Multiple Endocrine Neoplasia type 1 (MEN1), Multiple Endocrine Neoplasia type 2A (MEN2A), and familial isolated hyperparathyroidism (FIHP) [14-16]. PC poses a diagnostic challenge because of the lack of features that can definitively distinguish malignant from benign disease. Unfortunately, due to its rarity, there is no universal consensus regarding management and follow-up.
The aim of this study was to review the recent literature on PC and to report PCs treated at our Institution over the last 5 years.
METHODS
From January 2013 to December 2017, from a population of 358 patients affected by parathyroid (PTs) disease, 3 patients (0.8%) were managed for PC (1 Female and 2 Male; mean age: 52.33, range: 47-62) at our Academic Department of General Surgery. We retrospectively reviewed clinical presentation, diagnosis, treatment and follow up.
RESULTS
Case 1: A 62-year-old man with a history of nephrolithiasis, constipation, thalassemia trait and type-2 diabetes, was admitted with a large asymptomatic, left-sided palpable neck mass, hypercalcemia (2,92 mmol/L), high levels of PTH (391.7 pg/ml), and polyuria. Doppler ultrasound scan showed a multinodular thyroid and a partially retrosternal cystic large mass adjacent to the left lobe of the thyroid and to the oesophagus. CT confirmed a large lesion (9 cm in diameter) also extending into the upper mediastinum. FNAC demonstrated a PT neoplasm. The PT mass was excised in bloc with the thyroid gland and a central neck dissection (CND) was performed. During neck exploration another enlarged PT mass (PT4) was found and removed. A dense adhesion between the mass and pre-thyroid muscles, left recurrent laryngeal nerve (RLN) and oesophagus was evident, and a dissection was meticulously performed through microsurgical technique (loupe magnification 3x). Intraoperative upper gastro-intestinal endoscopy showed integrity of the oesophagus with no macroscopical infiltration. Pathology confirmed the diagnosis of PC without thyroid involvement or lymphatic metastases, while the other excised PT gland showed hyperplasia.
The patient’s brother was also diagnosed with PC in the interim, so a hereditary disease was suspected. A germline mutation of the MEN1gene (c.1252 G>A) was found. Genetic test was offered to the at-risk patient’s relatives, identifying the MEN 1 mutation in two of them. The patient was evaluated for MEN 1–related lesions. Magnetic Resonance Imaging (MRI) of the head showed no pituitary lesions; endoscopic US identified pancreatic lesions suggesting neuroendocrine tumours, and a non-functional adrenal nodule was found at CT scan. At 5-year follow-up, the patient shows normal calcemia and is free from recurrence.
Case 2
A 48-year-old woman was referred to our Department for thyroid disease. Past medical history revealed essential hypertension under treatment and no family history of endocrinological disease. Physical examination was otherwise normal. TSH (thyroid-stimulating hormone) was raised to 5.67 mUI/L (range 0.36–3.74 mUI/L), and FT4 (free triiodothyronine T4) and FT3 (free triiodothyronine T3) were normal. Routine biochemistry showed normal serum calcium, phosphorous, calcitonin, and thyroglobulin levels. PTH was not investigated. Neck US scan showed a normally sized thyroid and a 33x15x17 mm solid nodule with fluid areas inside, located at the posterior margin of the right thyroid lobe; no adenopathy was found. FNA of the solid part of the nodule demonstrated highly cellular groups of epithelial cells arranged in follicle-like groupings in a background lacking colloid. These findings led to a working diagnosis of follicular thyroid lesion. The patient underwent total thyroidectomy. During surgery, a solid grayish mass measuring 2.2×1.6×1 cm was found within the mid pole of the right thyroid gland. The mass was in close contact with the posterior side of the trachea and the right wall of the oesophagus, so a careful dissection was carried out through microsurgical technique. The surgeon could not find a distinct superior PT gland. Postoperative period was uneventful and the patient was discharged on the second post-operative day. Unexpectedly, pathology revealed an intrathyroidal PC of the right thyroid lobe with a cystic component, fibrosis and endocapillary proliferation. No invasion of the thyroid gland was found. The 30-month follow-up did not show residual-recurrent disease.
Case 3
A 47 year-old man was admitted as an emergency to the Department of Medicine for renal failure, hypercalcaemic crisis (5.33mmol/L) and symptomatic nephrolithiasis. He was then referred to our Department for PHPT. Physical examination was unremarkable with no evidence of neck mass or lymphadenopathy. Laboratory tests showed severe renal failure, hypercalcemia (5.33 mmol/L, n.v. = 2.25- 2.67 mmol/L), hypophosphataemia (0.55 mg/dL, n.v. = 2.5-4.50 mg/dL) and high PTH (919.0 p/mL; n.v.: 6.4–52 pg/mL). Excreted 24-hour urine calcium was elevated (494 mg/24 h, n.v. = 42–353 mg/24 h), phosphate excretion was normal and there was proteinuria. US scan identified a hypoechoic 17×16 mm nodule on the posterior margin of the inferior right lobe suggestive for parathyroid adenoma (PA). Technetium-99m-sestamibi (MIBI) dual-phase scan revealed increased uptake in the right inferior PT gland. The patient underwent right inferior minimally invasive video-assisted parathyroidectomy. During surgery a 4×2.5×2 cm solid brown mass was found. Intraoperative PTH dropped by more than 50% after resection. Postoperative course was uneventful, with decreasing PTH levels, and the patient was discharged 2 days after surgery. Pathology revealed a PC with microscopic aspects of vascular invasion and surrounding adipose tissue infiltration. Therefore the patient was scheduled for completion surgery while showing increasing PTH levels (429.0 pg/mL n.v.: 6.4–52 pg/mL). Hemythyroidectomy and CND were performed, with uneventful recovery and discharge on postoperative day 3. Final pathology showed no metastatic lymph nodes and no thyroid involvement.
DISCUSSION
Epidemiology
PA represents a common endocrine problem, whereas PCs are very rare tumours. With an estimated incidence of 0.015 per 100,000 population and an estimated prevalence of 0.005% in the United States, PC is one of the rarest of all human cancers [13, 17]. PC has been estimated to cause HPT in 0.017% to 5.2% of the cases and accounts for less than 1% of patients with PHPT in many series [17-20]. There is no gender or race dominance in PC and its onset is usually a decade earlier than PA, with a mean age of 45-51years [13, 17]. As for PHPT, its incidence has increased in the last decades following the introduction of routine serum calcium measurements among hospital admissions [21, 22]. An explanation for such increase in the incidence of PC could be that recommendations for PT for asymptomatic HPT became less stringent compared with previous recommendations [23]. The 90% of PC tumours are hormonally functional, and most patients present signs and symptoms of hypercalcemia as the initial manifestation of the disease [5]; to date, 38 cases of non-functional PC are have been described in literature, mostly presenting in the sixth or seventh decade [24].
Etiology
The etiology of PC is unknown, although PC has been associated with external radiation exposure [2, 25, 26]. Rare cases of PC have also been reported in patients with secondary and tertiary HPT due to chronic renal failure [22, 27, 28]. An association of PC in patients with a history of either PA or hyperplastic PT glands, or thyroid cancer and PA has also been reported, occurring either synchronously or metachronously [20, 29, 30]. Despite these associations, no evidence of PC arising from malignant transformation of pre-existing PT lesions has been found [31]. PC may occur sporadically or as part of a genetic syndrome [32] as in 15% of individuals with HPT-JT [16, 33, 34], in 1% of FIHP patients [13, 35, 36], and has rarely been reported in MEN2A syndrome [37]. PC is 0.28-1% of all cases undergoing surgical treatment for HPT in MEN 1[38, 39]. Somatic genes mutations have been associated with PC, such as HRPT2 (CDC73, or Parafibromin), abnormal expression of the retinoblastoma and p53 proteins, and tumour suppressor genes on chromosome 13 [40-42].
Clinical
PC shows low malignant potential and typically runs an indolent, albeit tenacious, course; patients often exhibit symptoms and complications of severe PHPT such as depression, anxiety, weight loss, weakness, bone disease, renal involvement, abdominal pain, nausea, pancreatitis and peptic ulcer disease [4, 6, 13, 43].
Moreover, at the time of presentation, 50% of patients with PC show simultaneous manifestations of renal and skeletal involvement including osteopenia, osteoporosis, osteofibrosis, osteitis fibrosa cystica, subperiostal resorption, “salt and pepper” skull and pathologic fractures demonstrated in up to 90% of patients [6, 14, 17, 20, 43]. Renal disease manifests mostly as nephrolithiasis and renal insufficiency with a reported prevalence of 56% and 84%, respectively [44]. Physical examination is commonly unrevealing, as in Case 2, but the finding of a palpable cervical mass has been described in 30–76% of patients [20, 44-46]. Another clinical sign that can be highly suggestive is the hoarseness due to RLN palsy [47].
Some patients, as Case 3, may present with a hypercalcaemic crisis. Entirely asymptomatic presentation of PC has been reported in 7-46% [8, 44, 48, 49]: non-functional PCs (less than 10%) usually present at a more advanced stage with symptoms of compression/invasion of adjacent structures [24, 29, 50-52]: neck mass and/or dysphagia (up to 80% of cases), hoarseness or dyspnoea [8, 24, 53].
Laboratory
There is no agreed threshold of PTH and serum calcium level to define PT malignancy. Serum calcium levels in PC are frequently higher than 3.5 mmol/L (vs. under 2.8 mmol/L in benign PT disease), and PTH serum levels are commonly 3 to 10 times higher than the upper normal limit while benign disease usually shows a more modest increase [8, 14, 25, 44, 53, 54]. In addition, alkaline phosphatase levels have been shown to be significantly higher in PC than in benign disease, with levels under 300 IU/L making PC unlikely [49]. Serum and urinary levels of human chorionic gonadotropin and its hyperglycosilated isoform are abnormally elevated in patients with PC, but not in those with PA [55].
Imaging
Imaging is useful, as in benign disease, for the tumour localization, but cannot reliably distinguish between benign and malignant disease. The diagnostic sensitivity and accuracy are increased when more than one imaging method is used [5], most commonly a combination of MIBI and neck US [14, 56, 57]. US is not able to definitely discern PC from benign cases, but some sonographic features may suggest PC and detect lymph node enlargement and invasion of adjacent structures [58, 59]; at neck US, size >3 cm should raise the suspicion of PC [60], as in Case 1. PCs are more likely to be inhomogeneous, hypoechoic, with lobulated/non-circumscribed margins, degenerative changes, intra-nodular calcification, suspicious vascularity, a thick capsule and local invasion; on the contrary, PAs appear as homogenous, smooth, and smaller masses [60-63]. MIBI allows identifying eutopic and ectopic PT tissue as well as recurrent disease, but there are no specific features to distinguish PA and PC [47, 57, 64]. CT usually shows low sensitivity in detecting PC [65], while MRI is characteristically adequate for soft tissue studies [66]; both modalities may provide information about lesion extension, eventual invasion into surrounding structures, lymph nodes or distant metastasis [5, 59]. Although selective venous catheterization with PTH measurement has shown high sensitivity in localization of PT lesions [67, 68], it is an invasive and not commonly available method. It should be performed only when other non-invasive studies have failed PC localization [6, 69]. Few studies are available on the use of 18F-fluorodeoxyglucose positron emission tomography (FDG PET), aimed at the early identification of metastases/recurrence [66, 70-72].
Cytology, Histopathology
Cytological and histopathological diagnosis are challenging [17, 20]. If PC is pre-operatively suspected, FNA should be avoided because of the risk of tumour seeding along the needle tract, with higher risk of recurrence [5, 65, 73, 74]. According Kendrick et al., indeed, before proceeding with the intervention, it is absolutely essential that the surgeon is convinced of the diagnosis considering the biopsy of a suspected parathyroid carcinoma not useful and in many cases harmful: a capsular rupture of parathyroid gland and its content diffusion into the surrounding tissue is also reported in literature [75,76].
In 1973, Schantz and Castleman first reported a set of morphologic criteria consisting of fibrous bands forming a trabecular architecture intersecting the tumours, capsular invasion [77-79], vascular invasion, and mitotic activity [31]. Capsular and vascular invasion appear to be unequivocally correlated with tumour recurrences and metastases and are considered the sole pathognomonic markers of malignancy [80,81]. An aneuploid DNA pattern appears to be associated with poorer prognosis [25, 56, 82].
The histological findings for non-functional PC are similar to its functional counterpart. These tumours are large, mainly consisting of clear or oxyphil cells, and can be misdiagnosed as thyroid or thymic cancers. A positive immunostaining for intracellular PTH and chromogranin A, together with absence of thyroglobulin, calcitonin and thyroid transcription factor 1, has been used to diagnose non-functional PC [50]. Immunohistochemistry may improve diagnostic accuracy of PC as also suggested by with the American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary HPT. Several oncogenes and tumour suppressor genes have been linked to PC [83]. Up to 70 % of PC carries a somatic mutation of CDC73, a tumour suppressor gene associated with parafibromin expression [84]. CDC73 mutations are found rarely in sporadic benign PAs (0.8%) [28, 85-87]. In one-third of PC cases mutations are germline [88], suggesting that a subset of patients may have a HPT-JT syndrome [85,89,90], as germline mutations of the CDC73 gene have been responsible for HPT-JT [28, 33] and few kindreds with FIHP [28, 52, 85, 86, 89-96]. Negative parafibromin staining together with a CDC73 gene mutation increases the likelihood of malignancy, and has been found very rarely in Pas [97-106].
Several other genes and/or their encoded proteins have been linked to PC: retinoblastoma (Rb), p53, breast carcinoma susceptibility (BRCA2), and cyclin D1/PA 1 oncogene (PRAD1) [50, 69, 107, 108]. However, none of them could consistently and reliably distinguish between PC and PA [108]. Aberrant expression of microRNAs (miRNAs) has also been reported in PC [109].
The current literature is lacking with respect to the immune microenvironment in parathyroid neoplasms, and the potential application of immunotherapeutic strategies for PC remains unknown. Some authors have suggested possible benefit from immunotherapy basing on the expression in the microenvironments in PCs of death-ligand 1, tumor-infiltrating lymphocytes and CD68+ as potential biomarkers target in cancer therapies [110].
Intra-Operative Diagnosis
Intra-operative findings have been described to raise the suspicion of PC. In most series, the median maximal diameter of PC is between 3 and 3.5 cm, with less than 10% of them larger than 4 cm, as in Case 1, compared with approximately 1.5 cm for PA, and their weight varies from 2 to 10 g [11, 13, 17, 111]. Their colour ranges from greyish to white. These tumours are firm, often showing a stony-hard consistency, occasionally lobulated and usually surrounded by a dense fibrous capsule. They can adhere to or invade surrounding structures such as the ipsilateral thyroid and strap muscles, the ipsilateral RLN, oesophagus and trachea (Case 1) [9, 56, 111, 112]. A cystic component has been reported in 21% of PC (Case 1) [5, 29]. Conversely PAs are smaller, soft, round, or oval in shape, and of a reddish-brown colour [20,111].
Stage Information
Because tumour size and lymph node status generally do not correlate with survival, and the disease is rarely diagnosed preoperatively or even intraoperatively, no agreed clinical and pathological staging system for PC has been universally adopted [10, 13, 26, 113, 114]. Schulte et al have proposed a staging system based on two classification schemes, the differentiated classification as in the framework of TNM classification and high-risk/low-risk classification that seems to show a significant predictive power for survival and recurrence [115, 116].
Surgical Treatment
Historically almost 96% of patients with PC underwent surgical treatment [11, 13], with a rate of patients surgically treated increasing over the decades. Surgery is the only effective therapy for PC [17, 20, 117]. At the time of the initial operation, complete surgical resection with microscopically negative margins, avoiding tumour capsule rupture, is the recommended treatment and offers the best chance of cure. Although it is certain that an incomplete resection of the tumour results in high local recurrence rate, there is no clear consensus on the appropriate extent of surgery. Reported surgical interventions can be grouped into two categories: local excision only, and en bloc excision. Local excision comprises only pericapsular excision of the PT lesion [116]. On the other hand, most authors recommend en bloc excision consisting in the resection of the tumour, ipsilateral thyroidectomy, and possibly resection of adjacent cervical muscles, paratracheal tissues, and the RLN segment if involved at the initial operation, to reduce the need for repeat surgery and improve survival outcomes [12, 81, 114]. Overall 8% local recurrence rate has been reported after en bloc resection, compared with a 51% after standard parathyroidectomy [26]. It has been recently reported that only 12.5% of patients underwent en bloc resection compared with 78.5% receiving parathyroidectomy alone, most likely because they are not identified preoperatively or even intraoperatively as having PC [11]. There is no clear evidence on performing prophylactic CND or lateral neck dissection, and it has not been proven to improve survival [11, 13, 14, 29, 118, 119]. Lymphadenectomy, beyond that necessary to achieve en bloc excision of the primary malignancy, is not currently indicated unless enlarged or firm nodes – particularly in the VI, III and IV levels – clinically indicate the presence of nodal disease [17]. On the other hand CND at initial surgery in all patients with PC has been proposed on the basis that omitting a central and/or ipsilateral jugular compartment dissection has been reported to carry a 1.5- to 2-fold higher risk for recurrence and death at 5 years, and that central compartment is involved in up to 10% of cases [115]. Intra-operative PTH levels can fall significantly after PC resection, but often not as rapidly as with the resection of benign disease. No PTH drop could mean that an incomplete tumour resection has been performed, or concomitant multiple gland hyperplasia [120], or even multiple PCs [121] should be suspected. Exploration of all four glands may be required as carcinoma of multiple glands and the concurrent presence of PC and PA, has been documented in the literature [122,123].
Follow-Up
Restoration of normal calcemia after surgery indicates that all hyperfunctioning tissue has been removed. Nevertheless, patients with PC should receive life-long monitoring because they may be at a relatively high risk of multiple relapses over prolonged periods of time [48]. During follow-up patients with functional PC should undergo serum calcium, PTH levels and regular US surveillance, whereas those with non-functional PC should only rely on imaging studies.
A common clinical situation is post-operative diagnosis of PC in a patient who was suspected to have a benign pathology, as in Cases 2 and 3. If the macroscopic features are typical of a PC and extensive vascular or capsular invasion are present at histology, a reoperation aimed at resecting the adjacent structures should be considered: vascular invasion has been reported as an important independent predictor associated with recurrence and haematogenous spread [115, 116]. Similarly, repeated surgery, after appropriate localization studies, should be considered in patients with persistent/relapsing hypercalcemia [20, 124]. If the patient is normocalcemic and the histology is equivocal, immediate reoperation is not indicated, as complete resection of the tumour may have been curative.
Metastasis and Local Recurrence
Lymph nodes and distant metastases are rare at the initial diagnosis, occurring respectively in 1-6% and 2-4% [7, 10, 11, 25, 26, 44, 48, 53, 125]. Approximately 40% to 60% of patients experience a postsurgical relapse between 2 to 5 years after the initial resection, presenting with a slowly increasing PTH and serum calcium level in functioning PCs only [24, 50, 114, 126]. Distant metastases have been reported to occur in 25% of patients [25, 127] during follow-up, even though more recent series indicate that the incidence of relapse may be higher [17]. The disease-free interval between initial surgery and the occurrence of metastases may be as long as 20 years [96, 114, 127]. The most common site of distant metastasis is the lung(40 %), followed by the liver(10 %) and, very rarely, bone, pleura, pericardium, and pancreas [19, 20].
Some patients experience years of survival even after the diagnosis of distant metastases, indeed the clinical course is usually indolent and when the disease progresses patients complain mostly because of the clinical manifestations of hypercalcemia and its complications, rather than from symptoms related to the tumour spread [20]. Recurrent or metastatic disease in a patient previously operated for hypercalcemia can be the first indicator of tumour malignancy [48].
Recurrence is typically regional, accounts for approximately two thirds of relapses [25] and is often difficult to identify as it may be small and multifocal, and involve scar tissue from the previous surgical procedure. Approximately 50% of the patients who experience recurrence will also have distant metastases [127].
The primary treatment for tumour relapse is the surgical removal of the local recurrences and distant metastases whenever this is possible, even though repeated resection [13, 17, 44, 128-131]. Although aggressive surgical resection has been associated with a 30% long-term survival in retrospective series, it can rarely result in cure [127, 129]. Resection of even very small tumour deposits in the neck, lymph nodes, lungs, or liver, may instead provide significant palliation making hypercalcemia more medically manageable, resulting in periods of normocalcemia ranging from months to years [7, 13, 25, 44, 98, 128, 130, 132].
At least two independent non-invasive preoperative localization studies should be performed in all patients before reoperation: US is effective in localizing local metastases, especially those involving neck lymph nodes, while MIBI scan can detect both local and distant metastases, which may also be visible on CT and MRI [64, 133, 134]. If previous imaging studies fail to locate the recurrence site(s) or show equivocal results, selective venous catheterization and PTH measurement could be considered [56, 69]. FNA of equivocal lesions should be avoided because of the potential for dissemination [74].
In redo neck surgeries the cumulative surgical complication risks greatly increase (up to 60%) and the RLN injury rate is higher (up to 38%) [29, 69, 135].
In patients affected by genetic syndromes as HPT-JT and MEN1, recurrent hypercalcemia after initial surgery may suggest either recurrence and/or metastases of the primary tumour or the involvement of an additional PT [136].
Radiofrequency ablation alone or in combination with arterial embolization has successfully been used in the treatment of hepatic and lung metastases showing improvement in serum calcium and PTH levels [137,138].
Percutaneous US-guided alcohol injection has been reported in local recurrences, producing short-term improvements in calcium and PTH levels [139]. However, in view of complications associated with ethanol toxicity and RLN injuries [140] its use in the central neck region should be carefully considered.
Chemotherapy and Radiotherapy
Non-operative therapies for PC generally have poor results [17, 20, 48, 117]. Chemotherapy is usually ineffective. Anecdotal reports of short-term remissions have been demonstrated with single-agent dacarbazine [114], a combination of flurouracil, cyclophosphamide and dacarbazine, and a combination of methotrexate, doxorubicin, cyclophosphamide, and lomustine in patients with metastatic disease with no overall survival gain [141-143].
The results of radiotherapy are also usually non satisfactory [44] and there is currently no evidence to support the use of radiation therapy as a primary modality of treatment. Despite these neoplasms show radiation resistance, some investigators have advocated the use of radiation to improve on local recurrence rates and overall survival in small series [13, 44, 45, 48, 83, 144]. Reported experience on palliative radiotherapy is even scarcer.
Prognosis
The prognosis of PC is quite variable. Overall survival rates are generally better than in most solid tumours, with 76-85% and 49–77% patients alive at 5 and 10 years follow-up, respectively [11, 13, 29, 48, 114].
Because there is no agreed-upon staging system for PC, it is currently not possible to provide patients with reliable prognostication system. Observations on the prognosis of PC mainly derive from longitudinal single-institution studies and small series [5, 145]. Schulte et al show that the relative risk of cancer-related death is substantially higher in high-risk patients, in fact almost exclusive to them, as the relative risk of tumour relapse is 12.8 times higher in such cases [116]. Once the tumour recurs, a complete cure is unlikely, although prolonged survival is still achievable with palliative surgery.
Complete resection of the tumour at initial surgery carries the best prognosis, showing survival rates up to 90% at 5 years and 67% at 10 years [146]. In studies where complete pathology reports on lymph node status were available, nodal status was determined to be a prognostic factor associated with mortality [29, 125].
Other independent negative prognostic factors for survival have been age, sex, distant metastases, time to first recurrence, higher serum calcium level at recurrence, numbers of neck recurrences, use of several calcium-lowering medications, simple parathyroidectomy as initial surgery, inability to completely resect tumour, and tumour DNA aneuploidy [11, 29, 48, 114]. In addition, patients whose tumour carried a CDC73 mutation, and/or loss of parafibromin or CASR expression revealed worse survival rate [103, 147]. The prognosis of non-functional PC also appears to be worse since they are often diagnosed in advanced stages, already showing local invasion, nodal and/or distant metastasis. Cancer-related death in non-functional PC patients is primarily due to the volume of regional disease and metastases, while in functional cancers it is usually due to uncontrollable hypercalcemia, causing complications such as renal failure, cardiac arrhythmias or pancreatitis [29, 148].
CONCLUSION
Despite its rarity, in the presence of HPT showing severe hypercalcemia, cervical mass and concomitant renal and skeletal disease, a PC should be always suspected. The earliest possible surgery is the gold standard in the treatment, and patients with suspected PC should be referred to an experienced PT centre as the delay in diagnosis is the main risk factor influencing prognosis. However, further multi-centric studies are needed to standardize the management and to improve results