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Tumour stromal and demographical factors affecting the metastatic aggressiveness of small differentiated papillary thyroid cancers in Sweden
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.ORCID iD: 0000-0002-4877-5150
2023 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Tumorstromats och demografiska faktorers samband med den metastatiska aggressiviteten hos smådifferentierade papillära tyroidea cancrar i Sverige (Swedish)
Abstract [en]

Background: The incidence of papillary thyroid cancer (PTC) has been increasing over the recent decades, especially that of small papillary thyroid cancers (sPTCs) (≤ 20mm in size). sPTCs are generally classified as low risk cancers with a very favourable diagnosis, yet some of these cancers still cause locoregional and distant metastasis, recurrence and even death.

Aims: To investigate the role of tumour stromal, environmental and demographical factors affecting the metastatic aggressiveness of sPTCs in Sweden.

Material & Methods: Selected tumour stromal proteins (Types I (Col1) and IV (Col4) collagens, alpha smooth muscle actin (a-SMA) and matrix metallopeptidase 9 (MMP-9)) were analysed for their role in metastatic disease (Paper I). Demographic and clinicopathological differences regarding recurrence between metastasized vs. non-metastasized sPTCs in Sweden were studied in 2 registry-based retrospective observational cohort studies (Papers II & III). The geographic distribution of patients with sPTC in Sweden was pinpointed and layered with maps of gamma radiation deposits of radionuclides Caesium-137 (Cs-137), Thorium-232 (Th-232), Uranium-238 (U-238) and Potassium-40 (K-40) using different spatial analysis methods (Paper IV).

Results: Col1 and Col4 were significantly more expressed in the non-metastatic tumours compared with metastatic ones. Patients with N1b disease were younger, had a smaller tumour size and higher recurrence rates compared to patients with N0 and N1a disease. The mean number of metastatic LNs at initial surgery was higher in the N1b group than the N1a group and correlated with more recurrent disease. The prevalence of metastatic sPTC was associated with significantly higher levels of gamma radiation from Th-232, U-238 and K-40.

Conclusions: The higher expression of Col1 and Col4 in the non-metastasized tumours indicates a potential protective role in tumour progression. LN stage N1b at diagnosis, and having five or more metastatic nodes, are strong risk factors for cancer recurrence and decreased disease-free survival in sPTC. Environmental factors such as gamma radiation are believed to play a major role in the pathogenesis of the PTC. These findings altogether underscore the importance of LN evaluation, tumour biological as well as environmental factors in sPTC patients, suggesting that the management of these patients should be based on an individual risk stratification instead of a “one size fits all” approach.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2023. , p. 71
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2240
Keywords [en]
Papillary thyroid cancer, Tumour stroma, Geographic information system, Register
National Category
Cancer and Oncology Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:umu:diva-214582ISBN: 978-91-8070-049-8 (print)ISBN: 978-91-8070-050-4 (electronic)OAI: oai:DiVA.org:umu-214582DiVA, id: diva2:1804411
Public defence
2023-11-10, Hörsalen, Östersunds sjukhus, Östersund, 21:08 (Swedish)
Opponent
Supervisors
Available from: 2023-10-20 Created: 2023-10-12 Last updated: 2023-10-12Bibliographically approved
List of papers
1. The expression of stromal biomarkers in small papillary thyroid carcinomas
Open this publication in new window or tab >>The expression of stromal biomarkers in small papillary thyroid carcinomas
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2022 (English)In: World Journal of Surgical Oncology, E-ISSN 1477-7819, Vol. 20, no 1, article id 340Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The importance of stroma for tumor progression is recognized for many cancer types. In this study, we aim to evaluate the expression of types I (Col1) and IV (Col4) collagens, alpha-smooth muscle actin (a-SMA), and matrix metallopeptidase 9 (MMP-9) in the tumor stroma of small papillary thyroid carcinoma (PTC).

MATERIAL AND METHODS: Twenty-five non-metastatic small PTCs (pT1N0) and nineteen metastatic small PTCs (pT1N1b) including corresponding metastatic lateral lymph nodes were selected and paraffinized tissue blocks retrieved. The samples were stained for Col1, COL4, a-SMA, and MMP-9 antibodies using immunohistochemistry. The expression of the stromal proteins was scored and analyzed based on the location, intensity, and distribution.

RESULTS: Col1 and Col4 expression were significantly higher in normal thyroid tissue compared to PTC tissue. On the contrary, expression of a-SMA and MMP-9 was higher in PTC tissue compared to normal thyroid tissue. Both Col1 and Col4 were significantly more highly expressed in the non-metastatic tumors compared with metastatic tumors. The expression of a-SMA and MMP9 was slightly, but not significantly, higher in the metastasized tumors and their respective lymph nodes. There was a significant correlation between the metastasized tumors and their respective lymph nodes in Col1 and MMP-9 expression.

CONCLUSIONS: Col1, Col4, a-SMA, and MMP-9 expression in PTCs differs significantly from that of normal thyroid tissue. The higher expression of Col1 and Col4 in normal thyroid tissue and in the non-metastasized tumors indicates that Col1 and 4 might have a potential protective role in tumor progression. The higher expression of a-SMA and MMP9 in PTCs indicates that these proteins might have a role in promoting PTC progression and aggressiveness.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2022
Keywords
Alpha-smooth muscle actin, Matrix metallopeptidase 9, Papillary thyroid cancer, Tumor stroma, Type 1 collagen, Type IV collagen
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-200669 (URN)10.1186/s12957-022-02805-w (DOI)000873694900001 ()36242015 (PubMedID)2-s2.0-85140136138 (Scopus ID)
Funder
Region Jämtland Härjedalen, 940567
Available from: 2022-11-02 Created: 2022-11-02 Last updated: 2024-01-16Bibliographically approved
2. Invasiveness and Metastatic Aggressiveness in Small Differentiated Thyroid Cancers: Demography of Small Papillary Thyroid Carcinomas in the Swedish Population
Open this publication in new window or tab >>Invasiveness and Metastatic Aggressiveness in Small Differentiated Thyroid Cancers: Demography of Small Papillary Thyroid Carcinomas in the Swedish Population
2020 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 44, no 2, p. 461-468Article in journal (Refereed) Published
Abstract [en]

Background: The western world is seeing a rising incidence of thyroid cancer. Improved diagnostic methods do not entirely explain this increase. Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer. Small PTC (<= 20 mm) and especially papillary thyroid microcarcinomas (PTMC <= 10 mm) are considered to be low-risk tumors but some cases are considerably more aggressive. Sufficient understanding of these mechanisms is a long-term goal for more efficient and safer treatment of these tumors.

Methods: We identified 959 cases of small PTCs in the validated Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery, grouped according to lymph node metastasis. These were analyzed according to age, gender, tumor size and geographic region.

Results: Patients with N1b disease (lateral lymph nodes metastases) had a smaller tumor size compared to patients with N1a disease (8.6 mm vs 10.1 mm respectively, p < 0.05). Patients and specifically females with N1b disease were younger than those with N0 or N1a disease. Patients with N1b disease had a lower proportion of females (60%) compared to N0 and N1a groups (81% and 78%, respectively). The incidence of operated small PTCs and of lymph node engagement differs between geographic regions in Sweden.

Conclusions: Small PTC and especially PTMC seem to show different patterns of aggressiveness and demography regarding lateral lymph node metastases and 7% had N1b disease and tumor <1 cm, underscoring the importance of lymph node evaluation in PTMC patients. More understanding of predictive factors, mechanisms for metastatic disease and causes of regional differences, is needed.

Place, publisher, year, edition, pages
Springer, 2020
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-168964 (URN)10.1007/s00268-019-05312-4 (DOI)000512046400019 ()31834455 (PubMedID)2-s2.0-85076563734 (Scopus ID)
Conference
IAES Meeting / 48th World Congress of Surgery, AUG 11-15, 2019, Krakow, POLAND
Available from: 2020-04-01 Created: 2020-04-01 Last updated: 2023-10-12Bibliographically approved
3. Risk factors for recurrent disease in small papillary thyroid cancers: a Swedish register-based study
Open this publication in new window or tab >>Risk factors for recurrent disease in small papillary thyroid cancers: a Swedish register-based study
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2023 (English)In: Langenbeck's archives of surgery (Print), ISSN 1435-2443, E-ISSN 1435-2451, Vol. 408, no 1, article id 162Article in journal (Refereed) Published
Abstract [en]

AIMS: To study the correlation between clinicopathological risk factors and the risk for intervention-requiring cancer recurrence in patients with small papillary thyroid cancers (sPTCs). MATERIALS AND METHODS: Records for 397 patients with sPTC (T1 ≤ 20mm) were obtained from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA) between 2010 and 2016. Follow-up time was at least 5 years. Data regarding intervention-requiring cancer recurrence were obtained from patient medical records and analysed regarding lymph node (LN) status (N0, N1a and N1b) and recurrence. RESULTS: Age was significantly lower in the N1a and N1b groups compared to N0 (45 vs. 40.5 vs. 49 years, respectively; p = 0.002). Tumour size was smaller in the N1a group compared to N1b group (9 vs. 11.8 mm; p <0.01). The mean number of metastatic LNs at initial surgery was higher in the N1b compared to N1a group (6.6 vs. 3; p = 0.001), and in the recurrent compared to the non-recurrent group (7 versus 3.9; p <0.01). The recurrence rate was higher in the N1b group than the N1a and N0 groups (25% vs. 2.4% vs. 1.4%, respectively; p = 0.001). CONCLUSIONS: Lymph node stage N1b at diagnosis, and having five or more metastatic nodes, are strong risk factors for cancer recurrence and decreased disease-free survival in sPTC. The management of patients with sPTC should include thorough lymph node mapping for optimal treatment and individual risk stratification.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
lateral lymph node metastasis (N1b), Papillary thyroid cancer (PTC), recurrence, risk factors, small PTC
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-208215 (URN)10.1007/s00423-023-02905-5 (DOI)000976875500001 ()37099203 (PubMedID)2-s2.0-85153993936 (Scopus ID)
Funder
Region Jämtland Härjedalen, JLL-940567Umeå University
Available from: 2023-05-12 Created: 2023-05-12 Last updated: 2024-02-02Bibliographically approved
4. The correlation between small papillary thyroid cancers and gamma radionuclides Cs-137, Th-232, U-238 and K-40 using spatially-explicit, register-based methods
Open this publication in new window or tab >>The correlation between small papillary thyroid cancers and gamma radionuclides Cs-137, Th-232, U-238 and K-40 using spatially-explicit, register-based methods
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2023 (English)In: Spatial and Spatio-temporal Epidemiology, ISSN 1877-5845, E-ISSN 1877-5853, Vol. 47, article id 100618Article in journal (Refereed) Published
Abstract [en]

A steep increase of small papillary thyroid cancers (sPTCs) has been observed globally. A major risk factor for developing PTC is ionizing radiation. The aim of this study is to investigate the spatial distribution of sPTC in Sweden and the extent to which prevalence is correlated to gamma radiation levels (Caesium-137 (Cs-137), Thorium-232 (Th-232), Uranium-238 (U-238) and Potassium-40 (K-40)) using multiple geospatial and geostatistical methods. The prevalence of metastatic sPTC was associated with significantly higher levels of Gamma radiation from Th-232, U-238 and K-40. The association is, however, inconsistent and the prevalence is higher in densely populated areas. The results clearly indicate that sPTC has causative factors that are neither evenly distributed among the population, nor geographically, calling for further studies with bigger cohorts. Environmental factors are believed to play a major role in the pathogenesis of the disease.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Papillary thyroid cancer, Radiation, Geographic information system (GIS), patial analysis
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-214811 (URN)10.1016/j.sste.2023.100618 (DOI)001083840000001 ()2-s2.0-85171996339 (Scopus ID)
Funder
Region Jämtland Härjedalen, JLL-940567Region Jämtland Härjedalen, 748
Available from: 2023-10-02 Created: 2023-10-02 Last updated: 2025-04-24Bibliographically approved

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