ORIGINAL ARTICLE
Molecular profile of parathyroid tissues and tumours: a heterogeneous landscape
1
Riga Stradins University, Riga, Latvia
2
Latvian Institute of Organic Synthesis, Riga, Latvia
Submission date: 2020-08-14
Final revision date: 2021-05-04
Acceptance date: 2021-05-05
Publication date: 2021-09-30
Pol J Pathol 2021;72(2):99-116
KEYWORDS
TOPICS
ABSTRACT
Advances in laboratory diagnostics and surgical treatment of primary hyperparathyroidism have ensured solid basis for research in parathyroid pathology in order to specify key molecules in pathogenesis and morphological diagnostics of difficult cases. The aim of this study was to assess the molecular landscape and its heterogeneity in primary parathyroid hyperplasia (PPH) and adenoma, compared to carcinoma and normal glands. In a retrospective analysis of 179 surgically removed parathyroid glands (102 adenomas; 27 PPH; 45 normal glands; 5 carcinomas), expression of Ki-67, p21, p27, p53, cyclin D1, Bcl-2 protein, vimentin, cytokeratin (CK) 19, E-cadherin, CD56, CD44 and parafibromin was detected by immunohistochemistry, followed by computer-assisted assessment of mean values and heterogeneity measures. Descriptive statistics and Kruskal-Wallis test were applied. Significant differences were disclosed regarding the mean and highest fraction of Ki-67 (both p < 0.001), p21 (both p < 0.001), cyclin D1 (p = 0.002) and p27-expressing cells (p = 0.010). Proliferative lesions (PPH, adenoma and carcinoma) showed statistically significantly up-regulated CK19 (p = 0.012), decreased E-cadherin levels and distinctive patterns of vimentin. CD44, CD56 and p53 were almost absent from parathyroid tissues. All carcinomas lacked parafibromin contrasting with invariable positivity in adenomas. Remarkable heterogeneity of cell cycle markers and intermediate filaments must be accounted for in scientific studies and elaboration of diagnostic cut-offs.
REFERENCES (106)
1.
Majcen M, Hocevar M. Surgical options in treating patients with primary hyperparathyroidism. Radiol Oncol 2020; 54: 22-32.
2.
Madkhali T, Alhefdhi A, Chen H, et al. Primary hyperparathyroidism. Ulus Cerrahi Derg 2016; 32: 58-66.
3.
Quaglino F, Manfrino L, Cestino L, et al. Parathyroid carcinoma: an up-to-date retrospective multicentric analysis. Int.
5.
Nelson JA, Alsayed M, Milas M. The role of parathyroidectomy in treating hypertension and other cardiac manifestations of primary hyperparathyroidism. Gland Surg 2020; 9: 136-141.
6.
Sluis K, Kim H, He Y, et al. Therapeutic challenges for elderly patients with primary hyperparathyroidism. Case Rep Endocrinol 2019; 2019: 4807081.
7.
Sajid-Crockett S, Singer FR, Hershman JM. Cinacalcet for the treatment of primary hyperparathyroidism. Metabolism 2008; 57: 517-521.
8.
Mizamtsidi M, Nastos C, Mastorakos G, et al. Diagnosis, management, histology and genetics of sporadic primary hyperparathyroidism: old knowledge with new tricks. Endocr Connect 2018; 7: R56-R68.
9.
Rudin AV, McKenzie TJ, Wermer RA, et al. Primary hyperparathyroidism: redefining cure. Am Surg 2019; 85: 214-218.
10.
DeLellis RA. Challenging lesions in the differential diagnosis of endocrine tumors: parathyroid carcinoma. Endocr Pathol 2008; 19: 221-225.
11.
Do Cao C, Aubert S, Trinel C, et al. Parathyroid carcinoma: diagnostic criteria, classification, evaluation. Ann Endocrinol (Paris) 2015; 76: 165-168.
12.
Gill AJ, Lim G, Cheung VKY, et al. Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) parathyroid tumors demonstrate distinctive morphologic features. Am J Surg Pathol 2019; 43: 35-46.
13.
Carlson D. Parathyroid pathology: hyperparathyroidism and parathyroid tumors. Arch Pathol Lab Med 2010; 134: 1639-1644.
14.
Fendrich V, Waldmann J, Feldmann G, et al. Unique expression pattern of the EMT markers Snail, Twist and E-cadherin in benign and malignant parathyroid neoplasia. Eur J Endocrinol 2009; 160: 695-703.
15.
Giordano TJ. Parathyroid glands. In: Rosai and Ackerman’s Surgical Pathology. Goldblum JR, Lamps LW, McKenney JK, Myers JL (eds). 11th ed. Elsevier, Philadelphia 2018; 355-369.
16.
Fang SH, Guidroz JA, O’Malley Y, et al. Expansion of a cell population expressing stem cell markers in parathyroid glands from patients with hyperparathyroidism. Ann Surg 2010; 251: 107-113.
17.
Briede I, Strumfa I, Vanags A, et al. The association between inflammation, epithelial mesenchymal transition and stemness in colorectal carcinoma. J Inflamm Res 2020; 13: 15-34.
18.
Stalhammar G, Fuentes Martinez N, Lippert M, et al. Digital image analysis outperforms manual biomarker assessment in breast cancer. Mod Pathol 2016; 29: 318-329.
19.
Simtniece Z, Vanags A, Strumfa I, et al. Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms. Pol J Pathol 2015; 66: 176-194.
20.
Cetani F, Ambrogini E, Viacava P, et al. Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma? Eur J Endocrinol 2007; 156: 547-554.
21.
Cetani F, Marcocci C, Torregrossa L, et al. Atypical parathyroid adenomas: challenging lesions in the differential diagnosis of endocrine tumors. Endocr Relat Cancer 2019; 26: R441-R464.
22.
Gill AJ. Understanding the genetic basis of parathyroid carcinoma. Endocr Pathol 2014; 25: 30-34.
23.
Yang YJ, Han JW, Youn HD, et al. The tumor suppressor, parafibromin, mediates histone H3 K9 methylation for cyclin D1.
25.
Truran PP, Johnson SJ, Bliss RD, et al. Parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1: using an immunohistochemical panel to aid in the diagnosis of parathyroid cancer. World J Surg 2014; 38: 2845-2854.
26.
Kruijff S, Sidhu SB, Sywak MS, et al. Negative parafibromin staining predicts malignant behavior in atypical parathyroid adenomas. Ann Surg Oncol 2014; 21: 426-433.
27.
Juhlin CC, Haglund F, Obara T, et al. Absence of nucleolar parafibromin immunoreactivity in subsets of parathyroid malignant tumours. Virchows Arch 2011; 459: 47-53.
28.
Jo JH, Chung TM, Youn H, et al. Cytoplasmic parafibromin/hCdc73 targets and destabilizes p53 mRNA to control p53-mediated apoptosis. Nat Commun 2014; 5: 5433.
29.
Juhlin CC, Villablanca A, Sandelin K, et al. Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification. Endocr Relat Cancer 2007; 14: 501-512.
30.
Kim HK, Oh YL, Kim SH, et al. Parafibromin immunohistochemical staining to differentiate parathyroid carcinoma from parathyroid adenoma. Head Neck 2012; 34: 201-206.
31.
Wang O, Wang CY, Shi J, et al. Expression of Ki-67, galectin-3, fragile histidine triad, and parafibromin in malignant and benign parathyroid tumors. Chin Med J (Engl) 2012; 125: 2895-2901.
32.
Guarnieri V, Battista C, Muscarella LA, et al. CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort. Cell Oncol (Dordr) 2012; 35: 411-422.
33.
Fernandez-Ranvier GG, Khanafshar E, Tacha D, et al. Defining a molecular phenotype for benign and malignant parathyroid tumors. Cancer 2009; 115: 334-344.
34.
Rekik N, Ben Naceur B, Mnif M, et al. Hyperparathyroidism-jaw tumor syndrome: a case report. Ann Endocrinol (Paris) 2010; 71: 121-126.
35.
Sun X, Kaufman PD. Ki-67: more than a proliferation marker. Chromosoma 2018; 127: 175-186.
36.
Robertson S, Acs B, Lippert M, et al. Prognostic potential of automated Ki67 evaluation in breast cancer: different hot spot definitions versus true global score. Breast Cancer Res Treat 2020; 183: 161-175.
37.
Wysocka J, Adamczyk A, Kruczak A, et al. High Ki-67 expression is a marker of poor survival in apocrine breast carcinoma. Pol J Pathol 2020; 71: 107-119.
38.
Thomopoulou GE, Tseleni-Balafouta S, Lazaris AC, et al. Immunohistochemical detection of cell cycle regulators, Fhit protein and apoptotic cells in parathyroid lesions. Eur J Endocrinol 2003; 148: 81-87.
39.
Inic Z, Inic M, Jancic S, et al. The relation between proliferation activity and parathyroid hormone levels in parathyroid tumours. J BUON 2015; 20: 562-566.
40.
Abbona GC, Papotti M, Gasparri G, et al. Proliferative activity in parathyroid tumors as detected by Ki-67 immunostaining. Hum Pathol 1995; 26: 135-138.
41.
Erickson LA, Jin L, Wollan P, et al. Parathyroid hyperplasia, adenomas, and carcinomas: differential expression of p27Kip1 protein. Am J Surg Pathol 1999; 23: 288-295.
42.
Lumachi F, Ermani M, Marino F, et al. PCNA-LII, Ki-67 immunostaining, p53 activity and histopathological variables in predicting the clinical outcome in patients with parathyroid carcinoma. Anticancer Res 2006; 26: 1305-1308.
43.
Kaczmarek E, Lacka K, Majewski P, et al. Selected markers of proliferation and apoptosis in the parathyroid lesions: a spatial visualisation and quantification. J Mol Histol 2008; 39: 509-517.
44.
Demiralay E, Altaca G, Demirhan B. Morphological evaluation of parathyroid adenomas and immunohistochemical analysis of PCNA and Ki-67 proliferation markers. Turk Patoloji Derg 2011; 27: 215-220.
45.
Hadar T, Shvero J, Yaniv E, et al. Expression of p53, Ki-67 and Bcl-2 in parathyroid adenoma and residual normal tissue. Pathol Oncol Res 2005; 11: 45-49.
46.
Okon K, Demczuk S, Klimkowska A, et al. Correlation of microsatellite status, proliferation, apoptotic and selected immunohistochemical markers in colorectal carcinoma studied with tissue microarray. Pol J Pathol 2006; 57: 105-111.
47.
Milek K, Kaczmarczyk-Sekula K, Strzepek A, et al. Mast cells influence neoangiogenesis in prostatic cancer independently of ERG status. Pol J Pathol 2016; 67: 244-249.
48.
Stojadinovic A, Hoos A, Nissan A, et al. Parathyroid neoplasms: clinical, histopathological, and tissue microarray-based molecular analysis. Hum Pathol 2003; 34: 54-64.
49.
Chung DC. Cyclin D1 in human neuroendocrine tumorigenesis. Ann N Y Acad Sci 2004; 1014: 209-217.
50.
Qie S, Diehl JA. Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl) 2016; 94: 1313-1326.
51.
Alao JP. The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention. Mol Cancer 2007; 6: 24.
52.
Imanishi Y, Hosokawa Y, Yoshimoto K, et al. Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J Clin Invest 2001; 107: 1093-1102.
53.
Rodriguez C, Naderi S, Hans C, et al. Parathyroid carcinoma: a difficult histological diagnosis. Eur Ann Otorhinolaryngol Head Neck Dis 2012; 129: 157-159.
54.
Woodard GE, Lin L, Zhang JH, et al. Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Oncogene 2005; 24: 1272-1276.
55.
Juhlin C, Larsson C, Yakoleva T, et al. Loss of parafibromin expression in a subset of parathyroid adenomas. Endocr Relat Cancer 2006; 13: 509-523.
56.
Bencivenga D, Caldarelli I, Stampone E, et al. p27(Kip1) and human cancers: a reappraisal of a still enigmatic protein. Cancer Lett 2017; 403: 354-365.
57.
Bachs O, Gallastegui E, Orlando S, et al. Role of p27Kip1 as a transcriptional regulator. Oncotarget 2018; 9: 26259-26278.
58.
Buchwald PC, Akerstrom G, Westin G. Reduced p18INK4c, p21CIP1/WAF1 and p27KIP1 mRNA levels in tumours of primary and secondary hyperparathyroidism. Clin Endocrinol (Oxf) 2004; 60: 389-393.
59.
Arvai K, Nagy K, Barti-Juhasz H, et al. Molecular profiling of parathyroid hyperplasia, adenoma and carcinoma. Pathol Oncol Res 2012; 18: 607-614.
60.
Cazzalini O, Scovassi AI, Savio M, et al. Multiple roles of the cell cycle inhibitor p21(CDKN1A) in the DNA damage response. Mutat Res 2010; 704: 12-20.
62.
Hassan M, Watari H, AbuAlmaaty A, et al. Apoptosis and molecular targeting therapy in cancer. Biomed Res Int 2014; 2014: 150845.
63.
Naccarato AG, Marcocci C, Miccoli P, et al. Bcl-2, p53 and MIB-1 expression in normal and neoplastic parathyroid tissues. J Endocrinol Invest 1998; 21: 136-141.
64.
Dabbs DJ. Diagnostic Immunohistochemistry. Theranostic and Genomic Applications. Dabbs DJ (ed.). 4th ed. Elsevier Saunders, Philadelphia 2014; 1-1008.
65.
Chen C, Zhao S, Karnad A, et al. The biology and role of CD44 in cancer progression: therapeutic implications.
67.
Jakovlevs A, Vanags A, Gardovskis J, et al. Molecular classification of diffuse gliomas. Pol J Pathol 2019; 70: 246-258.
68.
Zeromski J, Lawniczak M, Galbas K, et al. Expression of CD56/N-CAM antigen and some other adhesion molecules in various human endocrine glands. Folia Histochem Cytobiol 1998; 36: 119-125.
69.
Komminoth P, Seelentag WK, Saremaslani P, et al. CD44 isoform expression in the diffuse neuroendocrine system. II. Benign and malignant tumors. Histochem Cell Biol 1996; 106: 551-562.
70.
Peissig K, Condie BG, Manley NR. Embryology of the parathyroid glands. Endocrinol Metab Clin North Am 2018; 47: 733-742.
71.
Chojnowski JL, Masuda K, Trau HA, et al. Multiple roles for HOXA3 in regulating thymus and parathyroid differentiation and morphogenesis in mouse. Development 2014; 141: 3697-3708.
72.
Gordon J, Patel SR, Mishina Y, et al. Evidence for an early role for BMP4 signaling in thymus and parathyroid morphogenesis. Dev Biol 2010; 339: 141-154.
73.
Bain VE, Gordon J, O’Neil JD, et al. Tissue-specific roles for sonic hedgehog signaling in establishing thymus and parathyroid organ fate. Development 2016; 143: 4027-4037.
74.
Teshima TH, Lourenco SV, Tucker AS. Multiple cranial organ defects after conditionally knocking out Fgf10 in the neural crest. Front Physiol 2016; 7: 488.
75.
Seelentag WK, Komminoth P, Saremaslani P, et al. CD44 isoform expression in the diffuse neuroendocrine system.
77.
Zhu B, Wang Y, Wang X, et al. Evaluation of the correlation of MACC1, CD44, Twist1, and KiSS-1 in the metastasis and prognosis for colon carcinoma. Diagn Pathol 2018; 13: 45.
78.
Ma J, Li M, Chai J, et al. Expression of RSK4, CD44 and MMP-9 is upregulated and positively correlated in metastatic ccRCC. Diagn Pathol 2020; 15: 28.
79.
Zhou J, Du Y, Lu Y, et al. CD44 expression predicts prognosis of ovarian cancer patients through promoting epithelial-mesenchymal transition (EMT) by regulating Snail, ZEB1, and Caveolin-1. Front Oncol 2019; 9: 802.
80.
Biswas KH. Molecular mobility-mediated regulation of E-cadherin adhesion. Trends Biochem Sci 2020; 45: 163-173.
81.
Nagathihalli NS, Merchant NB. Src-mediated regulation of E-cadherin and EMT in pancreatic cancer. Front Biosci (Landmark Ed) 2012; 17: 2059-2069.
82.
Schneider R, Bartsch-Herzog S, Ramaswamy A, et al. Immunohistochemical expression of E-cadherin in atypical parathyroid adenoma. World J Surg 2015; 39: 2477-2483.
83.
Silva-Figueroa AM, Bassett R, Christakis I, et al. Using a novel diagnostic nomogram to differentiate malignant from benign parathyroid neoplasms. Endocr Pathol 2019; 30: 285-296.
84.
Handra-Luca A, Tissier F. Infracentimetric parathyroid cysts in hyperparathyroidemia. Pathol Res Pract 2018; 214: 455-458.
85.
Ozolins A, Narbuts Z, Strumfa I, et al. Diagnostic utility of immunohistochemical panel in various thyroid pathologies. Langenbecks Arch Surg 2010; 395: 885-891.
86.
Segiet OA, Michalski M, Brzozowa-Zasada M, et al. Angiogenesis in primary hyperparathyroidism. Ann Diagn Pathol 2015; 19: 91-98.
87.
Chen H, Shoumura S, Emura S. Nerve fibres in the parathyroid gland of the golden hamster (Mesocricetus auratus): immunohistochemical and ultrastructural investigations. Anat Histol Embryol 2005; 34: 34-37.
88.
Li J, Chen W, Liu A. Clinicopathologic features of parathyroid carcinoma: a study of 11 cases with review of literature. Zhonghua Bing Li Xue Za Zhi 2014; 43: 296-300.
89.
Miettinen M, Clark R, Lehto VP, et al. Intermediate-filament proteins in parathyroid glands and parathyroid adenomas. Arch Pathol Lab Med 1985; 109: 986-989.
90.
Domagala P, Domagala W. Nuclear CK19-immunopositive pseudoinclusions as a new additional objective diagnostic feature of papillary thyroid carcinoma. Pol J Pathol 2020; 71: 1-6.
91.
Cheng F, Eriksson JE. Intermediate filaments and the regulation of cell motility during regeneration and wound healing. Cold Spring Harb Perspect Biol 2017; 9: a022046.
92.
Gogusev J, Murakami I, Telvi L, et al. Establishment and characterization of a human parathyroid carcinoma derived cell line. Pathol Res Pract 2015; 211: 332-340.
93.
Abolins A, Vanags A, Trofimovics G, et al. Molecular subtype shift in breast cancer upon trastuzumab treatment: a case report. Pol J Pathol 2011; 62: 65-68.
94.
O’Donnell RL, Kaufmann A, Weeeoodhouse L, et al. Advanced ovarian cancer displays functional intratumor heterogeneity that correlates to ex vivo drug sensitivity. Int J Gynecol Cancer 2016; 26: 1004-1011.
95.
Fisher R, Pusztai L, Swanton C. Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer 2013; 108: 479-485.
96.
Marusyk A, Tabassum DP, Altrock PM, et al. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 2014; 514: 54-58.
97.
Tramm T, Kyndi M, Sorensen FB, et al. Influence of intra-tumoral heterogeneity on the evaluation of BCL2, E-cadherin, EGFR, EMMPRIN, and Ki-67 expression in tissue microarrays from breast cancer. Acta Oncol 2018; 57: 102-106.
98.
Haragan A, Field JK, Davies MPA, et al. Heterogeneity of PD-L1 expression in non-small cell lung cancer: Implications for specimen sampling in predicting treatment response. Lung Cancer 2019; 134: 79-84.
99.
Liszka L. Tissue heterogeneity contributes to suboptimal precision of WHO 2010 scoring criteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreas. Pol.
101.
Focke CM, Decker T, van Diest PJ. Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours. Histopathology 2016; 69: 849-861.
102.
Biserova K, Jakovlevs A, Uljanovs R, Strumfa I. Cancer stem cells: Significance in origin, pathogenesis and treatment of glioblastoma. Cells 2021; 10: 621.
103.
Leu ST, Batni S, Radeke MJ, et al. Drusen are cold spots for proteolysis: Expression of matrix metalloproteinases and their tissue inhibitor proteins in age-related macular degeneration. Exp Eye Res 2002; 74: 141-154.
104.
Lipp ES, Healy P, Austin A, et al. MGMT: Immunohistochemical detection in high-grade astrocytomas. J Neuropathol Exp Neurol 2019; 78: 57-64.
105.
Humphries A, Cereser B, Gay LJ, et al. Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution. Proc Natl Acad Sci U S A 2013; 110: E2490-E2499.
106.
Mehine M, Heinonen HR, Sarvilinna N, et al. Clonally related uterine leiomyomas are common and display branched tumor evolution. Hum Mol Genet 2015; 24: 4407-4416.
Share
RELATED ARTICLE
| eISSN: | 2084-9869 |
| ISSN: | 1233-9687 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
