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Endocrine Pathology Mar 2022The 2022 WHO classification reflects increases in the knowledge of the underlying pathogenesis of parathyroid disease. In addition to the classic characteristic features... (Review)
Review
The 2022 WHO classification reflects increases in the knowledge of the underlying pathogenesis of parathyroid disease. In addition to the classic characteristic features of parathyroid neoplasms, subtleties in histologic features which may indicate an underlying genetic abnormality reflect increased understanding of the clinical manifestations, histologic, and genetic correlation in parathyroid disease. The importance of underlying genetic aberrancies is emphasized due to their significance to the care of the patient. Traditionally, the term "parathyroid hyperplasia" has been applied to multiglandular parathyroid disease; however, the concept of hyperplasia is generally no longer supported in the context of primary hyperparathyroidism since affected glands are usually composed of multiple "clonal" neoplastic proliferations. In light of these findings and management implications for patient care, the 2022 WHO classification endorses primary hyperparathyroidism-related multiglandular parathyroid disease (multiglandular multiple parathyroid adenomas) as a germline susceptibility-driven multiglandular parathyroid neoplasia. From such a perspective, pathologists can provide additional value to genetic triaging by recognizing morphological and immunohistochemical harbingers of MEN1, CDKN1B, MAX, and CDC73-related manifestations. In the current WHO classification, the term "parathyroid hyperplasia" is now used primarily in the setting of secondary hyperplasia which is most often caused by chronic renal failure. In addition to expansion in the histological features, including those that may be suggestive of an underlying genetic abnormality, there are additional nomenclature changes in the 2022 WHO classification reflecting increased understanding of the underlying pathogenesis of parathyroid disease. The new classification no longer endorses the use of "atypical parathyroid adenoma". This entity is now being replaced with the term of "atypical parathyroid tumor" to reflect a parathyroid neoplasm of uncertain malignant potential. The differential diagnoses of atypical parathyroid tumor are discussed along with the details of worrisome clinical and laboratory findings, and also features that define atypical histological and immunohistochemical findings to qualify for this diagnosis. The histological definition of parathyroid carcinoma still requires one of the following findings: (i) angioinvasion (vascular invasion) characterized by tumor invading through a vessel wall and associated thrombus, or intravascular tumor cells admixed with thrombus, (ii) lymphatic invasion, (iii) perineural (intraneural) invasion, (iv) local malignant invasion into adjacent anatomic structures, or (v) histologically/cytologically documented metastatic disease. In parathyroid carcinomas, the documentation of mitotic activity (e.g., mitoses per 10mm) and Ki67 labeling index is recommended. Furthermore, the importance of complete submission of parathyroidectomy specimens for microscopic examination, and the crucial role of multiple levels along with ancillary biomarkers have expanded the diagnostic workup of atypical parathyroid tumors and parathyroid carcinoma to ensure accurate characterization of parathyroid neoplasms. The concept of parafibromin deficiency has been expanded upon and term "parafibromin deficient parathyroid neoplasm" is applied to a parathyroid neoplasm showing complete absence of nuclear parafibromin immunoreactivity. Nucleolar loss is considered as abnormal finding that requires further molecular testing to confirm its biological significance. The 2022 WHO classification emphasizes the role of molecular immunohistochemistry in parathyroid disease. By adopting a question-answer framework, this review highlights advances in knowledge of histological features, ancillary studies, and associated genetic findings that increase the understanding of the underlying pathogenesis of parathyroid disease that are now reflected in the updated classification and new entities in the 2022 WHO classification.
Topics: Humans; Hyperparathyroidism, Primary; Parathyroid Glands; Parathyroid Neoplasms; Tumor Suppressor Proteins; World Health Organization
PubMed: 35175514
DOI: 10.1007/s12022-022-09709-1 -
Frontiers of Hormone Research 2019Parathyroid carcinoma (PC) is a rare endocrine malignancy, accounting for <1% of all cases of sporadic primary hyperparathyroidism (PHPT) and up to 15% in the hereditary... (Review)
Review
Parathyroid carcinoma (PC) is a rare endocrine malignancy, accounting for <1% of all cases of sporadic primary hyperparathyroidism (PHPT) and up to 15% in the hereditary hyperparathyroidism-jaw tumor syndrome. Genomic alterations identified in PC are mostly represented by CDC73 gene mutations, codifying for a loss-of-function protein termed parafibromin. Whole exome sequencing identified mutations in other genes, such as mTOR, KMT2D, CDKN2C, THRAP3, PIK3CA, and EZH2 genes, CCND1 gene amplification. The diagnosis of PC is quite difficult due to the lack of reliable clinical diagnostic criteria, and in the majority of cases is made postoperatively at histological examination. The clinical manifestations of PC are primarily due to the excessive secretion of PTH by the tumor rather than spread to local or distant organs. En bloc resection of the parathyroid tumor represents the initial mainstay treatment of patients with PC. Multiple surgical procedures may be required, although surgical morbidity should be taken into account. A 5- and 10-year survival between 77-100 and 49-91%, respectively, has been reported. When the tumor is no more resectable, medical treatment of hypercalcemia has a pivotal role in the management of these patients.
Topics: Humans; Parathyroid Neoplasms
PubMed: 30641523
DOI: 10.1159/000491039 -
Cancer Treatment Reviews Jun 2020Parathyroid cancer (PC) is a rare malignant tumor which comprises 0.5-5% of patients with primary hyperparathyroidism (PHPT). Most of these cancers are sporadic,... (Review)
Review
Parathyroid cancer (PC) is a rare malignant tumor which comprises 0.5-5% of patients with primary hyperparathyroidism (PHPT). Most of these cancers are sporadic, although it may also occur as a feature of various genetic syndromes including hyperparathyroidism-jaw tumor syndrome (HPT-JT) and multiple endocrine neoplasia (MEN) types 1 and 2A. Although PC is characterized by high levels of serum ionized calcium (Ca) and parathyroid hormone (PTH), the challenge to the clinician is to distinguish PC from the far more common entities of parathyroid adenoma (PA) or hyperplasia, as there are no specific clinical, biochemical, or radiological characteristic of PC. Complete surgical resection is the only known curative treatment for PC with the surgical approach during initial surgery strongly influencing the outcome. In order to avoid local recurrence, the lesion must be removed en-bloc with clear margins. PC has high recurrence rates of up to 50% but with favorable long-term survival rates (10-year overall survival of 60-70%) due to its slow-growing nature. Most patients die not from tumor burden directly but from uncontrolled severe hypercalcemia. In this article we have updated the information on PC by reviewing the literature over the past 10 years and summarizing the findings of the largest series published in this period.
Topics: Humans; Hyperparathyroidism; Neoplasm Recurrence, Local; Parathyroid Neoplasms
PubMed: 32247225
DOI: 10.1016/j.ctrv.2020.102012 -
Endocrine Sep 2023Parathyroid carcinoma (PC) is an extremely rare malignant tumor of the parathyroid glands, accounting for less than 1% of primary hyperparathyroidism, commonly... (Review)
Review
Parathyroid carcinoma (PC) is an extremely rare malignant tumor of the parathyroid glands, accounting for less than 1% of primary hyperparathyroidism, commonly characterized by severe and unmanageable hypercalcemia, aggressive behavior, high metastatic potential, and poor prognosis. PC manifests prevalently as a sporadic tumor and only occasionally it is part of congenital syndromic and non-syndromic endocrine diseases. Molecular pathogenesis of this form of parathyroid tumor is not fully elucidated and it appears to be caused by multiple genetic and epigenetic drivers, differing among affected patients and not yet clearly stated in distinguishing PC from the benign parathyroid adenoma (PA). Congenital forms of PC have been prevalently associated with germline heterozygous loss-of-function mutations of the CDC73 tumor suppressor gene, both in the context of the hyperparathyroidism jaw-tumor syndrome (HPT-JT) and of the isolated familial hyperparathyroidism (FIPH). Currently, surgical en bloc resection of affected gland(s) and other involved structures is the elective therapy for both primary and recurrent PC. However, it usually results ineffective for advance and metastatic disease, and a high percentage of post-operative recurrence is reported. Targeted medical therapies for surgically untreatable PC, based on the molecular profile of PC samples, are, therefore, needed. The characterization of genetic and epigenetic alterations and deregulated pathways in PC samples will be of fundamental importance to tailor treatment for each patient. Here, we reviewed main findings on molecular pathogenetic aspects of PC, and the current state of the art of therapies.
Topics: Humans; Parathyroid Neoplasms; Tumor Suppressor Proteins; Neoplasm Recurrence, Local; Jaw Neoplasms; Hyperparathyroidism, Primary
PubMed: 37160841
DOI: 10.1007/s12020-023-03376-w -
Annals of Surgical Oncology Sep 2016The differentiation of benign parathyroid gland atypia and true parathyroid carcinoma (PC) can be challenging. In some instances, patients are classified as having...
INTRODUCTION
The differentiation of benign parathyroid gland atypia and true parathyroid carcinoma (PC) can be challenging. In some instances, patients are classified as having 'atypical parathyroid neoplasms' (APNs), explicitly acknowledging that the distinction between benign and malignant disease appears impossible to determine. This 'grey area' diagnosis makes rendering an accurate prognosis difficult, and clouds clinical management and treatment planning.
METHODS
We performed a retrospective chart review of all patients undergoing operation for primary hyperparathyroidism in our institution (2000-2014). Patients with a histopathological diagnosis of PC or APN were included. Demographics, clinical characteristics, and survival rates were analyzed, and analysis was conducted using SAS 9.4 (SAS Institute, Inc., Cary, NC, USA).
RESULTS
Fifty-four patients were included in the study-31 (57.41 %) with PC and 23 (42.59 %) with APN. PC versus APN was associated with higher parathyroid hormone (PTH) (p = 0.005) and with males (p = 0.002). Five-year overall survival (OS) from diagnosis was 82.64 % [95 % confidence interval (CI) 59.82-93.17] for the PC group and 93.33 % (95 % CI 61.26-99.03) for the APN group, while the 5-year recurrence-free survival rate was 59.63 % (95 % CI 36.32-76.81) in the PC group and 90.91 % (95 % CI 50.81-98.67) in the APN group.
CONCLUSION
PC and APN are distinct clinical entities with differences in tumor biology reflected in overall recurrence rates, disease-free survival, and OS. APNs present with a less accentuated biochemical profile and demonstrate an indolent clinical course compared with PCs. Efforts to improve categorization and staging of PC and APN are needed.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma; Disease-Free Survival; Fatigue; Female; Humans; Hyperparathyroidism, Primary; Kidney Calculi; Male; Memory Disorders; Middle Aged; Neoplasm Recurrence, Local; Parathyroid Hormone; Parathyroid Neoplasms; Retrospective Studies; Sex Factors; Survival Rate; Young Adult
PubMed: 27160525
DOI: 10.1245/s10434-016-5248-6 -
Current Treatment Options in Oncology Aug 2001Although parathyroid neoplasms are common and cause primary hyperparathyroidism, parathyroid carcinoma is a rare entity. At times it can be difficult to diagnose.... (Review)
Review
Although parathyroid neoplasms are common and cause primary hyperparathyroidism, parathyroid carcinoma is a rare entity. At times it can be difficult to diagnose. Patients with parathyroid carcinoma usually present with profound symptoms of hyperparathyroidism and highly elevated serum calcium and parathyroid hormone (PTH) levels. At the time of neck exploration, a large, gray-white, locally invasive tumor is commonly encountered. The course of patients with parathyroid carcinoma is variable; unfortunately, more than 50% have persistent or recurrent disease due to regional or distant disease. Surgical resection is the principal treatment for patients with parathyroid carcinoma. The optimal surgical treatment is en bloc tumor resection with ipsilateral thyroid lobectomy when the diagnosis is suspected and until it is proven otherwise. Patients who have persistent or recurrent parathyroid carcinoma should have localizing studies to identify loco-regional or distant tumor sites. Reoperation in patients with localized parathyroid carcinoma is recommended because it relieves symptoms of hypercalcemia, and it normalizes serum calcium and PTH levels in most patients. For patients who have unresectable parathyroid carcinoma, a protocol-based treatment with chemotherapy and external radiotherapy should be considered. Additionally, second-generation bisphosphonates and the NPS R-568 calcimimetic agent may be useful in normalizing the serum calcium and improving symptoms of hypercalcemia. However, they do not treat the tumor and are rarely effective in the long term.
Topics: Adenocarcinoma; Adenoma; Adult; Aged; Algorithms; Combined Modality Therapy; Diuretics; Epidemiologic Methods; Female; Fluid Therapy; Furosemide; Humans; Hypercalcemia; Hyperparathyroidism; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia; Neoplasm Invasiveness; Neoplasm Metastasis; Parathyroid Glands; Parathyroid Neoplasms; Parathyroidectomy; Reoperation
PubMed: 12057115
DOI: 10.1007/s11864-001-0028-2 -
Diagnostic Cytopathology 1986Cytologic criteria for diagnosing parathyroid adenomas and hyperplasia have not been elucidated. This report will present the cytomorphology of parathyroid tissue in the...
Cytologic criteria for diagnosing parathyroid adenomas and hyperplasia have not been elucidated. This report will present the cytomorphology of parathyroid tissue in the spectrum of normal, hyperplastic, and neoplastic states. We examined clinical needle aspirates from three patients with parathyroid lesions as well as 15 needle aspirations or touch preparations from surgical specimens. The series included three with hyperparathyroidism secondary to chronic renal failure, four with primary chief cell hyperplasia, nine with typical adenomas, and two with atypical adenomas. Normal parathyroid glands were also studied. Most parathyroid lesions could be distinguished from thyroid lesions by frequent thick fragments of cohesive cells with frayed edges and typical nuclear features. In general, the nuclei were small (6-8 mu) and round with regular coarse granular chromatin. Occasional larger nuclei (10-30 mu) with similar chromatin were observed in some cases. Oxyphil cells with abundant granular cytoplasm were present in some cases; one case with mostly oxyphil cells was difficult to differentiate from a thyroid neoplasm. Pseudocolloid was found in seven cases. Criteria for the differentiation between parathyroid hyperplasia and adenomas were not discovered. In addition, the cytology and differential diagnosis of atypical parathyroid adenomas are described and illustrated.
Topics: Adenoma; Humans; Hyperplasia; Parathyroid Glands; Parathyroid Neoplasms; Staining and Labeling
PubMed: 2424691
DOI: 10.1002/dc.2840020116 -
International Journal of Molecular... Jun 2022Immunohistochemistry remains an indispensable tool in diagnostic surgical pathology. In parathyroid tumours, it has four main applications: to detect (1) loss of... (Review)
Review
Immunohistochemistry remains an indispensable tool in diagnostic surgical pathology. In parathyroid tumours, it has four main applications: to detect (1) loss of parafibromin; (2) other manifestations of an aberrant immunophenotype hinting towards carcinoma; (3) histogenesis of a neck mass and (4) pathogenetic events, including features of tumour microenvironment and immune landscape. Parafibromin stain is mandatory to identify the new entity of parafibromin-deficient parathyroid neoplasm, defined in the WHO classification (2022). Loss of parafibromin indicates a greater probability of malignant course and should trigger the search for inherited or somatic mutations. Aberrant immunophenotype is characterised by a set of markers that are lost (parafibromin), down-regulated (e.g., APC protein, p27 protein, calcium-sensing receptor) or up-regulated (e.g., proliferation activity by Ki-67 exceeding 5%) in parathyroid carcinoma compared to benign parathyroid disease. Aberrant immunophenotype is not the final proof of malignancy but should prompt the search for the definitive criteria for carcinoma. Histogenetic studies can be necessary for differential diagnosis between thyroid vs. parathyroid origin of cervical or intrathyroidal mass; detection of parathyroid hormone (PTH), chromogranin A, TTF-1, calcitonin or CD56 can be helpful. Finally, immunohistochemistry is useful in pathogenetic studies due to its ability to highlight both the presence and the tissue location of certain proteins. The main markers and challenges (technological variations, heterogeneity) are discussed here in the light of the current WHO classification (2022) of parathyroid tumours.
Topics: Adenoma; Carcinoma; Humans; Immunohistochemistry; Parathyroid Neoplasms; Tumor Microenvironment; Tumor Suppressor Proteins
PubMed: 35805976
DOI: 10.3390/ijms23136981 -
Clinical Endocrinology Sep 2022Parathyroid Carcinoma is a rare malignant neoplasm, accounting for less than 1% of primary hyperparathyroidism cases. Parathyroid carcinomas are characterized by...
OBJECTIVE
Parathyroid Carcinoma is a rare malignant neoplasm, accounting for less than 1% of primary hyperparathyroidism cases. Parathyroid carcinomas are characterized by markedly elevated levels of PTH, severe hypercalcemia and established target organ damage. The authors report the experience of a single centre regarding the management and outcome of patients with parathyroid carcinomas and revise relevant literature.
DESIGN
Retrospective review of all patients with parathyroid carcinoma evaluated at a tertiary oncologic centre from 1991 until 2021.
RESULTS
Seventeen patients were identified (10 males), with a mean age at diagnosis of 53 ± 16 years and a median follow-up of 16.5 years. Most patients presented with hypercalcemia (n = 15), with a mean serum calcium concentration of 13.5 mg/dl (9.6-16.5) and mean PTH of 1173 pg/ml (276-2500). Hyperparathyroidism-mediated organ damage was observed in most patients (n = 16), with predominant renal (n = 12) and skeletal (n = 9) complications. En bloc surgical resection was performed in nine patients. Three patients underwent adjuvant radiotherapy. Recurrence was observed in 8 cases (47.1%) after a median of 24 months following surgery and no independent predictors of recurrence were identified. The overall survival and disease specific survival at 5-year was 88% and 94%, respectively. CDC73 mutations were present in 38.5% of analysed patients and one patient was diagnosed with MEN1.
CONCLUSION
Parathyroid carcinoma is associated with a significant rate of recurrence and limited effective treatment beyond initial complete surgical resection. Therefore, preoperatively high index of suspicion is paramount to optimize patient care. This is, to our knowledge, the largest Portuguese cohort published so far.
Topics: Adult; Aged; Female; Humans; Hypercalcemia; Hyperparathyroidism; Male; Middle Aged; Parathyroid Hormone; Parathyroid Neoplasms; Retrospective Studies; Treatment Outcome
PubMed: 35120263
DOI: 10.1111/cen.14684 -
The Veterinary Clinics of North... Mar 2022This article provides a review with a focus on clinical updates in treating patients with surgical parathyroid or thyroid disease. Primary hyperparathyroidism is a... (Review)
Review
This article provides a review with a focus on clinical updates in treating patients with surgical parathyroid or thyroid disease. Primary hyperparathyroidism is a common cause of hypercalcemia. Patients are older and often asymptomatic, and urinary stones and urinary tract infection are common. Surgical treatment is recommended with an excellent prognosis. Thyroid tumors in dogs are the most common endocrine neoplasm. Functional thyroid testing, laryngeal examinations, and regional lymphadenectomy should be considered during surgery, along with use of vessel-sealing devices to mitigate hemorrhage. Long-term outcomes for dogs with advanced disease can be reached, so surgical resection should be an option.
Topics: Animals; Dog Diseases; Dogs; Hypercalcemia; Hyperparathyroidism; Parathyroid Neoplasms; Parathyroidectomy; Thyroid Gland
PubMed: 35210059
DOI: 10.1016/j.cvsm.2021.12.004