Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing Correlation

*Maria V. Deligiorgi and Dimitrios T. Trafalis*

#### **Abstract**

Illustrating the ancient link connecting inflammation with cancer, the correlation of papillary thyroid carcinoma (PTC) with Hashimoto's thyroiditis (HT) has long been pursued as intersection of autoimmunity-induced chronic inflammation and tumor-induced immunity. The dramatic rise of the incidence of PTC οver the last decades—the main culprit for "thyroid cancer (TC) epidemic"—parallels the increasing incidence of HT, potentially reflecting a pathogenetic link that could be harnessed in diagnostics and therapeutics. Prompted by this perspective, in the present chapter, we dissect the hitherto elusive interrelationship of PTC with HT, focusing on four issues: firstly, an unresolved conundrum is whether PTC emerges due to or notwithstanding immune response or mirrors the "tumor defense-induced autoimmunity." Secondly, the interrelationship of HT with PTC may be merely epiphenomenon of selection bias inherent in thyroidectomy series. Thirdly, the impact of HT on coexistent PTC is equivocal—host protective versus tumor protective. Fourthly, translating serum concentrations of thyroid autoantibodies and thyroidstimulating hormone (TSH) into predictive and prognostic PTC biomarkers dichotomizes, till now, the researchers. In the era of precision medicine, illuminating whether HT precipitates PTC or *vice versa* is awaited with anticipation in order to refine the preventive and therapeutic policy counteracting "TC epidemic."

**Keywords:** papillary thyroid carcinoma, hashimoto's thyroiditis, anti-thyroglobulin autoantibodies, anti-thyroperoxidase autoantibodies, thyroid-stimulating hormone

#### **1. Introduction**

Initially reported by Dailey et al. in 1955, the correlation of papillary thyroid carcinoma (PTC)—the most common thyroid cancer (TC) histotype—with Hashimoto's thyroiditis (HT) [1] has long been pursued, rekindling the ancient link between inflammation and cancer [2]. Bearing in mind the rising incidence of PTC over the last decades [3], establishing causality between PTC and HT an issue highly contested—could lay the groundwork for a preventive policy. Moreover, harnessing the interrelationship of PTC with HT could refine therapeutics with respect to PTC. The present chapter dissects the correlation of PTC with HT, delving into a strongly insinuated immunological link. A comprehensive review of current literature emphasizes on the bewildering clinical significance of the interrelationship of PTC with HT. The intriguing predictive and prognostic value of serum concentrations of thyroid autoantibodies and thyroid-stimulating hormone (TSH) in the context of PTC coexistent with HT paints a more nuanced and sophisticated picture.

#### **2. Tailoring the treatment of PTC: where does coexistent HT stand?**

Thyroid cancer (TC) is the most common endocrine malignancy [4], though comprising only 2.1% of global cancer burden [5]. It is estimated that 52,070 new TC cases will occur in 2019 in the United States, while 2170 patients will die of this cancer type [6]. Derived from follicular epithelial cells, PTC constitutes the most common TC subtype in iodine sufficient areas, accounting for 85% of differentiated TC (DTC) [7] and 70–80% of TC [8]. In light of the interface between "TC epidemic" and "epidemic of diagnosis," a true increase of the incidence of PTC due to environmental, hormonal, and lifestyle risk factors appears to be merged with overdiagnosis of subclinical disease owing to meticulous screening [3, 9–11].

The indolent nature of PTC imposes a paradigm shift from ameliorating 10-year survival rates exceeding 90% to eliminating the recurrence incidence that hovers at 15–30% [12]. Individualization of therapeutic approach is deemed to confront the emerging challenges [13]. Seminal studies [4, 14, 15] recently illuminated the "dark matter" of the previously unidentified driver genetic events in 96% of PTC [4], being translated into molecular-based risk-adapted therapeutic strategies [7]. Although surgery is the cornerstone of treatment of PTC, a tailored approach with respect to the extent of thyroidectomy and lymph node dissection, the radioiodine ablation, and the management of radioiodine-refractory recurrent/metastatic disease has been endorsed [7].

Provided that the clinical relevance of the increasingly reported interrelationship of PTC with HT is clarified, the incorporation thereof in current PTC risk stratification systems may empower a personalized treatment. This perspective is anticipated to build on accomplishing a fine-tuned balance in terms of decisionmaking concerning PTC, precluding both overestimating an innocent disease and ignoring a metastatic potential.

#### **3. HT at a glance**

HT, originally designated as "struma lymphomatosa" by Dr. Hakaru Hashimoto in 1912 [16], is the most common autoimmune thyroid disease and the most common cause of hypothyroidism in iodine sufficient areas, showing a worldwide annual incidence varying from 0.3 to 1.5 cases per 1000 individuals [17]. An insightful approach concerning the multifactorial etiology of HT has been proposed by Weetman et al.: aligned in a way reminiscent of the wholes of the Swiss cheese are genetic factors acting as susceptibility loci—major histocompatibility human leukocyte antigen (HLA) genes, immunoregulatory genes, thyroid specific genesenvironmental factors—excess iodine intake, viral infections, stress, endocrine disruptors—as well as non-modifiable intrinsic factors—female sex, parity, age. Traversed by a hypothetical arrow, this conceivable line translates in a catastrophic event [18].

The histopathologically confirmed HT is characterized by diffuse lymphocytic infiltrate, formation of lymphoid follicles with germinal centers within normal

**39**

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing…*

**4. Rationality in the investigation of the interrelationship of** 

Apart from the well-established connection of HT with thyroid lymphoma [26], which is beyond the scope of the present chapter, the association of TC with HT concerns almost exclusively the PTC [27], alluding to a discriminating, though

Since PTC is conceived as the main culprit for the explosive rise of TC incidence [3], the hypothesis that the increasing incidence of HT hastens the "TC epidemic" is appealing. Considering that the inflammation has been envisaged as the "seventh hallmark of cancer" [28], the autoimmunity-induced inflammatory milieu [29] merits further interrogation as the missing piece in the puzzle of the interrelation-

An alternative explanation that cannot be ruled out is that third extraneous variables actually cause the coexistence of PTC with HT. Indeed, both PTC and HT are precipitated by an interplay among genetic factors and environmental influences most of which are shared by the two entities. Emphasis is placed on risk factors implicated in the pathogenesis of both PTC and HT, such as female predominance, excess iodine intake, and exposure to radiation [30–34], implying a

Nonetheless, a common origin of PTC and HT from cancer stem cells expressing p63 proteins—homologs of p53 proteins postulated to regulate squamous stem cell commitment—has been suggested. In fact, the cancer stem cells constitute pluripotent cells deemed to remain undifferentiated or undergo benign squamoid and glandural maturation or be differentiated to follicular epithelial cells, harboring the

The interrelationship of PTC with HT spurs a realm of intense research, principally in four respects. Firstly, the pathogenetic link between HT and PTC remains elusive; however, accumulative evidence suggests that these two entities are immunologically linked [29]. Secondly, some authors argue that this interrelationship is merely epiphenomenon of selection bias inherent in studies encompassing surgical series [37, 38]. Thirdly, equivocal—favorable versus unfavorable—is the impact of HT on the prognosis of concurrent PTC [39–48]. Finally, the translation of the serum concentrations of thyroid autoantibodies [49–56] and thyroid-stimulating hormone (TSH) [55, 57–63] into predictive and prognostic PTC biomarkers incites

thyroid tissue [19], and, potentially, atrophy of parenchymal tissue gradually replaced by fibrous tissue [20]. The identification of the autoantibodies hallmark of HT in 1936 [21] paved the way for Rose and Witebsky to designate HT as the archetype of autoimmune destructive disorders [22]. Whereas the pathogenesis of HT is unclear, crucial is considered the imbalance between T-helper (Th)2 cells—Th CD (cluster of differentiation)4+ cells credited with stimulation of B cells, which in turn produce thyroid autoantibodies- and Th1 cells-cytotoxic Th CD4+ cells directly attacking the thyroid follicular cells. This concept has been refined by the imbalance between Th17 cells and Th cells producing mainly IL-17, involved also in carcinomas- and T regulatory (Treg) cells-Th CD4+ cells deemed to halt the immune response [23]. Especially, an increased TH17/Treg ratio ascribed to both enhancement of TH17 expression and decrease of Treg is involved in the pathogenesis of HT [24]. Incriminated for the depletion of thyrocytes in HT is principally the autocrine/paracrine Fas-/Fas ligand (FasL)-induced

*DOI: http://dx.doi.org/10.5772/intechopen.85128*

extrinsic apoptotic pathway [24, 25].

**PTC with HT**

ship of PTC with HT.

spurious correlation.

a perpetual conflict.

potential to elicit both PTC and HT [35, 36].

unknown, pathogenetic link.

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing… DOI: http://dx.doi.org/10.5772/intechopen.85128*

thyroid tissue [19], and, potentially, atrophy of parenchymal tissue gradually replaced by fibrous tissue [20]. The identification of the autoantibodies hallmark of HT in 1936 [21] paved the way for Rose and Witebsky to designate HT as the archetype of autoimmune destructive disorders [22]. Whereas the pathogenesis of HT is unclear, crucial is considered the imbalance between T-helper (Th)2 cells—Th CD (cluster of differentiation)4+ cells credited with stimulation of B cells, which in turn produce thyroid autoantibodies- and Th1 cells-cytotoxic Th CD4+ cells directly attacking the thyroid follicular cells. This concept has been refined by the imbalance between Th17 cells and Th cells producing mainly IL-17, involved also in carcinomas- and T regulatory (Treg) cells-Th CD4+ cells deemed to halt the immune response [23]. Especially, an increased TH17/Treg ratio ascribed to both enhancement of TH17 expression and decrease of Treg is involved in the pathogenesis of HT [24]. Incriminated for the depletion of thyrocytes in HT is principally the autocrine/paracrine Fas-/Fas ligand (FasL)-induced extrinsic apoptotic pathway [24, 25].

#### **4. Rationality in the investigation of the interrelationship of PTC with HT**

Apart from the well-established connection of HT with thyroid lymphoma [26], which is beyond the scope of the present chapter, the association of TC with HT concerns almost exclusively the PTC [27], alluding to a discriminating, though unknown, pathogenetic link.

Since PTC is conceived as the main culprit for the explosive rise of TC incidence [3], the hypothesis that the increasing incidence of HT hastens the "TC epidemic" is appealing. Considering that the inflammation has been envisaged as the "seventh hallmark of cancer" [28], the autoimmunity-induced inflammatory milieu [29] merits further interrogation as the missing piece in the puzzle of the interrelationship of PTC with HT.

An alternative explanation that cannot be ruled out is that third extraneous variables actually cause the coexistence of PTC with HT. Indeed, both PTC and HT are precipitated by an interplay among genetic factors and environmental influences most of which are shared by the two entities. Emphasis is placed on risk factors implicated in the pathogenesis of both PTC and HT, such as female predominance, excess iodine intake, and exposure to radiation [30–34], implying a spurious correlation.

Nonetheless, a common origin of PTC and HT from cancer stem cells expressing p63 proteins—homologs of p53 proteins postulated to regulate squamous stem cell commitment—has been suggested. In fact, the cancer stem cells constitute pluripotent cells deemed to remain undifferentiated or undergo benign squamoid and glandural maturation or be differentiated to follicular epithelial cells, harboring the potential to elicit both PTC and HT [35, 36].

The interrelationship of PTC with HT spurs a realm of intense research, principally in four respects. Firstly, the pathogenetic link between HT and PTC remains elusive; however, accumulative evidence suggests that these two entities are immunologically linked [29]. Secondly, some authors argue that this interrelationship is merely epiphenomenon of selection bias inherent in studies encompassing surgical series [37, 38]. Thirdly, equivocal—favorable versus unfavorable—is the impact of HT on the prognosis of concurrent PTC [39–48]. Finally, the translation of the serum concentrations of thyroid autoantibodies [49–56] and thyroid-stimulating hormone (TSH) [55, 57–63] into predictive and prognostic PTC biomarkers incites a perpetual conflict.

*Knowledges on Thyroid Cancer*

and sophisticated picture.

disease has been endorsed [7].

ignoring a metastatic potential.

**3. HT at a glance**

with HT, delving into a strongly insinuated immunological link. A comprehensive review of current literature emphasizes on the bewildering clinical significance of the interrelationship of PTC with HT. The intriguing predictive and prognostic value of serum concentrations of thyroid autoantibodies and thyroid-stimulating hormone (TSH) in the context of PTC coexistent with HT paints a more nuanced

**2. Tailoring the treatment of PTC: where does coexistent HT stand?**

Thyroid cancer (TC) is the most common endocrine malignancy [4], though comprising only 2.1% of global cancer burden [5]. It is estimated that 52,070 new TC cases will occur in 2019 in the United States, while 2170 patients will die of this cancer type [6]. Derived from follicular epithelial cells, PTC constitutes the most common TC subtype in iodine sufficient areas, accounting for 85% of differentiated TC (DTC) [7] and 70–80% of TC [8]. In light of the interface between "TC epidemic" and "epidemic of diagnosis," a true increase of the incidence of PTC due to environmental, hormonal, and lifestyle risk factors appears to be merged with overdiagnosis of subclinical disease owing to meticulous screening [3, 9–11].

The indolent nature of PTC imposes a paradigm shift from ameliorating 10-year survival rates exceeding 90% to eliminating the recurrence incidence that hovers at 15–30% [12]. Individualization of therapeutic approach is deemed to confront the emerging challenges [13]. Seminal studies [4, 14, 15] recently illuminated the "dark matter" of the previously unidentified driver genetic events in 96% of PTC [4], being translated into molecular-based risk-adapted therapeutic strategies [7]. Although surgery is the cornerstone of treatment of PTC, a tailored approach with respect to the extent of thyroidectomy and lymph node dissection, the radioiodine ablation, and the management of radioiodine-refractory recurrent/metastatic

Provided that the clinical relevance of the increasingly reported interrelationship of PTC with HT is clarified, the incorporation thereof in current PTC risk stratification systems may empower a personalized treatment. This perspective is anticipated to build on accomplishing a fine-tuned balance in terms of decisionmaking concerning PTC, precluding both overestimating an innocent disease and

HT, originally designated as "struma lymphomatosa" by Dr. Hakaru Hashimoto in 1912 [16], is the most common autoimmune thyroid disease and the most common cause of hypothyroidism in iodine sufficient areas, showing a worldwide annual incidence varying from 0.3 to 1.5 cases per 1000 individuals [17]. An

insightful approach concerning the multifactorial etiology of HT has been proposed by Weetman et al.: aligned in a way reminiscent of the wholes of the Swiss cheese are genetic factors acting as susceptibility loci—major histocompatibility human leukocyte antigen (HLA) genes, immunoregulatory genes, thyroid specific genesenvironmental factors—excess iodine intake, viral infections, stress, endocrine disruptors—as well as non-modifiable intrinsic factors—female sex, parity, age. Traversed by a hypothetical arrow, this conceivable line translates in a catastrophic

The histopathologically confirmed HT is characterized by diffuse lymphocytic infiltrate, formation of lymphoid follicles with germinal centers within normal

**38**

event [18].

#### **5. Exploring the immunological link between PTC and HT**

Compelling evidence insinuate that the PTC and the HT represent two extremes in the continuum of immune response. In cancer, dominant is an anti-inflammatory response dictated by cancer cells per se, counteracting the antitumor immune surveillance. Quite the contrary, an overactivated inflammatory response owing to breakage of self-tolerance attacks host tissue cells, resulting in tissue damage in the context of autoimmune diseases. Despite the fundamental differences between the tumor microenvironment and the autoimmune milieu, certain parallel aspects of these two landscapes have been recognized [64]. For instance, the macrophages (M) and the neutrophils (N)—cells of myeloid origin—are encountered in both cancer and autoimmunity that act as well-coordinated partners to orchestrate the innate immune attack. Showing plasticity, these cells transition from proinflammatory M1/N1 polarization, devoted to kill pathogens or cancer cells, to anti-inflammatory M2/N2 polarization, dedicated to repair tissue damage and promote angiogenesis. A shift toward M2 macrophage polarization is a core component of tumor microenvironment, observed in autoimmune milieu as well, providing a hint to the interface thereof. Furthermore, supportive of the tumor-promoting M2 macrophage polarization is the local hypoxic milieu inherent in both autoimmune and cancerous diseases [64].

The elucidation of the continuum of immune response could provide insights into the pathogenetic background of the coexistence of PTC with HT. Given that the macrophage phenotype M2 is considered tumor-promoting contrary to the antitumor effect of M1 phenotype, an appealing hypothesis connecting PTC with HT is derived from the intrathyroidal immune profiling of euthyroid HT conducted very recently by Imam et al. [65]. The immune infiltrate in euthyroid HT proved to contain low count of natural killer (NK) cells, facilitating the differentiation of the macrophage phenotype M0 to the M2 phenotype, which in concert with the observed low count of M1 macrophages may interpret the higher risk of PTC inherent in euthyroid HT [65].

Interestingly, overexpression of Toll-like receptors (TLR)—cell surface receptors credited with recognition of pathogen-related molecules, crucial for activation of innate and adaptive immunity—is detected immunohistochemically in human thyrocytes surrounded by immune cells in all patients with HT. The high basal TLR3 mRNA levels observed in PTC, reinforcing the shared immunological landscape, are consistent [66, 67].

Dissecting the interface of HT with PTC is expected to unveil novel targets for immunomodulation. For instance, triggering the innate immunity via the TLR5 agonist flagellin, being already in clinical trials as inducer of NK activation [68], could be interrogated as a modality to reverse the M2 macrophage phenotype in PTC coexistent with HT.

In pursuit of the immunological link connecting PTC with HT, three hypotheses, rather interrelated, shape a conceptual framework outlined below.

#### **5.1 Thyroid malignancy develops despite immune response in the context of HT**

Manifold mechanisms have been proposed to underlie the escape of PTC cells from immune response in the context of autoimmunity: (i) the ability of PTC cells to manipulate the expression of immune-regulatory cytokines, editing the immune response; (ii) the enhancement of Treg known to suppress the NK cell effector functions, mainly the cytotoxicity; and (iii) the promotion of expression of specific surface molecules facilitating tumor development and growth, such as the membrane-bound transforming growth factor b (TGFb), histocompatibility antigen, class 1, G (HLA-G), FasL, and B7 homolog 1(B7H1) [28].

**41**

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing…*

**5.2 Thyroid malignancy develops owing to thyroid autoimmunity**

The first detection of lymphocytes in neoplastic tissues by Virchow in 1863 [73] paved the way for the endorsement of chronic inflammation as a precipitating factor for certain cancer types. In that respect, thyroid gland could be conceived as an intersection of HT-induced chronic inflammation and cancer; however, a causal relationship is yet to be defined. In light of the cancer-related inflammation (CRI), the concurrence of PTC with HT might reflect either the malignant transformation ascribed to an autoimmunity-induced chronic inflammatory milieu (extrinsic

pathway) or the inflammatory response to tumor (intrinsic pathway) [74].

The perpetually overactive immune response in the context of HT initiates an inflammatory vicious cycle with the potential to gear the journey of normal cells toward malignancy, rendering the interrelationship of PTC with HT the epitome of

Central in the extrinsic pathway is the "smoldering inflammation," an ungoverned inflammatory milieu orchestrated by immune/inflammatory cells, involving macrophages, immature DCs, and mast cells, expressing a myriad of cytokines, chemokines, and growth factors, such as interleukin (IL)-1b, tumor necrosis factor a (TNFa), IL-6, (C-C motif) ligand 2 (CCL2)/monocyte chemoattractant protein 1 (MCP-1), CXC chemokine ligand (CXCL8)/IL-8, vascular endothelial growth factor (VEGF), as well as reactive oxygen species (ROS) and reactive nitrogen species (RNS), spurring tissue damage, neo-angiogenesis, and tissue remodeling [75, 76]. Implicated in this milieu is the hypoxic microenvironment, inherent in both PTC and HT, favoring the progression of tumor, reinforcing, among others, the neo-angiogenesis and the shift

Overexpression of cyclooxygenase-2 (COX-2)—an enzyme involved in initiation [77] and progression of thyroid tumors [78]—and inducible nitric oxide synthases (iNOS), key elements of CRI, has been observed in epithelial cells of lymphocytic thyroiditis, follicular adenoma, and PTC contrary to the absence or the limited expression thereof in normal thyroid epithelium, potentially linking carcinogenesis to autoimmunity [79]. Intertwined with the extrinsic pathway is the intrinsic pathway: genetic alterations caused by DNA damage induced by the "smoldering inflammation" [80] trigger a proinflammatory transcriptional program [74]. For instance, the oncogene RAS is involved in the induction of chemokine CXCL8 [75], an inflammatory mediator of both cancer [75] and autoimmunity [64]. Moreover, phosphatase and tensin homolog (PTEN) mutation, a key element of the oncogenic phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, leads to upregulation of hypoxiainducible factor-1 (HIF1), which, in turn, upregulates the CXC chemokine receptor 4 (CXCR4) [75], well-recognized player of autoimmunity [81]. Accordingly, the observed activation of the PI3K/AKT pathway in HT, PTC, and HT coexistent with PTC contrary to the absence of activation thereof in normal follicles is rational [82].

Moreover, the interrelationship of PTC with HT may empower the escape of cancer cells from immune surveillance, consolidating the dogma that "cancer is a wound that never heals since tumor cells hijack the wound healing machinery for their own gain" [69]. In fact, a recently discovered "unexpected player", the T cell double negative (DN) CD4(−) CD8(−), expressed both in PTC and in thyroid autoimmunity, downregulates the proliferation of activated T effector cells and the cytokine production, fostering an immunosuppressive microenvironment [70]. Favoring immune tolerance, the FOXP3+ Treg cells—crucial players of thyroid autoimmunity [71]—are encountered also in PTC [70]. The dendritic cells (DCs), beyond governing the autoimmune milieu, are also expressed in PTC, being responsible for the expansion of FOXP3+ Treg cells, allowing the tumor immune evasion and, thus, enabling the PTC progression [72].

*DOI: http://dx.doi.org/10.5772/intechopen.85128*

the extrinsic pathway of CRI [74].

of metabolism toward anaerobic glycolysis [64].

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing… DOI: http://dx.doi.org/10.5772/intechopen.85128*

Moreover, the interrelationship of PTC with HT may empower the escape of cancer cells from immune surveillance, consolidating the dogma that "cancer is a wound that never heals since tumor cells hijack the wound healing machinery for their own gain" [69]. In fact, a recently discovered "unexpected player", the T cell double negative (DN) CD4(−) CD8(−), expressed both in PTC and in thyroid autoimmunity, downregulates the proliferation of activated T effector cells and the cytokine production, fostering an immunosuppressive microenvironment [70]. Favoring immune tolerance, the FOXP3+ Treg cells—crucial players of thyroid autoimmunity [71]—are encountered also in PTC [70]. The dendritic cells (DCs), beyond governing the autoimmune milieu, are also expressed in PTC, being responsible for the expansion of FOXP3+ Treg cells, allowing the tumor immune evasion and, thus, enabling the PTC progression [72].

#### **5.2 Thyroid malignancy develops owing to thyroid autoimmunity**

The first detection of lymphocytes in neoplastic tissues by Virchow in 1863 [73] paved the way for the endorsement of chronic inflammation as a precipitating factor for certain cancer types. In that respect, thyroid gland could be conceived as an intersection of HT-induced chronic inflammation and cancer; however, a causal relationship is yet to be defined. In light of the cancer-related inflammation (CRI), the concurrence of PTC with HT might reflect either the malignant transformation ascribed to an autoimmunity-induced chronic inflammatory milieu (extrinsic pathway) or the inflammatory response to tumor (intrinsic pathway) [74].

The perpetually overactive immune response in the context of HT initiates an inflammatory vicious cycle with the potential to gear the journey of normal cells toward malignancy, rendering the interrelationship of PTC with HT the epitome of the extrinsic pathway of CRI [74].

Central in the extrinsic pathway is the "smoldering inflammation," an ungoverned inflammatory milieu orchestrated by immune/inflammatory cells, involving macrophages, immature DCs, and mast cells, expressing a myriad of cytokines, chemokines, and growth factors, such as interleukin (IL)-1b, tumor necrosis factor a (TNFa), IL-6, (C-C motif) ligand 2 (CCL2)/monocyte chemoattractant protein 1 (MCP-1), CXC chemokine ligand (CXCL8)/IL-8, vascular endothelial growth factor (VEGF), as well as reactive oxygen species (ROS) and reactive nitrogen species (RNS), spurring tissue damage, neo-angiogenesis, and tissue remodeling [75, 76]. Implicated in this milieu is the hypoxic microenvironment, inherent in both PTC and HT, favoring the progression of tumor, reinforcing, among others, the neo-angiogenesis and the shift of metabolism toward anaerobic glycolysis [64].

Overexpression of cyclooxygenase-2 (COX-2)—an enzyme involved in initiation [77] and progression of thyroid tumors [78]—and inducible nitric oxide synthases (iNOS), key elements of CRI, has been observed in epithelial cells of lymphocytic thyroiditis, follicular adenoma, and PTC contrary to the absence or the limited expression thereof in normal thyroid epithelium, potentially linking carcinogenesis to autoimmunity [79].

Intertwined with the extrinsic pathway is the intrinsic pathway: genetic alterations caused by DNA damage induced by the "smoldering inflammation" [80] trigger a proinflammatory transcriptional program [74]. For instance, the oncogene RAS is involved in the induction of chemokine CXCL8 [75], an inflammatory mediator of both cancer [75] and autoimmunity [64]. Moreover, phosphatase and tensin homolog (PTEN) mutation, a key element of the oncogenic phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, leads to upregulation of hypoxiainducible factor-1 (HIF1), which, in turn, upregulates the CXC chemokine receptor 4 (CXCR4) [75], well-recognized player of autoimmunity [81]. Accordingly, the observed activation of the PI3K/AKT pathway in HT, PTC, and HT coexistent with PTC contrary to the absence of activation thereof in normal follicles is rational [82].

*Knowledges on Thyroid Cancer*

are consistent [66, 67].

PTC coexistent with HT.

**context of HT**

**5. Exploring the immunological link between PTC and HT**

Compelling evidence insinuate that the PTC and the HT represent two extremes in the continuum of immune response. In cancer, dominant is an anti-inflammatory response dictated by cancer cells per se, counteracting the antitumor immune surveillance. Quite the contrary, an overactivated inflammatory response owing to breakage of self-tolerance attacks host tissue cells, resulting in tissue damage in the context of autoimmune diseases. Despite the fundamental differences between the tumor microenvironment and the autoimmune milieu, certain parallel aspects of these two landscapes have been recognized [64]. For instance, the macrophages (M) and the neutrophils (N)—cells of myeloid origin—are encountered in both cancer and autoimmunity that act as well-coordinated partners to orchestrate the innate immune attack. Showing plasticity, these cells transition from proinflammatory M1/N1 polarization, devoted to kill pathogens or cancer cells, to anti-inflammatory M2/N2 polarization, dedicated to repair tissue damage and promote angiogenesis. A shift toward M2 macrophage polarization is a core component of tumor microenvironment, observed in autoimmune milieu as well, providing a hint to the interface thereof. Furthermore, supportive of the tumor-promoting M2 macrophage polarization is the local hypoxic milieu inherent in both autoimmune and cancerous diseases [64].

The elucidation of the continuum of immune response could provide insights into the pathogenetic background of the coexistence of PTC with HT. Given that the macrophage phenotype M2 is considered tumor-promoting contrary to the antitumor effect of M1 phenotype, an appealing hypothesis connecting PTC with HT is derived from the intrathyroidal immune profiling of euthyroid HT conducted very recently by Imam et al. [65]. The immune infiltrate in euthyroid HT proved to contain low count of natural killer (NK) cells, facilitating the differentiation of the macrophage phenotype M0 to the M2 phenotype, which in concert with the observed low count of M1 macrophages may interpret the higher risk of PTC inherent in euthyroid HT [65]. Interestingly, overexpression of Toll-like receptors (TLR)—cell surface receptors credited with recognition of pathogen-related molecules, crucial for activation of innate and adaptive immunity—is detected immunohistochemically in human thyrocytes surrounded by immune cells in all patients with HT. The high basal TLR3 mRNA levels observed in PTC, reinforcing the shared immunological landscape,

Dissecting the interface of HT with PTC is expected to unveil novel targets for immunomodulation. For instance, triggering the innate immunity via the TLR5 agonist flagellin, being already in clinical trials as inducer of NK activation [68], could be interrogated as a modality to reverse the M2 macrophage phenotype in

In pursuit of the immunological link connecting PTC with HT, three hypotheses,

Manifold mechanisms have been proposed to underlie the escape of PTC cells from immune response in the context of autoimmunity: (i) the ability of PTC cells to manipulate the expression of immune-regulatory cytokines, editing the immune response; (ii) the enhancement of Treg known to suppress the NK cell effector functions, mainly the cytotoxicity; and (iii) the promotion of expression of specific surface molecules facilitating tumor development and growth, such as the membrane-bound transforming growth factor b (TGFb), histocompatibility

rather interrelated, shape a conceptual framework outlined below.

antigen, class 1, G (HLA-G), FasL, and B7 homolog 1(B7H1) [28].

**5.1 Thyroid malignancy develops despite immune response in the** 

**40**

Illustrating the common molecular background shared by PTC and HT, the rearranged during transfection (RET)/PTC rearrangements—landmarks of PTC are detected in 95% of HT [83]. Moreover, the RET/PTC1 rearrangement has been detected more frequently in PTC coexistent with autoimmunity than PTC alone (31% versus 13%, respectively) [84]. The inflammatory milieu fosters the genesis of RET/PTC rearrangements either via secreting ROS and RNS [85]—the main culprit for mutagenic-mediated DNA damage [2]—or sustaining the survival of thyroid cells that harbor RET/PTC rearrangements.

The oncogenic RET/PTC-RAS-BRAF-mitogen-activated protein kinase (MAPK) cascade [74] may connect the oxyphil cell metaplasia of HT with PTC, considering the enhancement of the expression of RET, nuclear RAS, and extracellular signalregulated kinases (ERKs)—core components of MAPK cascade—not only in PTC but also in oxyphil cells in the context of HT [86].

Further, experimental data unravel that the RET/PTC1 exogenously expressed on normal human thyroid cells induces an inflammatory milieu involving crucial chemokines and their receptors, promoting functions vital for tumor progression, such as proliferation and survival of cancer cells [e.g., CXCR4/CXCL1] as well as neo-angiogenesis (e.g., CXL1, 2, 3, 5, 6, and 8) [87].

Additionally, a constellation of RET/PTC1-induced molecules fosters the genesis and evolution of cancer, including (i) matrix metalloproteinases (MMPs) and dipeptidyl peptidase IV (DPP IV), molecules crucial for tissue remodeling, tumor invasiveness, and neo-angiogenesis [87]; (ii) urokinase-type plasminogen activator (UPA) and urokinase-type plasminogen activator receptor (UPAR), involved in cancer progression and metastasis [87]; (iii) l-selectin [87], an adhesion molecule facilitating metastasis [88]; and (iv) osteopontin (OPN) and CD44, implicated in proliferation and invasion of transformed PCCl 3 cells, rat thyroid follicular cells [89].

An intriguing RET/PTC3-induced mechanism pivotal for tumor progression is the recruitment of CD11b+Gr1+ myeloid-derived suppressor cells, providing cancer cells with the advantage of evading immune surveillance [90, 91].

However, skepticism raise the technical limitations of the applied PCR techniques and the lack of reproducibility of the results of studies detecting the RET/ PTC rearrangements in HT [92]. Furthermore, the equivocal nature of RET/PTCinduced transcriptional program—tumor-promoting versus antitumor—should be considered [87].

#### **5.3 The immune attack against PTC triggers thyroid autoimmunity**

The association of PTC with HT seems more intricate than initially conceived in view of a seminal cyclic model governed by the overactive immune response, acting as a driving force for carcinogenesis, while being also a marker of tumor immunity [93]. An assumption that merits further exploration is whether the cross reaction of antitumor immunity with normal thyrocytes may precipitate HT in PTC patients genetically predisposed to thyroid autoimmunity, consolidating the hypothesis of "tumor defense-induced autoimmunity" [29]. With the advent of the era of cancer immunotherapy, new light on the coexistence of HT with PTC is shed by the increasingly reported development of HT as an adverse event of the monoclonal antibodies blocking programmed cell death (PD) protein 1 (PD-1) and PD ligand 1 (PD-L1). This revolutionary anticancer treatment unleashes the antitumor immunity at the expense of abrogating the self-tolerance, exemplifying the "tumor defense-induced" immunity [94]. For instance, a loss of circulatory PD1+ CD4+ and CD8+ T cells, an increase in peripheral CD56+CD16+ NK cells and an increase in activated monocytes have been implicated in pembrolizumab (anti-PD1 monoclonal antibody)-induced thyroiditis [94].

**43**

**Table 1.**

**Reference Results**

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing…*

An issue of major concern is whether the coexistence of PTC with HT is real or a myth nurtured by methodological pitfalls implicit in studies addressing this issue. The great variety of the incidence of the coexistence of PTC with HT ranging from 0.5 to 38% [95] or, alternatively, from 5 to 85% is noticeable [96]. The results of the meta-analyses addressing the coexistence of PTC with HT are highly divergent [40, 48, 96, 97], as depicted in **Table 1**. The broad array of the mean rate of PTC among patients with HT extending from 1.1 to 40.1% blurs the landscape [97]. Nevertheless, according to a systematic review, the correlation of PTC with HT is statistically significant with a relative risk (RR) of HT among PTC equal to

In an attempt to annotate the diverse epidemiological profile of the coexistence

of PTC with HT, attention should be paid to the discrepancy among pertinent studies concerning the design, the enrolled populations, and the histopathologic definitions of HT [99]. Moreover, certain caveats hamper hitherto the interpretation of the lymphocytic infiltration and the positivity of thyroid autoantibodies. Firstly, thyroid lymphocytic infiltration confirmed on histology has been significantly associated with PTC even in the absence of thyroid autoantibodies [100]. Secondly, the pattern of Tg recognition by anti-thyroglobulin autoantibodies (TgAbs) differs between autoimmune and non-autoimmune thyroid disorders, being more restricted in autoimmune disorders as compared with nodular goiter and PTC harboring no thyroid lymphocytic infiltration [101]. However, in PTC correlated with histopathologically confirmed HT, the pattern of Tg recognition does not differ from that observed in HT [101]. Thirdly, it should be mentioned that the thyroid autoantibodies may be detected in healthy individuals [102]. Finally, the

discordance among available TgAbs assays should be considered [103].

recurrence (RR: 0.50, 95% CI, 0.41–0.61)

Lai et al. [97] Range of mean rate of PTC among patients with HT: 1.12–40.11%

Lee et al. [96] Frequency of HT in PTC: ≈23%

2.77, 95% CI, 1.24–6.21)

*Meta-analyses addressing the correlation of PTC with HT.*

CI, 1.02–3.50)

Another hurdle in evaluating the coexistence of PTC with HT is the selection bias inherent in data derived from surgical specimens wherein the prevalence of PTC is a priori higher than that in fine needle aspiration biopsy (FNAB) studies.

Moon et al. [48] PTC coexistent with HT is negatively associated with ETE (OR: 0.74, 95% CI, 0.68–0.81),

2.4 times higher incidence of HT in PTC than in other TC (p < 0.001)

Singh et al. [40] 2.77 times elevated rate of PTC in patients with HT compared with control population (OR:

*Abbreviations: CI, confidence interval; ETE, extrathyroidal extension; HR, hazard ratio; HT, Hashimoto's thyroiditis, LNM, lymph node metastasis; OR, odds ratio; PTC, papillary thyroid carcinoma, RR, risk ratio; TC, thyroid cancer.*

p = 0.041), long recurrence-free survival (HR: 0.6, p = 0.001)

LNM (OR: 0.82, 95% CI, 0.72–0.94), distant metastasis (OR: 0.49, 95% CI, 0.32–0.76), and

2.8 times higher occurrence rate of HT in PTC than in benign thyroid diseases (p < 0.001)

Significant association of PTC concurrent with HT with female sex (OR: 2.7; p < 0.001), multifocality (OR: 1.5, p = 0.010), absence of ETE (OR: 1.3, p = 0.002) and LNM (OR: 1.3,

Overall pooled OR of PTC risk for HT (HT versus non-HT): 2.12 (95% CI, 1.78–2.52)

Increased PTC-free survival in patients with coexistent HT (r: 0.08, 95% CI, 0.05–0.12) Increased overall survival in PTC patients with coexistent HT (r: 0.11; 95% CI, 0.07–0.14)

1.89 times higher rate of HT in patients with PTC compared with other TC types (OR: 1.89, 95%

**6. Does the coexistence of HT with PTC really exist?**

2.36 and a RR of PTC among HT equal to 1.40 [98].

*DOI: http://dx.doi.org/10.5772/intechopen.85128*

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing… DOI: http://dx.doi.org/10.5772/intechopen.85128*

#### **6. Does the coexistence of HT with PTC really exist?**

*Knowledges on Thyroid Cancer*

cells that harbor RET/PTC rearrangements.

(e.g., CXL1, 2, 3, 5, 6, and 8) [87].

considered [87].

but also in oxyphil cells in the context of HT [86].

Illustrating the common molecular background shared by PTC and HT, the rearranged during transfection (RET)/PTC rearrangements—landmarks of PTC are detected in 95% of HT [83]. Moreover, the RET/PTC1 rearrangement has been detected more frequently in PTC coexistent with autoimmunity than PTC alone (31% versus 13%, respectively) [84]. The inflammatory milieu fosters the genesis of RET/PTC rearrangements either via secreting ROS and RNS [85]—the main culprit for mutagenic-mediated DNA damage [2]—or sustaining the survival of thyroid

The oncogenic RET/PTC-RAS-BRAF-mitogen-activated protein kinase (MAPK) cascade [74] may connect the oxyphil cell metaplasia of HT with PTC, considering the enhancement of the expression of RET, nuclear RAS, and extracellular signalregulated kinases (ERKs)—core components of MAPK cascade—not only in PTC

Further, experimental data unravel that the RET/PTC1 exogenously expressed on normal human thyroid cells induces an inflammatory milieu involving crucial chemokines and their receptors, promoting functions vital for tumor progression, such as proliferation and survival of cancer cells [e.g., CXCR4/CXCL1] as well as neo-angiogenesis

Additionally, a constellation of RET/PTC1-induced molecules fosters the genesis and evolution of cancer, including (i) matrix metalloproteinases (MMPs) and dipeptidyl peptidase IV (DPP IV), molecules crucial for tissue remodeling, tumor invasiveness, and neo-angiogenesis [87]; (ii) urokinase-type plasminogen activator (UPA) and urokinase-type plasminogen activator receptor (UPAR), involved in cancer progression and metastasis [87]; (iii) l-selectin [87], an adhesion molecule facilitating metastasis [88]; and (iv) osteopontin (OPN) and CD44, implicated in proliferation and invasion of transformed PCCl 3 cells, rat thyroid follicular cells [89]. An intriguing RET/PTC3-induced mechanism pivotal for tumor progression is the recruitment of CD11b+Gr1+ myeloid-derived suppressor cells, providing cancer

However, skepticism raise the technical limitations of the applied PCR techniques and the lack of reproducibility of the results of studies detecting the RET/ PTC rearrangements in HT [92]. Furthermore, the equivocal nature of RET/PTCinduced transcriptional program—tumor-promoting versus antitumor—should be

The association of PTC with HT seems more intricate than initially conceived in view of a seminal cyclic model governed by the overactive immune response, acting as a driving force for carcinogenesis, while being also a marker of tumor immunity [93]. An assumption that merits further exploration is whether the cross reaction of antitumor immunity with normal thyrocytes may precipitate HT in PTC patients genetically predisposed to thyroid autoimmunity, consolidating the hypothesis of "tumor defense-induced autoimmunity" [29]. With the advent of the era of cancer immunotherapy, new light on the coexistence of HT with PTC is shed by the increasingly reported development of HT as an adverse event of the monoclonal antibodies blocking programmed cell death (PD) protein 1 (PD-1) and PD ligand 1 (PD-L1). This revolutionary anticancer treatment unleashes the antitumor immunity at the expense of abrogating the self-tolerance, exemplifying the "tumor defense-induced" immunity [94]. For instance, a loss of circulatory PD1+ CD4+ and CD8+ T cells, an increase in peripheral CD56+CD16+ NK cells and an increase in activated monocytes have been implicated in pembrolizumab (anti-PD1 monoclo-

cells with the advantage of evading immune surveillance [90, 91].

**5.3 The immune attack against PTC triggers thyroid autoimmunity**

**42**

nal antibody)-induced thyroiditis [94].

An issue of major concern is whether the coexistence of PTC with HT is real or a myth nurtured by methodological pitfalls implicit in studies addressing this issue.

The great variety of the incidence of the coexistence of PTC with HT ranging from 0.5 to 38% [95] or, alternatively, from 5 to 85% is noticeable [96]. The results of the meta-analyses addressing the coexistence of PTC with HT are highly divergent [40, 48, 96, 97], as depicted in **Table 1**. The broad array of the mean rate of PTC among patients with HT extending from 1.1 to 40.1% blurs the landscape [97]. Nevertheless, according to a systematic review, the correlation of PTC with HT is statistically significant with a relative risk (RR) of HT among PTC equal to 2.36 and a RR of PTC among HT equal to 1.40 [98].

In an attempt to annotate the diverse epidemiological profile of the coexistence of PTC with HT, attention should be paid to the discrepancy among pertinent studies concerning the design, the enrolled populations, and the histopathologic definitions of HT [99]. Moreover, certain caveats hamper hitherto the interpretation of the lymphocytic infiltration and the positivity of thyroid autoantibodies. Firstly, thyroid lymphocytic infiltration confirmed on histology has been significantly associated with PTC even in the absence of thyroid autoantibodies [100]. Secondly, the pattern of Tg recognition by anti-thyroglobulin autoantibodies (TgAbs) differs between autoimmune and non-autoimmune thyroid disorders, being more restricted in autoimmune disorders as compared with nodular goiter and PTC harboring no thyroid lymphocytic infiltration [101]. However, in PTC correlated with histopathologically confirmed HT, the pattern of Tg recognition does not differ from that observed in HT [101]. Thirdly, it should be mentioned that the thyroid autoantibodies may be detected in healthy individuals [102]. Finally, the discordance among available TgAbs assays should be considered [103].

Another hurdle in evaluating the coexistence of PTC with HT is the selection bias inherent in data derived from surgical specimens wherein the prevalence of PTC is a priori higher than that in fine needle aspiration biopsy (FNAB) studies.


*Abbreviations: CI, confidence interval; ETE, extrathyroidal extension; HR, hazard ratio; HT, Hashimoto's thyroiditis, LNM, lymph node metastasis; OR, odds ratio; PTC, papillary thyroid carcinoma, RR, risk ratio; TC, thyroid cancer.*

#### **Table 1.**

*Meta-analyses addressing the correlation of PTC with HT.*

Jankovic et al. showed that the average prevalence rate of PTC in HT patients differed significantly between FNAB and thyroidectomy studies: 1.20 and 27.56%, respectively. Likewise, the relative risk of PTC in HT patients extended from 0.39 to 1.00 in the FNAB studies, significantly lower than that observed in the thyroidectomy studies (1.15–4.16) [37]. In that respect, Castagna et al. demonstrated absence of association of nodular HT with TC based on cytology. The same authors observed a significantly higher prevalence of DTC in nodular HT compared to nodular Graves' disease, nodular goiter with either negative or positive thyroid autoantibodies, according to surgical series. This result raised the possibility of selection bias ascribed to the fact that 60.7% of patients with nodular HT underwent surgery due to cytological data suspicious of thyroid malignancy [38]. The FNAB data from 10,508 patients revealing no statistically significant relationship between PTC and HT are consistent [104].

Nevertheless, the fear of the selection bias was abolished by the recent demonstration of a significant association of PTC with HT based on either pathological examination of surgical specimens or FNAB studies [60].

#### **7. Effect of HT on coexistent PTC: host protective or tumor protective?**

Irrespectively of whether HT is etiologically linked to PTC or merely judged "guilty by association," the importance of this coexistence lies on its clinical significance. Since a complex immune network has been considered a core component of PTC microenvironment, it is rational to assume that HT—the epitome of aberrant immune reaction—influences the progression of coexistent PTC [105]. In that respect, the positive association of a favorable outcome of coexistent PTC with HT, tumor-associated macrophage infiltration, and CD8+ lymphocytes highlights the antitumor potential of the immunological landscape intrinsic in HT [106]. The recently reported negative correlation of RORγt—a nuclear transcription protein of Th17—with lymph node metastases in PTC concurrent with HT is consistent. In fact, RORγt is positively associated with the upregulation of caveolin 1, a tumor suppressor gene [107]. Another plausible mechanism underlying the host-protective effect of HT coexistent with PTC could be the lower frequency of BRAF V600E mutation—a genetic alteration associated with aggressive PTC phenotype—in PTC concurrent with HT compared with PTC alone [41, 42].

A rich repertoire of features indicative of auspicious PTC prognosis are significantly associated with coexistent HT, including increased relapse-free and overall survival [39], increased survival rate [96, 108], decreased risk of recurrence [108], lower rate [108] or absence of extrathyroidal extension [96], and lower rate [41] or absence of lymph node metastases [96], observed in PTC coexistent with HT compared with PTC alone. The results of a recent meta-analysis including 71 published studies with 44,034 participants revealing that PTC coexistent with HT significantly correlated with reduced incidence of extrathyroidal extension, lymph node, and distant metastasis and increased recurrence-free survival duration compared with PTC alone are seminal [47]. Noticeably, the coexistence of HT with PTC has been proven an independent indicator of favorable prognosis of PTC [105], irrespectively of the extent of lymph node dissection [46], though inconsistently [108]. On the other hand, the reported absence of host-protective effect of HT on coexistent PTC [42–45] hampers the endorsement of HT as a prognostic PTC biomarker.

In fact, the inflammatory cell infiltration of tumor microenvironment plays an equivocal role, tumor-promoting versus antitumor, posing a "Dr. Jekyll or Mr. Hyde" enigma [109]. Challenging is the illumination of the precise factors that define the fate of cancer cells in the context of the interface of PTC with HT.

**45**

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing…*

**predictive and/or prognostic PTC biomarkers or not?**

**8. Thyroid autoantibodies in the context of HT coexistent with PTC:** 

Whether HT constitutes the driving force for PTC or *vice versa* remains elusive; nevertheless, the thyroid autoantibodies, the landmark of HT, and especially the anti-thyroperoxidase autoantibodies (TPOAbs)—a more sensitive marker of HT than the TgAbs—merit interrogation as potential hallmarks of the interrelationship

A great body of evidence sustains that the positivity of thyroid autoantibodies translates into predictive and prognostic knowledge. In particular, the positivity of TPOAbs [49, 52, 53], TgAbs [51, 53, 110], as well as TPOAbs coexistent with TgAbs [52], has been shown to harbor a predictive value. Moreover, the positivity of TPOAbs [52, 57] and TgAbs [50–53, 110] has been designated as an independent predictive factor for thyroid malignancy in nodular goiter. Interestingly, the coexistence of TgAbs and TPOAbs is associated with a PTC risk greater than that connected with isolated positivity of either TgAbs or TPOAbs [52]. A host-protective role of TPOAbs in the context of coexistent PTC has been demonstrated [27, 54, 55], rationalized by the speculation that the TPOAbs exert a cytotoxic effect [110]. However, skepticism imposes a multivariate analysis failing to consolidate the host-protective effect of thyroid autoantibodies in the case of coexistent PTC [55]. Importantly, awareness raises the correlation of the positivity of thyroid autoantibodies with features indicative of ominous PTC prognosis, such as advanced disease stage [52]. As a potential link between positive thyroid autoantibodies and aggressive phenotype of PTC could be suggested the excess iodine intake that unmasks a cryptic epitope on Tg, triggering the development of TgAbs [33, 34], while exerting stimulative effect on the genesis of BRAF V600E mutation as well [111]. However, this hypothesis is debunked by the observation that the BRAF V600E mutation in DTC is inversely correlated with coexistent HT [42]. In the light of the foregoing, the designation of thyroid autoantibodies as predictive and/or prognostic biomark-

**9. Elevated TSH levels in HT coexistent with PTC: the mediator of the** 

A strong argument in favor of the role of TSH in thyroid tumorigenesis is the detection of activating mutations of TSH receptors (TSH-R) in DTC [112]. Moreover, the cross-talk between the TSH-R/protein kinase A (PKA) signaling transduction and the well-recognized oncogenic pathways involving Wingless/int-1 (Wnt), PI3K, and MAPK has been implicated in initiation and progression of TC [113]. However, many arguments against the pathogenetic role of TSH in TC have

Nevertheless, the demonstration of HT as a risk factor for PTC in univariate analysis while being a host-protective factor in multivariate analysis after controlling TSH levels should be mentioned [61]. Similarly, multivariate analysis showed that increased TSH levels were an independent risk factor of malignancy in most FNAB studies, albeit not consistently related to HT [60]. Consequently, the subclinical or overt hypothyroidism due to autoimmune destruction of thyroid—and not HT per se—could be the real culprit for the increased PTC risk in the context of HT.

Considering that TSH constitutes a growth factor for thyrocytes [58], rational is the designation of increased, even within the normal range, serum TSH levels, in the case of PTC concurrent with HT, as a predictor of PTC risk [49, 52, 58] and a

*DOI: http://dx.doi.org/10.5772/intechopen.85128*

of PTC with HT.

ers of PTC is not yet feasible.

**effect of HT on PTC?**

been raised [114–117].

harbinger of aggressive tumor behavior [55, 59].

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing… DOI: http://dx.doi.org/10.5772/intechopen.85128*

#### **8. Thyroid autoantibodies in the context of HT coexistent with PTC: predictive and/or prognostic PTC biomarkers or not?**

Whether HT constitutes the driving force for PTC or *vice versa* remains elusive; nevertheless, the thyroid autoantibodies, the landmark of HT, and especially the anti-thyroperoxidase autoantibodies (TPOAbs)—a more sensitive marker of HT than the TgAbs—merit interrogation as potential hallmarks of the interrelationship of PTC with HT.

A great body of evidence sustains that the positivity of thyroid autoantibodies translates into predictive and prognostic knowledge. In particular, the positivity of TPOAbs [49, 52, 53], TgAbs [51, 53, 110], as well as TPOAbs coexistent with TgAbs [52], has been shown to harbor a predictive value. Moreover, the positivity of TPOAbs [52, 57] and TgAbs [50–53, 110] has been designated as an independent predictive factor for thyroid malignancy in nodular goiter. Interestingly, the coexistence of TgAbs and TPOAbs is associated with a PTC risk greater than that connected with isolated positivity of either TgAbs or TPOAbs [52]. A host-protective role of TPOAbs in the context of coexistent PTC has been demonstrated [27, 54, 55], rationalized by the speculation that the TPOAbs exert a cytotoxic effect [110].

However, skepticism imposes a multivariate analysis failing to consolidate the host-protective effect of thyroid autoantibodies in the case of coexistent PTC [55]. Importantly, awareness raises the correlation of the positivity of thyroid autoantibodies with features indicative of ominous PTC prognosis, such as advanced disease stage [52]. As a potential link between positive thyroid autoantibodies and aggressive phenotype of PTC could be suggested the excess iodine intake that unmasks a cryptic epitope on Tg, triggering the development of TgAbs [33, 34], while exerting stimulative effect on the genesis of BRAF V600E mutation as well [111]. However, this hypothesis is debunked by the observation that the BRAF V600E mutation in DTC is inversely correlated with coexistent HT [42]. In the light of the foregoing, the designation of thyroid autoantibodies as predictive and/or prognostic biomarkers of PTC is not yet feasible.

#### **9. Elevated TSH levels in HT coexistent with PTC: the mediator of the effect of HT on PTC?**

Considering that TSH constitutes a growth factor for thyrocytes [58], rational is the designation of increased, even within the normal range, serum TSH levels, in the case of PTC concurrent with HT, as a predictor of PTC risk [49, 52, 58] and a harbinger of aggressive tumor behavior [55, 59].

A strong argument in favor of the role of TSH in thyroid tumorigenesis is the detection of activating mutations of TSH receptors (TSH-R) in DTC [112]. Moreover, the cross-talk between the TSH-R/protein kinase A (PKA) signaling transduction and the well-recognized oncogenic pathways involving Wingless/int-1 (Wnt), PI3K, and MAPK has been implicated in initiation and progression of TC [113]. However, many arguments against the pathogenetic role of TSH in TC have been raised [114–117].

Nevertheless, the demonstration of HT as a risk factor for PTC in univariate analysis while being a host-protective factor in multivariate analysis after controlling TSH levels should be mentioned [61]. Similarly, multivariate analysis showed that increased TSH levels were an independent risk factor of malignancy in most FNAB studies, albeit not consistently related to HT [60]. Consequently, the subclinical or overt hypothyroidism due to autoimmune destruction of thyroid—and not HT per se—could be the real culprit for the increased PTC risk in the context of HT.

*Knowledges on Thyroid Cancer*

between PTC and HT are consistent [104].

examination of surgical specimens or FNAB studies [60].

Jankovic et al. showed that the average prevalence rate of PTC in HT patients differed significantly between FNAB and thyroidectomy studies: 1.20 and 27.56%, respectively. Likewise, the relative risk of PTC in HT patients extended from 0.39 to 1.00 in the FNAB studies, significantly lower than that observed in the thyroidectomy studies (1.15–4.16) [37]. In that respect, Castagna et al. demonstrated absence of association of nodular HT with TC based on cytology. The same authors observed a significantly higher prevalence of DTC in nodular HT compared to nodular Graves' disease, nodular goiter with either negative or positive thyroid autoantibodies, according to surgical series. This result raised the possibility of selection bias ascribed to the fact that 60.7% of patients with nodular HT underwent surgery due to cytological data suspicious of thyroid malignancy [38]. The FNAB data from 10,508 patients revealing no statistically significant relationship

Nevertheless, the fear of the selection bias was abolished by the recent demonstration of a significant association of PTC with HT based on either pathological

**7. Effect of HT on coexistent PTC: host protective or tumor protective?**

Irrespectively of whether HT is etiologically linked to PTC or merely judged "guilty by association," the importance of this coexistence lies on its clinical significance. Since a complex immune network has been considered a core component of PTC microenvironment, it is rational to assume that HT—the epitome of aberrant immune reaction—influences the progression of coexistent PTC [105]. In that respect, the positive association of a favorable outcome of coexistent PTC with HT, tumor-associated macrophage infiltration, and CD8+ lymphocytes highlights the antitumor potential of the immunological landscape intrinsic in HT [106]. The recently reported negative correlation of RORγt—a nuclear transcription protein of Th17—with lymph node metastases in PTC concurrent with HT is consistent. In fact, RORγt is positively associated with the upregulation of caveolin 1, a tumor suppressor gene [107]. Another plausible mechanism underlying the host-protective effect of HT coexistent with PTC could be the lower frequency of BRAF V600E mutation—a genetic alteration associated with aggressive PTC phenotype—in PTC concurrent with HT compared with PTC alone [41, 42].

A rich repertoire of features indicative of auspicious PTC prognosis are significantly associated with coexistent HT, including increased relapse-free and overall survival [39], increased survival rate [96, 108], decreased risk of recurrence [108], lower rate [108] or absence of extrathyroidal extension [96], and lower rate [41] or absence of lymph node metastases [96], observed in PTC coexistent with HT compared with PTC alone. The results of a recent meta-analysis including 71 published studies with 44,034 participants revealing that PTC coexistent with HT significantly correlated with reduced incidence of extrathyroidal extension, lymph node, and distant metastasis and increased recurrence-free survival duration compared with PTC alone are seminal [47]. Noticeably, the coexistence of HT with PTC has been proven an independent indicator of favorable prognosis of PTC [105], irrespectively of the extent of lymph node dissection [46], though inconsistently [108]. On the other hand, the reported absence of host-protective effect of HT on coexistent PTC

[42–45] hampers the endorsement of HT as a prognostic PTC biomarker.

fate of cancer cells in the context of the interface of PTC with HT.

In fact, the inflammatory cell infiltration of tumor microenvironment plays an equivocal role, tumor-promoting versus antitumor, posing a "Dr. Jekyll or Mr. Hyde" enigma [109]. Challenging is the illumination of the precise factors that define the

**44**

Experimental data derived from mouse models suggest the TSH-induced signaling mediated via cyclic adenosine monophosphate (cAMP) as a prerequisite for the BRAF V600E-stimulated PTC genesis, providing a plausible explanation for the implication of elevated TSH levels in PTC [62]. Furthermore, a protein kinase C (PKC)-mediated pathway has been demonstrated in vitro to transduce the TSHinduced signaling, dictating the invasiveness and the growth of human follicular TC cell lines [118].

However, the reported association of subclinical hypothyroidism with a less aggressive PTC phenotype compared with euthyroidism cannot be ignored [119]. Consistent is the higher risk of DTC enclosed in HT requiring low levothyroxine (LT4) replacement doses as compared with HT-induced hypothyroidism requiring higher LT4 replacement doses [27]. A hypothesis mandating further exploration is that the toxic effect of TSH mediated by H2O2—an element essential for thyroid hormone synthesis being simultaneously a mitogenic and mutagenic factor concerns the residual functioning thyroid tissue, while sparing the completely destructed thyroid [27].

Intriguingly, according to the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, low TSH levels may induce DTC [63], likely forming a less differentiated epithelium susceptible to malignant transformation [27]. Interestingly, two genetic variants predisposing to PTC located on 9q22.23 and 14q13.3 have been also associated with low TSH levels [120]. Consequently, the perplexing role of TSH in PTC fuels a contention regarding the endorsement of TSH levels as predictive and/or prognostic biomarker of PTC.

#### **10. Conclusions**

Despite the major strides toward the elucidation of the correlation of PTC with HT, integrating coexistent HT per se, as well as thyroid autoantibodies and TSH levels into PTC risk stratification systems, awaits further consolidation. Translating the coexistence of PTC with HT into the therapeutic approach of PTC is currently uncertain. A burning question is whether the broad clinical spectrum of HT, mirroring the wide array of HT histopathology, defines the trajectory of the coexistence of PTC with HT. The designation of HT as a premalignant lesion or PTC as a precipitating factor for HT is thwarted by the blurred, till now, pathogenetic landscape. Illuminating the temporal precedence, a parameter sine qua non for the embracement of a causal relationship between PTC and TC, is daunting. Nevertheless, harnessing the immunological link between PTC and HT should guide future efforts in clinical research, aiming to widen the horizons of immunotherapy.

In the interim, active surveillance of HT cannot be undermined, since it yields a tangible perspective of a prompt therapeutic intervention in the case of coexistent PTC.

Nonetheless, striking is, to date, the dearth of solid evidence to guide clinical decision-making on surveillance of HT based on the presumptive correlation thereof with PTC; in fact, a patient-oriented standard of care of HT should be applauded. Although thyroid ultrasonography (US) is not required for diagnosing and monitoring the majority of HT, an individualized approach should be endorsed in clinical settings. Bearing in mind the negativity of TPOAbs and/or TgAbs in 10% of HT patients [121] and approximately 20% of patients with subclinical hypothyroidism [122], identifying a hypoechoic or an inhomogeneous US thyroid pattern will provide invaluable information as regards the diagnosis of HT. Even though a thyroid/neck US is not routinely recommended unless a palpable thyroid lesion is detected [7], averting underdiagnosis of a PTC smaller than 1 centimeter (cm) in greatest dimension—the so-called papillary thyroid microcarcinoma—raises

**47**

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing…*

judgment, implementing the principle "*primum non nocere*."

The authors declare no conflicts of interest.

cAMP cyclic adenosine monophosphate CCL chemokine (C-C motif) ligand CD cluster of differentiation

CRI cancer-related inflammation CXCL CXC chemokine ligand CXCR4 CXC chemokine receptor 4

DPP IV dipeptidyl peptidase IV DTC differentiated thyroid cancer

HT Hashimoto's thyroiditis

FNAB fine needle aspiration biopsy HIF-1 hypoxia-inducible factor-1 HLA human leukocyte antigen

ERKs extracellular signal-regulated kinases

leukocyte antigen G

iNOS inducible nitric oxide synthases

MAPK mitogen-activated protein kinase MCP-1 monocyte chemoattractant protein 1

MMPs matrix metalloproteinases

HLA-G histocompatibility antigen, class 1, G, known also as human

awareness. In that respect, US could unravel a nodular variant of HT that merits further evaluation. The management of nodules in the context of HT is governed by the rules applied for any thyroid nodule irrespectively of HT, based on US-guided stratification of risk of malignancy [7]. FNAB is indicated in (i) nodules equal to or larger than 1 cm in greatest dimension presenting sonographic features of high or intermediate suspicion for PTC, (ii) nodules equal to or greater than 1.5 cm in greatest dimension presenting sonographic features of low suspicion for PTC, and (iii) nodules equal to or greater than 2 cm in greatest dimension presenting features of very low suspicion for PTC. Lower size cutoffs are embraced in the presence of clinical risk factors for PTC [7]. Pending the illumination of the clinical significance of the correlation of PTC with HT, clinicians should rely on their discretion and

*DOI: http://dx.doi.org/10.5772/intechopen.85128*

**Conflict of interest**

**Acronyms and abbreviations**

AKT protein kinase B B7H1 B7 Homolog 1

cm centimeter COX-2 cyclooxygenase-2

DCs dendritic cells DN double negative

FasL Fas ligand

IL interleukin

LT4 levothyroxine M macrophages

N neutrophils NK natural killer OPN osteopontin

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing… DOI: http://dx.doi.org/10.5772/intechopen.85128*

awareness. In that respect, US could unravel a nodular variant of HT that merits further evaluation. The management of nodules in the context of HT is governed by the rules applied for any thyroid nodule irrespectively of HT, based on US-guided stratification of risk of malignancy [7]. FNAB is indicated in (i) nodules equal to or larger than 1 cm in greatest dimension presenting sonographic features of high or intermediate suspicion for PTC, (ii) nodules equal to or greater than 1.5 cm in greatest dimension presenting sonographic features of low suspicion for PTC, and (iii) nodules equal to or greater than 2 cm in greatest dimension presenting features of very low suspicion for PTC. Lower size cutoffs are embraced in the presence of clinical risk factors for PTC [7]. Pending the illumination of the clinical significance of the correlation of PTC with HT, clinicians should rely on their discretion and judgment, implementing the principle "*primum non nocere*."

### **Conflict of interest**

*Knowledges on Thyroid Cancer*

cell lines [118].

destructed thyroid [27].

**10. Conclusions**

Experimental data derived from mouse models suggest the TSH-induced signaling mediated via cyclic adenosine monophosphate (cAMP) as a prerequisite for the BRAF V600E-stimulated PTC genesis, providing a plausible explanation for the implication of elevated TSH levels in PTC [62]. Furthermore, a protein kinase C (PKC)-mediated pathway has been demonstrated in vitro to transduce the TSHinduced signaling, dictating the invasiveness and the growth of human follicular TC

However, the reported association of subclinical hypothyroidism with a less aggressive PTC phenotype compared with euthyroidism cannot be ignored [119]. Consistent is the higher risk of DTC enclosed in HT requiring low levothyroxine (LT4) replacement doses as compared with HT-induced hypothyroidism requiring higher LT4 replacement doses [27]. A hypothesis mandating further exploration is that the toxic effect of TSH mediated by H2O2—an element essential for thyroid hormone synthesis being simultaneously a mitogenic and mutagenic factor concerns the residual functioning thyroid tissue, while sparing the completely

Intriguingly, according to the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, low TSH levels may induce DTC [63], likely forming a less differentiated epithelium susceptible to malignant transformation [27]. Interestingly, two genetic variants predisposing to PTC located on 9q22.23 and 14q13.3 have been also associated with low TSH levels [120]. Consequently, the perplexing role of TSH in PTC fuels a contention regarding the endorsement of

Despite the major strides toward the elucidation of the correlation of PTC with HT, integrating coexistent HT per se, as well as thyroid autoantibodies and TSH levels into PTC risk stratification systems, awaits further consolidation. Translating the coexistence of PTC with HT into the therapeutic approach of PTC is currently uncertain. A burning question is whether the broad clinical spectrum of HT, mirroring the wide array of HT histopathology, defines the trajectory of the coexistence of PTC with HT. The designation of HT as a premalignant lesion or PTC as a precipitating factor for HT is thwarted by the blurred, till now, pathogenetic landscape. Illuminating the temporal precedence, a parameter sine qua non for the embracement of a causal relationship between PTC and TC, is daunting. Nevertheless, harnessing the immunological link between PTC and HT should guide future efforts in

In the interim, active surveillance of HT cannot be undermined, since it yields a tangible perspective of a prompt therapeutic intervention in the case of coexistent PTC. Nonetheless, striking is, to date, the dearth of solid evidence to guide clinical decision-making on surveillance of HT based on the presumptive correlation thereof with PTC; in fact, a patient-oriented standard of care of HT should be applauded. Although thyroid ultrasonography (US) is not required for diagnosing and monitoring the majority of HT, an individualized approach should be endorsed in clinical settings. Bearing in mind the negativity of TPOAbs and/or TgAbs in 10% of HT patients [121] and approximately 20% of patients with subclinical hypothyroidism [122], identifying a hypoechoic or an inhomogeneous US thyroid pattern will provide invaluable information as regards the diagnosis of HT. Even though a thyroid/neck US is not routinely recommended unless a palpable thyroid lesion is detected [7], averting underdiagnosis of a PTC smaller than 1 centimeter (cm) in greatest dimension—the so-called papillary thyroid microcarcinoma—raises

TSH levels as predictive and/or prognostic biomarker of PTC.

clinical research, aiming to widen the horizons of immunotherapy.

**46**

The authors declare no conflicts of interest.

### **Acronyms and abbreviations**



### **Author details**

Maria V. Deligiorgi\* and Dimitrios T. Trafalis Clinical Pharmacology Unit, Laboratory of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

\*Address all correspondence to: mdeligiorgi@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**49**

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing…*

RA. Diagnosis and treatment of patients with thyroid cancer. American Health &

[9] Vigneri R, Malandrino P, Vigneri P.

[10] Udelsman R, Zhang Y. The epidemic of thyroid cancer in the United States: The role of endocrinologists and ultrasounds. Thyroid. 2014;**24**:472-479.

[11] Morris LG, Myssiorek D. Improved detection does not fully explain the rising incidence of well-differentiated thyroid cancer: A population-based analysis. American Journal of Surgery. 2010;**200**:454-461. DOI: 10.1016/j.

[12] Wong KP, Lang BHH. The role of prophylactic central neck dissection in differentiated thyroid carcinoma: Issues and controversies. Journal of Oncology. 2011;**2011**:127929. DOI:

differentiated thyroid cancer. Endocrine

[14] Qiu WH, Chen GY, Cui L, Zhang TM, Wei F, Yang Y. Identification of differential pathways in papillary thyroid carcinoma utilizing pathway co-expression analysis. Journal of

[15] Zhao M, Wang KJ, Tan Z, Zheng CM, Liang Z, Zhao JQ. Identification of potential therapeutic targets for papillary thyroid carcinoma by bioinformatics analysis. Oncology

Drug Benefits. 2015;**8**:30-40

The changing epidemiology of thyroid cancer: Why is incidence increasing? Current Opinion in Oncology. 2015;**27**:1-7. DOI: 10.1097/

CCO.0000000000000148

DOI: 10.1089/thy.2013.0257

amjsurg.2009.11.008

10.1155/2011/127929

10.4158/EP12047.CO

[13] Shaha AR. Recurrent

BUON. 2016;**21**:1501-1509

Letters. 2016;**11**:51-58

Practice. 2012;**18**:600-603. DOI:

*DOI: http://dx.doi.org/10.5772/intechopen.85128*

[2] Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;**420**:860-867.

[3] Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: Update on epidemiology and risk factors. Journal of Cancer Epidemiology. 2013;**2013**:965212. DOI:

[4] Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;**159**:676-690. DOI: 10.1016/j.cell.2014.09.050

[5] Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2015;**136**:E359-E386. DOI:

[6] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: A Cancer Journal for Clinicians. 2019;**69**:7-34.

[7] Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;**26**:1-133. DOI:

[8] Nguyen QT, Lee EJ, Huang MG, Park YI, Khullar A, Plodkowski

DOI: 10.1038/nature01322

10.1155/2013/965212

10.1002/ijc.29210

DOI: 10.3322/caac.21551

10.1089/thy.2015.0020

[1] Dailey ME, Lindsay S, Skahen R. Relation of thyroid neoplasms to Hashimoto disease of the thyroid gland. AMA Archives of Surgery. 1955;**70**:291-297. DOI: 10.1001/ archsurg.1955.01270080137023

**References**

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing… DOI: http://dx.doi.org/10.5772/intechopen.85128*

#### **References**

*Knowledges on Thyroid Cancer*

PD-1 PD protein 1

PKA protein kinase A PKC protein kinase C

TC thyroid cancer

TLR Toll-like receptors TNFa tumor necrosis factor a

Treg T regulatory cells

US ultrasonography

Wnt Wingless/int-1

TSH-R TSH receptor

Th T-helper

PD programmed cell death

PD-L1 programmed cell death ligand 1 PI3K phosphoinositide 3-kinase

PTC papillary thyroid carcinoma PTEN phosphatase and tensin homolog RET rearranged during transfection RNS reactive nitrogen species ROS reactive oxygen species

TgAbs anti-thyroglobulin autoantibodies TGFb transforming growth factor b

TPOAbs anti-thyroperoxidase autoantibodies

UPA urokinase-type plasminogen activator

VEGF vascular endothelial growth factor

UPAR urokinase-type plasminogen activator receptor

TSH thyroid-stimulating hormone

**48**

**Author details**

provided the original work is properly cited.

Maria V. Deligiorgi\* and Dimitrios T. Trafalis

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Clinical Pharmacology Unit, Laboratory of Pharmacology, Medical School,

National and Kapodistrian University of Athens, Athens, Greece

\*Address all correspondence to: mdeligiorgi@yahoo.com

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[3] Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: Update on epidemiology and risk factors. Journal of Cancer Epidemiology. 2013;**2013**:965212. DOI: 10.1155/2013/965212

[4] Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;**159**:676-690. DOI: 10.1016/j.cell.2014.09.050

[5] Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2015;**136**:E359-E386. DOI: 10.1002/ijc.29210

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[13] Shaha AR. Recurrent differentiated thyroid cancer. Endocrine Practice. 2012;**18**:600-603. DOI: 10.4158/EP12047.CO

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[30] Dong LQ, Sun XM, Xiang CF, Wu J, Yu P. Hashimoto's thyroiditis and papillary carcinoma in an adolescent girl: A case report. Molecular and Clinical Oncology. 2016;**5**:129-131. DOI: 10.3892/mco.2016.895

**51**

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[42] Kim SK, Song KH, Lim SOD, Lim YC, Yoo YB, Kim JS, et al. Clinical and pathological features and the BRAF mutation in patients with papillary thyroid carcinoma with and without concurrent Hashimoto thyroiditis. Thyroid. 2009;**19**:137-141. DOI: 10.1089/

[43] Ye Z, Gu D, Hu H, Zhou Y, Hu X, Zhang X. Hashimoto's Thyroiditis, microcalcification and raised thyrotropin levels within normal range are associated with thyroid cancer. World Journal of

[40] Singh B, Shaha AR, Trivedi H, Carew JF, Poluri A, Shah JP. Coexistent Hashimoto's thyroiditis with papillary

10.1210/jc.2012-2978

jc.2014-1302

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[33] Li Y, Teng D, Shan Z, Teng X, Guan H, Yu X, et al. Antithyroperoxidase and antithyroglobulin antibodies in a fiveyear follow-up survey of populations with different iodine intakes. The Journal of Clinical Endocrinology and Metabolism. 2008;**93**:1751-1757. DOI:

DOI: 10.1530/EJE-14-0047

EJOM.2017.966

10.1210/jc.2007-2368

s13044-015-0020-8

humpath.2003.10.027

[34] Zimmermann MB, Valeria GV. Iodine intake as a risk factor for thyroid cancer: A comprehensive review of animal and human studies. Thyroid Research. 2015;**8**:8. DOI: 10.1186/

[35] Burstein DE, Nagi C, Wang BY, Unger P. Immunohistochemical detection of p53 homolog p63 in solid cell nests, papillary thyroid carcinoma, and Hashimoto's thyroiditis: A stem cell hypothesis of papillary carcinoma oncogenesis. Human Pathology. 2004;**35**:465-473. DOI: 10.1016/j.

[36] Unger P, Ewart M, Wang BY, Gan L, Kohtz DS, Burstein DE. Expression of p63 in papillary thyroid carcinoma and in Hashimoto's thyroiditis: A pathobiologic link? Human Pathology. 2003;**34**:764-769. DOI: 10.1016/ S0046-8177(03)00239-9

[37] Jankovic B, Le KT, Hershman JM. Clinical review: Hashimoto's thyroiditis and papillary thyroid carcinoma: Is there a correlation? The Journal of Clinical Endocrinology and

[31] Effraimidis G, Wiersinga WM. Mechanisms in endocrinology:

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing… DOI: http://dx.doi.org/10.5772/intechopen.85128*

Autoimmune thyroid disease: Old and new players. European Journal of Endocrinology. 2014;**170**:R241-R252. DOI: 10.1530/EJE-14-0047

*Knowledges on Thyroid Cancer*

[16] Hashimoto H. Zur Kenntis der lymphomatosen Veranderung der Schilddruse (Struma lymphomatosa). Langenbecks Archiv für klinische Chirurgie ... vereinigt mit Deutsche Zeitschrift für Chirurgie. 1912;**97**:219-248 so far? Journal of Immunology Research. 2015;**2015**:979167. DOI:

[24] Li C, Yuan J, Zhu YF, Yang XJ, Wang Q, Xu J, et al. Imbalance of Th17/Treg in different subtypes of autoimmune thyroid diseases. Cellular Physiology and Biochemistry. 2016;**40**:245-252.

[25] Stassi G, Todaro M, Bucchieri F, Stoppacciaro A, Farina F, Zummo G, et al. Fas/Fas ligand-driven T cell apoptosis as a consequence of ineffective thyroid immunoprivilege in Hashimoto's thyroiditis. Journal of Immunology. 1999;**162**:263-267

[26] Foppiani L, Secondo V, Arlandini A, Quilici P, Cabria M, Del Monte P. Thyroid lymphoma: A rare tumor requiring combined management. Hormones (Athens, Greece).

[27] Paparodis R, Imam S, Todorova-Koteva K, Staii A, Jaume JC. Hashimoto's thyroiditis pathology and risk for thyroid cancer. Thyroid. 2014;**24**: 1107-1114. DOI: 10.1089/thy.2013.0588

[28] Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;**144**:646-741. DOI: 10.1016/j.cell.2011.02.013

10.1016/j.tem.2014.09.001

10.3892/mco.2016.895

[29] Ehlers M, Schott M. Hashimoto's thyroiditis and papillary thyroid cancer: Are they immunologically linked? Trends in Endocrinology and Metabolism. 2014;**25**:656-664. DOI:

[30] Dong LQ, Sun XM, Xiang CF, Wu J, Yu P. Hashimoto's thyroiditis and papillary carcinoma in an adolescent girl: A case report. Molecular and Clinical Oncology. 2016;**5**:129-131. DOI:

[31] Effraimidis G, Wiersinga WM. Mechanisms in endocrinology:

10.1155/2015/979167

DOI: 10.1159/000452541

2009;**8**:214-218

[17] Ahmed R, Al-Shaikh S, Akhtar M. Hashimoto thyroiditis: A century later. Advances in Anatomic Pathology.

2012;**19**:181-186. DOI: 10.1097/ PAP.0b013e3182534868

immunopathogenesis of chronic autoimmune thyroiditis one century after Hashimoto. European Thyroid Journal. 2013;**1**:243-250. DOI:

[19] Liu X, Zhu L, Cui D, Wang Z, Chen H, Duan Y, et al. Coexistence

Endocrinology. 2014;**2014**:769294. DOI:

[20] Ward LS. Immune response in thyroid cancer: Widening the boundaries. Scientifica (Cairo). 2014;**2014**:125450. DOI:

[21] Picado C, Rotter W. Precipitines seriques antithyroidiennes chez le goitreux. Comptes rendus des séances de la Société de biologie et de ses filiales.

[22] Rose NR, Witebsky E. Studies in organ specificity. V. Changes in the thyroid glands of rabbits following active immunization with rabbit thyroid extracts. Journal of Immunology.

of histologically confirmed Hashimoto's thyroiditis with different stages of papillary thyroid carcinoma in a consecutive Chinese cohort. International Journal of

[18] Weetman AP. The

10.1159/000343834

10.1155/2014/769294

10.1155/2014/125450

1936;**123**:1111

1956;**76**:417-427

[23] Pyzik A, Grywalska E, Matyjaszek-Matuszek B, Roliński J. Immune disorders in Hashimoto's thyroiditis: What do we know

**50**

[32] Farahat SA, Mansour N, Sheta MM, Alramlawy SA, Ramadan M. Autoimmune thyroiditis among ionizing radiation exposed workers in cardiac catheterization units. Egyptian Journal of Occupational Medicine. 2017;**41**:127-1241. DOI: 10.21608/ EJOM.2017.966

[33] Li Y, Teng D, Shan Z, Teng X, Guan H, Yu X, et al. Antithyroperoxidase and antithyroglobulin antibodies in a fiveyear follow-up survey of populations with different iodine intakes. The Journal of Clinical Endocrinology and Metabolism. 2008;**93**:1751-1757. DOI: 10.1210/jc.2007-2368

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[35] Burstein DE, Nagi C, Wang BY, Unger P. Immunohistochemical detection of p53 homolog p63 in solid cell nests, papillary thyroid carcinoma, and Hashimoto's thyroiditis: A stem cell hypothesis of papillary carcinoma oncogenesis. Human Pathology. 2004;**35**:465-473. DOI: 10.1016/j. humpath.2003.10.027

[36] Unger P, Ewart M, Wang BY, Gan L, Kohtz DS, Burstein DE. Expression of p63 in papillary thyroid carcinoma and in Hashimoto's thyroiditis: A pathobiologic link? Human Pathology. 2003;**34**:764-769. DOI: 10.1016/ S0046-8177(03)00239-9

[37] Jankovic B, Le KT, Hershman JM. Clinical review: Hashimoto's thyroiditis and papillary thyroid carcinoma: Is there a correlation? The Journal of Clinical Endocrinology and Metabolism. 2013;**98**:474-482. DOI: 10.1210/jc.2012-2978

[38] Castagna MG, Belardini V, Memmo S, Maino F, Di Santo A, Toti P, et al. Nodules in autoimmune thyroiditis are associated with increased risk of thyroid cancer in surgical series but not in cytological series: Evidence for selection bias. The Journal of Clinical Endocrinology and Metabolism. 2014;**99**:3193-3198. DOI: 10.1210/ jc.2014-1302

[39] Kashima K, Yokoyama S, Noguchi S, Murakami N, Yamashita H, Watanabe S, et al. Chronic thyroiditis as a favorable prognostic factor in papillary thyroid carcinoma. Thyroid. 1998;**8**:197-202. DOI: 10.1089/thy.1998.8.197

[40] Singh B, Shaha AR, Trivedi H, Carew JF, Poluri A, Shah JP. Coexistent Hashimoto's thyroiditis with papillary thyroid carcinoma: Impact on presentation, management, and outcome. Surgery. 1999;**126**:1070-1076. DOI: 10.1067/msy.2099.101431

[41] Ma H, Li L, Li K, Wang T, Zhang Y, Zhang C, et al. Hashimoto's thyroiditis, nodular goiter or follicular adenoma combined with papillary thyroid carcinoma play protective role in patients. Neoplasma. 2018;**65**:436-440. DOI: 10.4149/ neo\_2018\_170428N317

[42] Kim SK, Song KH, Lim SOD, Lim YC, Yoo YB, Kim JS, et al. Clinical and pathological features and the BRAF mutation in patients with papillary thyroid carcinoma with and without concurrent Hashimoto thyroiditis. Thyroid. 2009;**19**:137-141. DOI: 10.1089/ thy.2008.0144

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[103] Latrofa F, Ricci D, Montanelli L, Rocchi R, Piaggi P, Sisti E, et al. Thyroglobulin autoantibodies in patients with papillary thyroid carcinoma: Comparison of different assays and evaluation of causes of discrepancies. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**:3974-3982. DOI: 10.1210/ jc.2012-2406

[104] Matesa-Anic D, Matesa N, Dabelic N, Kusic Z. Coexistence of papillary carcinoma and Hashimoto's thyroiditis. Acta Clinica Croatica. 2009;**48**:9-12

[105] Marotta V, Sciammarella C, Chiofalo MG, Gambardella C, Bellevicine C, Grasso M, et al. Hashimoto's thyroiditis predicts outcome in intrathyroidal papillary thyroid cancer. Endocrine-Related Cancer. 2017;**24**:485-493. DOI: 10.1530/ERC-17-0085

[106] Cunha LL, Morari EC, Guihen AC, Razolli D, Gerhard R, Nonogaki S, et al. Infiltration of a mixture of immune cells may be related to good prognosis in patients with differentiated thyroid carcinoma. Clinical Endocrinology. 2012;**77**:918-925. DOI: 10.1111/j.1365-2265.2012.04482.x

[107] Zeng R, Lyu Y, Zhang G, et al. Positive effect of RORγt on the prognosis of thyroid papillary carcinoma patients combined with Hashimoto's thyroiditis. American Journal of Translational Research. 2018;**10**:3011-3024

[108] Jeong JS, Kim HK, Lee CR, Park S, Park JH, Kang SW, et al. Coexistence of chronic lymphocytic thyroiditis with papillary thyroid carcinoma: Clinical manifestation and prognostic outcome. Journal of Korean Medical Science. 2012;**27**:883-889. DOI: 10.3346/ jkms.2012.27.8.883

[109] Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Reviews. 2007;**26**:373-400. DOI: 10.1007/s10555-007-9072-0

[110] Azizi G, Keller JM, Lewis M, et al. Association of Hashimoto's thyroiditis with thyroid cancer. Endocrine-Related Cancer. 2014;**21**:845-852. DOI: 10.1530/ ERC-14-0258

[111] Kim HJ, Park HK, Byun DW, Suh K, Yoo MH, Min YK, et al. Iodine intake

**57**

*Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing…*

Communications. 1993;**195**:1230-1236.

[119] Ahn D, Sohn JH, Kim JH, Shin CM, Jeon JH, Park JY. Preoperative subclinical hypothyroidism in patients with papillary thyroid carcinoma. American Journal of Otolaryngology. 2013;**34**:312-319. DOI: 10.1016/j. amjoto.2012.12.013. Epub 2013 Jan 26

[120] Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasoon JG, Sigurdsson A, Bergthorsson JT, et al. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nature Genetics. 2009;**41**:460-464. DOI: 10.1038/ng.339

[121] Mincer DL, Jialal I. Hashimoto thyroiditis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls

[122] Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. 2013 ETA guideline: Management of subclinical hypothyroidism. European Thyroid Journal. 2013;**2**:215-228

Publishing; 2018

DOI: 10.1006/bbrc.1993.2176

*DOI: http://dx.doi.org/10.5772/intechopen.85128*

as a risk factor for BRAF mutations in papillary thyroid cancer patients from an iodine-replete area. European Journal of Nutrition. 2018;**57**:809-815. DOI:

10.1007/s00394-016-1370-2

[112] Russo D, Arturi F, Chiefari E, Filetti S. Thyrotropin receptor: A role for thyroid tumourigenesis? Forum (Genoa, Italy). 1999;**9**(2):166-175

[113] García-Jiménez C, Santisteban P. TSH signalling and cancer. Arquivos

[114] Matsuo K, Friedman E, Gejman PV, Fagin JA. The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: Structural studies of the TSH-R and the α-subunit of Gs in human thyroid neoplasms. The Journal of Clinical Endocrinology and Metabolism.

1993;**76**:1446-1451. DOI: 10.1210/

[115] Derwahl M, Broecker M, Kraiem Z. Thyrotropin may not be the dominant growth factor in benign and malignant thyroid tumors. The Journal of Clinical Endocrinology and Metabolism. 1998;**84**:829-834. DOI: 10.1210/

[116] Shi Y, Zou M, Farid NR. Expression of thyrotropin receptor gene in thyroid carcinoma is associated with good prognosis. Clinical Endocrinology.

[117] Satta MA, DeRosa G, Testa A, Maussier ML, Valenza V, Rabitti C, et al. Thyroid cancer in suppressed contralateral lobe of patients with hot thyroid nodule. European Journal of

[118] Hoelting T, Tezelman S, Siperstein AE, Duh QY, Clark OH. Thyrotropin stimulates invasion and growth of follicular thyroid cancer cells via PKC- rather than PKA-activation. Biochemical and Biophysical Research

Cancer. 1993;**29A**:1190-1192

jcem.76.6.8501149

jcem.84.3.5519

1993;**39**:269-274

Brasileiros de Endocrinologia e Metabologia. 2007;**51**(5):654-671 *Papillary Thyroid Carcinoma Intertwined with Hashimoto's Thyroiditis: An Intriguing… DOI: http://dx.doi.org/10.5772/intechopen.85128*

as a risk factor for BRAF mutations in papillary thyroid cancer patients from an iodine-replete area. European Journal of Nutrition. 2018;**57**:809-815. DOI: 10.1007/s00394-016-1370-2

*Knowledges on Thyroid Cancer*

10.18632/oncotarget.18620

[97] Lai X, Xia Y, Zhang B, Li J, Jiang Y. A meta-analysis of Hashimoto's thyroiditis and papillary thyroid carcinoma risk. Oncotarget. 2017;**8**:62414-62424. DOI:

[104] Matesa-Anic D, Matesa N, Dabelic N, Kusic Z. Coexistence of papillary carcinoma and Hashimoto's thyroiditis. Acta Clinica Croatica. 2009;**48**:9-12

[105] Marotta V, Sciammarella C, Chiofalo MG, Gambardella C, Bellevicine C, Grasso M, et al. Hashimoto's thyroiditis predicts outcome in intrathyroidal papillary thyroid cancer. Endocrine-Related Cancer. 2017;**24**:485-493. DOI:

[106] Cunha LL, Morari EC, Guihen AC, Razolli D, Gerhard R, Nonogaki S, et al. Infiltration of a mixture of immune cells may be related to good prognosis in patients with differentiated

Endocrinology. 2012;**77**:918-925. DOI: 10.1111/j.1365-2265.2012.04482.x

[108] Jeong JS, Kim HK, Lee CR, Park S, Park JH, Kang SW, et al. Coexistence of chronic lymphocytic thyroiditis with papillary thyroid carcinoma: Clinical manifestation and prognostic outcome. Journal of Korean Medical Science. 2012;**27**:883-889. DOI: 10.3346/

[109] Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Reviews. 2007;**26**:373-400. DOI: 10.1007/s10555-007-9072-0

[110] Azizi G, Keller JM, Lewis M, et al. Association of Hashimoto's thyroiditis with thyroid cancer. Endocrine-Related Cancer. 2014;**21**:845-852. DOI: 10.1530/

[111] Kim HJ, Park HK, Byun DW, Suh K, Yoo MH, Min YK, et al. Iodine intake

thyroid carcinoma. Clinical

[107] Zeng R, Lyu Y, Zhang G, et al. Positive effect of RORγt on the prognosis of thyroid papillary carcinoma patients combined with Hashimoto's thyroiditis. American Journal of Translational Research.

2018;**10**:3011-3024

jkms.2012.27.8.883

ERC-14-0258

10.1530/ERC-17-0085

[98] Resende de Paiva C, Grønhøj C, Feldt-Rasmussen U, von Buchwald C. Association between Hashimoto's thyroiditis and thyroid cancer in 64,628 patients. Frontiers in Oncology. 2017;**7**:53. DOI: 10.3389/fonc.2017.00053

[99] McLeod DSA, Cooper DS. The incidence and prevalence of thyroid autoimmunity. Endocrine Journal.

[100] Fiore E, Rago T, Scutari M, Ugolini C, Proietti A, Di Coscio G, et al. Papillary

[101] Fiore E, Latrofa F, Vitti P. Iodine, thyroid autoimmunity and cancer. European Thyroid Journal. 2015;**4**: 26-35. DOI: 10.1159/000371741

[102] Kohno Y, Yamaguchi F, Saito K, Niimi H, Nishikawa T, Hosoya T. Antithyroid peroxidase antibodies in sera from healthy subjects and from patients with chronic thyroiditis: Differences in the ability to inhibit thyroid peroxidase activities. Clinical and Experimental Immunology. 1991;**85**:459-463

[103] Latrofa F, Ricci D, Montanelli L, Rocchi R, Piaggi P, Sisti E, et al. Thyroglobulin autoantibodies in patients with papillary thyroid carcinoma: Comparison of different assays and evaluation of causes of discrepancies. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**:3974-3982. DOI: 10.1210/

thyroid cancer, although strongly associated with lymphocytic infiltration on histology, is only weakly predicted by serum thyroid auto-antibodies in patients with nodular thyroid diseases. Journal of Endocrinological Investigation. 2009;**32**:344-335. DOI:

2012;**42**:252-265

10.1007/BF03345725

**56**

jc.2012-2406

[112] Russo D, Arturi F, Chiefari E, Filetti S. Thyrotropin receptor: A role for thyroid tumourigenesis? Forum (Genoa, Italy). 1999;**9**(2):166-175

[113] García-Jiménez C, Santisteban P. TSH signalling and cancer. Arquivos Brasileiros de Endocrinologia e Metabologia. 2007;**51**(5):654-671

[114] Matsuo K, Friedman E, Gejman PV, Fagin JA. The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: Structural studies of the TSH-R and the α-subunit of Gs in human thyroid neoplasms. The Journal of Clinical Endocrinology and Metabolism. 1993;**76**:1446-1451. DOI: 10.1210/ jcem.76.6.8501149

[115] Derwahl M, Broecker M, Kraiem Z. Thyrotropin may not be the dominant growth factor in benign and malignant thyroid tumors. The Journal of Clinical Endocrinology and Metabolism. 1998;**84**:829-834. DOI: 10.1210/ jcem.84.3.5519

[116] Shi Y, Zou M, Farid NR. Expression of thyrotropin receptor gene in thyroid carcinoma is associated with good prognosis. Clinical Endocrinology. 1993;**39**:269-274

[117] Satta MA, DeRosa G, Testa A, Maussier ML, Valenza V, Rabitti C, et al. Thyroid cancer in suppressed contralateral lobe of patients with hot thyroid nodule. European Journal of Cancer. 1993;**29A**:1190-1192

[118] Hoelting T, Tezelman S, Siperstein AE, Duh QY, Clark OH. Thyrotropin stimulates invasion and growth of follicular thyroid cancer cells via PKC- rather than PKA-activation. Biochemical and Biophysical Research

Communications. 1993;**195**:1230-1236. DOI: 10.1006/bbrc.1993.2176

[119] Ahn D, Sohn JH, Kim JH, Shin CM, Jeon JH, Park JY. Preoperative subclinical hypothyroidism in patients with papillary thyroid carcinoma. American Journal of Otolaryngology. 2013;**34**:312-319. DOI: 10.1016/j. amjoto.2012.12.013. Epub 2013 Jan 26

[120] Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasoon JG, Sigurdsson A, Bergthorsson JT, et al. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nature Genetics. 2009;**41**:460-464. DOI: 10.1038/ng.339

[121] Mincer DL, Jialal I. Hashimoto thyroiditis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018

[122] Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. 2013 ETA guideline: Management of subclinical hypothyroidism. European Thyroid Journal. 2013;**2**:215-228

**59**

**Chapter 5**

**Abstract**

**1. Introduction**

malignancy, among others [5].

disease, particularly thyroid cancer.

Thyroid Cancer and Acromegaly

Acromegaly results from oversecretion of growth hormone and subsequent insulin growth factor-I. Some studies have described an association between acromegaly and increased risk of some cancers, including thyroid cancer, the most common endocrine malignancy. It is well known that follicular thyroid cells express IGF-I receptor and that GH and IGF-I have both proliferative and anti-apoptotic effects and their hypersecretion may theoretically induce tumor development and stimulate its growth, despite the fact that research data is conflicting and population-based data on thyroid cancer and acromegaly is rare. Some molecular alterations, including point mutations in *BRAF* and *RAS* genes and *RET/PTC* gene rearrangements, have been associated with oncogenesis of PTC. However, the implications of these genetic markers in the development of PTC in patients with acromegaly are not yet well known. In this chapter, we discuss epidemiology, pathogenesis, molecular biology aspects, and how to screen and to manage acromegalic

*Carla Souza Pereira Sobral, Marcelo Magalhães* 

patients with nodular thyroid disease and thyroid cancer.

**Keywords:** acromegaly and thyroid cancer, IGF-I and cancer, thyroid and acromegaly, GH and cancer, molecular markers and thyroid cancer

Acromegaly is a rare disease that results from the oversecretion of growth hormone (GH) and subsequent insulin growth factor I (IGF-I) [1]. It is associated with important complications that may reduce life expectancy of these patients [2, 3]. Most acromegalic patients die from cardiovascular, cerebrovascular, or respiratory diseases [3, 4]. Nevertheless, in the past two decades, some studies have also described an association between acromegaly and an increased risk of some cancers such as colorectal and thyroid cancer (TC), which is the most common endocrine

Part of the difficulty in determining the true incidence of cancer in this population is due to the relative rarity of acromegaly [6]. On the other hand, with improvement in surgical and radiotherapeutic procedures as well as advances in medical treatment, an increase of the survival rate of patients with acromegaly has been shown. As a result, patients may have a longer exposure to high GH levels [7].

As the prevalence of thyroid cancer has been shown to increase among patients with acromegaly, this should draw attention for clinicians to investigate thyroid

*and Manuel dos Santos Faria*

#### **Chapter 5**
