Hyperthyroidism, hyperfunctioning thyroid nodule, and thyroid cancer in a young female: a rare and unusual coexistence.
Abstract: The prevalence of concomitant thyroid carcinoma with Grave's disease has been reported to range from 0 to 10%. Many controversies exist in the literature regarding the diagnostic workup and management in these types of patients. We are reporting a case of a 31 year old woman who had Graves' disease, a palpable thyroid nodule, and results from a thyroid scan revealed a "hot" nodule. Interestingly, an ultrasound guided FNA of the "hot" nodule showed papillary thyroid microcarcinoma. Finally, a total thyroidectomy showed multilobar tumor involvement. The diagnostic tools employed to establish the proper management strategy for this patient were based on data in the literature that is full of discrepancies. The fact that Grave's disease occurs concomitantly with thyroid cancer, specifically the papillary type, is an indisputably rare combination. One rare feature on our clinical case was the reported malignancy of a papillary carcinoma within a "hot" nodule which usually is much less that 1%. Many studies describe an increasing incidence of Grave's disease patients with concomitant papillary thyroid carcinoma. One possible explanation for these findings could be improvements in medical technology of screening tools. We propose that, thyroid ultrasonography should be integrated in the diagnostic workup in patients presenting with Graves' disease, especially in those presenting with palpable nodules. Fine needle biopsy should not be restricted to cold nodules. [P R Health Sci J 2010;1:78-82]

Key words: Graves' disease, Thyroid stimulating immunoglobulin, Papillary thyroid carcinoma, Thyroid stimulating hormone, Nucleomegaly, Hot nodule, Psammoma bodies, Follicular carcinoma, Radioactive iodine, Thyroidectomy

Se ha reportado que la prevalencia de la enfermedad de Graves' en coexistencia con carcinoma del tiroide fluctua entre 0 a 10%. Existen muchas discrepancias en la literatura acerca de los examenes diagnosticos y el manejo en este tipo de pacientes. Una femina de 30 anos de edad fue referida a nuestra clinica de endocrinologia por un nodulo palpable en el tiroide. En el ultrasonido del tiroide se encontro un nodulo hipoecoico con una sombra acustica posterior. Los resultados de la cintigrafia de tiroide reportaron un nodulo caliente. Finalmente, se le realizo una biopsia de aguja fina guiada por ultrasonido la cual demostro ser positiva para carcinoma papilar de tiroide. La tiroidectomia total demostro envolvimiento multilobular. Las herramientas diagnosticas empleadas para establecer el manejo adecuado fueron basadas en literatura que esta llena de discrepancias. El hecho de que la enfermedad de Graves' exista concomitantemente con carcinoma papilar del tiroide es una combinacion indiscutiblemente inusual. Un punto importante en nuestro caso es que la probabilidad reportada de que exista carcinoma papilar de tiroide dentro de un nodulo caliente es menos de 1%. Muchos estudios describen el aumento en la incidencia de la enfermedad de Graves' en coexistencia con carcinoma papilar de tiroide. Una posible explicacion podria ser la mejoria en la tecnologia de los instrumentos medicos. Nosotros proponemos que la ultrasonografia de tiroide sea integrada como manejo estandar en pacientes que sufren la enfermedad de Graves', especialmente en aquellos que tienen nodulos palpables. Tambien, que la biopsia de aguja fina no debe estar restringida a nodulos frios.
Article Type: Perspectiva general de la enfermedad/trastorno
Subject: Cancer de la tiroides (Investigacion cientifica)
Cancer de la tiroides (Analisis de casos)
Cancer de la tiroides (Diagnostico)
Authors: Hernan-Martinez, Jose
Uzcategui, Maria
Corder, Eric
Castillo, Manuel
Sostre, Samuel
Alicea, Luz
Pub Date: 03/01/2010
Publication: Name: Puerto Rico Health Sciences Journal Publisher: Universidad de Puerto Rico, Recinto de Ciencias Medicas Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 Universidad de Puerto Rico, Recinto de Ciencias Medicas ISSN: 0738-0658
Issue: Date: March, 2010 Source Volume: 29 Source Issue: 1
Geographic: Geographic Name: Puerto Rico
Accession Number: 219519255
Full Text: Grave's disease, first described in 1825, is an autoimmune disease characterized by antibodies against the thyroid stimulating hormone (TSH) receptor. It manifests clinically as hyperthyroidism with diffuse goiter, exophthalmus, proximal muscle weakness, and pretibial myxedema. The prevalence of concomitant thyroid carcinoma with Grave's disease has been reported to range from 0 to 10% (1-2). The most commonly encountered thyroid cancer is of the papillary histologic subtype. When these two diseases coexist the clinical behavior has been described as ranging from benign to very aggressive. Previous studies indicate that 2 to 20% of autopsies have reported the incidental discovery of papillary thyroid carcinoma (1-2). Thyroid cancers occurring in combination with Grave's disease have a variable presentation and the literature divides it into incidental thyroid cancer and nonincidental thyroid cancer (3). Incidental thyroid carcinomas are nodules that usually measure less than 1 cm hence the name, thyroid microcarcinomas (1). They are rarely palpated during physical examination. Non-incidental thyroid cancer refers to patients with Grave's disease who also have a thyroid nodule or cancer during the pre-operative workup. These thyroid cancers are usually larger that 1 cm.

Case Report

A 31 year-old woman was referred to our endocrinology clinic due to a palpable right lobe thyroid nodule on November 2005. Laboratory data revealed normal thyroid function test, anti-microsomal and anti-thyroglobulin antibodies, calcitonin and thyroglobulin levels. A thyroid ultrasound, done elsewhere, was originally read as a heterogeneous thyroid with adenoma-like nodules on the right lobe. The left lobe was read as essentially homogeneous without cystic or solid components. A fine needle aspiration biopsy guided by palpation of the right lobe nodule failed to reveal any malignancy. She was lost to follow up and returned to the clinic in December, 2007 with the chief complaint of nervousness and palpitations. Her past medical history was negative for neck or head irradiation and for radioiodine therapy. There was a strong family history of thyroid disease but a negative history of thyroid cancer. The most remarkable physical findings were a regular pulse of 120 beats per minute, palpable diffuse goiter with palpable right thyroid nodule, exophthalmic measurement OD of 18 and OS of 20, lid lag and hypereflexia. The laboratory data are illustrated on Table 1. The most remarkable laboratory results were a low TSH of 0.0001 IU/mL, a high T4, and borderline high Free T3, all of which are consistent with hyperthyroidism. Furthermore, a high thyroid stimulating immunoglobulin confirmed the autoimmune etiology of the hyperthyroidism. Also remarkable were the elevated levels of quantitative thyroglobulin levels and normal levels of anti-thyroid antibodies. The original thyroid ultrasonography was revised by a nuclear medicine specialist. The right lobe measured 4.8 X 1.9 X 2.0 cm. It showed an echogenic pattern and revealed a solid nodule of 0.8 X 0.8 cm in the mid-lobe (Figure 1). The walls were irregular as well as the halo surrounding it. There was posterior shadowing of the nodule and multiple speckled calcifications within the nodule which raised the suspicion of malignancy. These findings were not previously reported. A hypogenic nodule of 1.2 X 0.9 X 0.7 cm was also identified within the right lobe (Figure 2). The left lobe measured 4.3 X 1.4 X 1.5 cm and exhibited an echogenic pattern in which no nodules or cysts were detected. On the thyroid scan of 24 hours I 131, the uptake was 41.5% (normal: 9-36%). The gland revealed markedly increased tracer trapping (Figure 3) when compared to the salivary glands, which were not visualized in this study. In addition, there was a small "hot" nodule in the mid-right lobe, medially located. No "cold" thyroid nodules could be identified. A fine needle aspiration cytology of mid-right lower lobe nodule revealed "clusters of papillary caps of atypical follicular cells with nucleomegaly and nuclear grooves", compatible with papillary carcinoma (Figure 4). The patient was started on Methimazole (30 mg) and Propanolol (40 mg) in March, 2008. Gradual reduction in the Methimazole dosage was done until September, 2008 when she achieved an euthyroid state (TSH 2.02). A total thyroidectomy was performed. On examination of the carotid compartments no nodules were palpated. Macroscopic examination of the thyroid gland revealed a weight of 15.5 g. The measurements were a left lobe 3.8 X 3.0 X 1.5 cm and a right lobe 4.3 X 4.0 X 1.8 cm. The capsule was purple/brown and smooth. On section, the right lobe showed two nodular lesions, which were pink/tan, measured 0.7 cm and 1.2 cm respectively (Figure 5). Sections through the left lobe and isthmus revealed red/pink parenchyma. The pathologic diagnosis of the right lobe was papillary carcinoma in which the tumor measured 6 mm in diameter. It showed cystic degeneration and psammoma bodies. It was at 0.2 mm of the nearest inked margins. A second nodule that was previously identified as a hypogenic nodule on the thyroid ultrasonography was found to be a microfollicular adenoma. Incidentally, on the left thyroid lobe a micropapillary carcinoma, follicular-variant that measured 2 mm in diameter and totally excised was also identified. The thyroid isthmus was without significant pathological changes. Table 2 shows the histopathology description of the thyroid specimens. In the post-operative course no chemical or clinical hypocalcemic symptoms were noted. Radioactive iodine I 131 therapy was given and suppressive thyroid supplementation was started.

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Discussion

Different studies around the world have confirmed the rare coexistence of Grave's disease and thyroid cancer. The prevalence ranges form 1.1 to 7.1% (1). Papillary thyroid microcarcinoma is the most common histologic subtype, ranging from 42 to 100% in these series. Anaplastic thyroid carcinoma has also been associated with Graves' disease however, it is even less frequently reported than the papillary type (3). Data reported in the literature has raised the issue concerning the clinical aggressiveness of thyroid cancer in patients with Grave's disease. Some of these data revealed a poor prognostic clinical outcome when such a combination occurs, however recent clinical studies provide evidence on the contrary (4-6). The incidence of Grave's disease with concomitant thyroid cancer, specifically the papillary type, is an indisputably rare combination. Evidence shows that patients with Graves' disease may have cytopathologic findings that resemble papillary thyroid carcinoma. In these types of patients cytokeratin 19 may help in the differentiation between the two (7).

The diagnostic tools employed to establish the proper management strategy for this patient were based on data in the literature that is full of discrepancies. Preoperatively, the patient had a palpable thyroid nodule corroborated by ultrasonography. Thyroid ultrasonography showed "posterior shadowing" surrounding the nodule. The shadow represented a hypoechoic area behind the nodule, a finding that may be suggestive of malignancy. Results from a thyroid scan showed a "hot" autonomous nodule. Despite this finding ultrasonography-guided FNA was performed yielding results concordant with papillary carcinoma. A total thyroidectomy was performed. It has been found that in patients with these concomitant conditions a better outcome is associated with the more aggressive approach (8). Gross examination of the thyroid specimen showed multifocal nodules that were not detected by thyroid ultrasonogram or by thyroid scan.

When multifocal nodules are diagnosed this is associated with a poor prognosis because it magnifies the metastatic potential of the cancer. Our patient had several influencing factors that might point towards a more aggressive clinical course: the elevated T4, TSI, and thyroglobulin levels pre-operatively, and the multifocal involvement within the two thyroid lobes.

One rare feature on our clinical case was the reported malignancy of a papillary carcinoma within a "hot" nodule which usually is much less that 1% (1). The laboratory values, as described in the literature, as well as physical examination findings, FNA biopsy, and ultrasonography can be useful tools in predicting prognosis (1, 9). Some data suggests that in patients with these concurrent conditions, serum concentrations of T3 and T4 prior to anti-thyroid treatment were reliable prognostic indicators (10). These concentrations may predict aggressiveness and metastatic tendency in these types of patients (10). Past studies from the 1990s proposed that thyroid stimulating immunoglobulin (TSI) may play a role in determining aggressiveness of thyroid cancers in patients with Grave's disease (11). Recent clinical studies in 2007 reported that TSI levels were found to have an inverse correlation with the tumor size (5). While other publications support the hypothesis that TSI levels correlate with tumor growth, other investigators published data in 2008 that strongly suggests that TSI does not change the behavior of preexisting thyroid cancers (1, 3). Besides being expressed in normal thyroid tissue, TSH receptors are also expressed on the plasma membrane of benign and malignant thyroid tumors. Studies suggest that TSH stimulates thyroid tumor growth. This is supported by existing evidence showing that increasing TSH concentrations correlate directly with malignancy, reflecting a trophic effect promoting neoplasia and carcinogenesis (12). It has been reported that suppression of TSH by administering exogenous thyroid hormone is associated with reduced recurrence and mortality in patients with thyroid cancer (10).

Thyroid ultrasonography has become the most sensitive screening tool when screening for thyroid nodules and fine needle aspiration guided by ultrasonography has even better diagnostic accuracy than by palpation (9). When performing an ultrasound in a patient with Grave's disease there are some indicators that can raise the suspicion of malignancy. These indicators are based on characteristic impression of the nodule(s) such as irregularity, vascularity, and microcalcifications (8). Kim et.al. recommends that all patients with Grave's disease, regardless of having a palpable nodule or not, should be screened using ultrasonography (9). This could be due to the fact that most of the papillary thyroid microcarciomas that were found on those patients were incidental findings post-operatively (9). Our patient had a non-incidental papillary thyroid microcarcinoma of 6 mm that was detected by palpation. On post-operative histologic examination an incidental follicular variant of papillary thyroid microcarcinoma that measured 2 mm was discovered in the opposite lobe.

Conclusions

Many studies describe an increasing incidence of Grave's disease with concomitant papillary thyroid carcinoma. One possible explanation for these findings could be improvements in medical technology of screening tools. The discrepancies in the literature regarding screening, diagnostic methods, epidemiology, disease course, and treatment, might be due to differences among the patient population. Geographic, genetic, ethnic, iodine intake, or other unknown factors may be responsible. In view of the lack of medical experience in Puerto Rico, regarding Grave's disease with concomitant thyroid carcinoma, we propose further prospective clinical studies to evaluate the prevalence and clinical course in these types of patients. We also recommend that thyroid ultrasonography should be integrated in the diagnostic workup in patients presenting with Graves' disease (13). Fine needle aspiration should not be restricted to cold nodules.

References

(1.) Phitayakorn R, McHenry C. Incidental thyroid carcinoma in patients with Graves' disease. Am J Surg 2008;195:292-297.

(2.) Ahmad A, Al-Omari, Haddad F. Case Report: Graves' disease and papillary thyroid cancer. Saudi Med J 2005;26:1280-1282.

(3.) Majima T, Komatsu Y, Doi K. Anaplastic thyroid carcinoma associated with Graves' disease. Endocr J 2005;52:551-557.

(4.) Lin JD, Kuo SF. Incidental and nonincidental papillary thyroid microcarcinoma. Ann Surg Oncol 2008;15:2287-2292.

(5.) Yano Y, Shibuya H. Recent outcome of Graves' disease in patients with papillary thyroid cancer. Eur J Endocrinol 2007;157:325-329.

(6.) Chao TC, Lin JD. Surgical treatment of thyroid cancer with concurrent

Graves' disease. Ann Surg Oncol 2004;11:407-412.

(7.) Erkilic S, Emrah N. The role of cytokeratin 19 in the differential diagnosis of true papillary carcinoma of thyroid and papillary carcinoma-like changes in Graves' disease. Endocrine 2005;16:63-66.

(8.) Duh QY. Thyroid cancer in Graves' disease: Incidental versus clinical cancer. J Surg Oncol 2004;11:356-357.

(9.) Kim WB, Han SM, Kim TY. Ultrasonographic screening for detection of thyroid cancer in patients with Graves' disease. Clin Endocrinol 2004;60:719-725.

(10.) Ross DS. Predicting thyroid malignancy. J Clin Endocrinol Metab 2006;91:256-260.

(11.) Belfore A, Garofalo MR. Increased aggressiveness of thryoid cancer in patients with Graves' disease. J Endocrinol Metab 1990;70:830-835.

(12.) Chao TC, Lin JD, Jeng LB. Thyroid cancer with concurrent hyperthyroid ism. Arch Surg 1999;34:130-134.

(13.) Lee J, Hyun Nam K. Clinicopathologic features and treatment outcomes in differentiated thyroid carcinoma patients with concurrent Graves' disease. J Korean Med Sci 2008;23:796-801.

(14.) Hales IB, McElduff M, Crummer P. Does Graves' disease or thyrotoxicosis affect the prognosis of thyroid cancer? J Clin Endocrinol Metab 1992;75:886-889.

Jose Hernan-Martinez, MD, FACP[*]; Maria Uzcategui, MS IV[dagger]; Eric Corder, MS IV[dagger]; Manuel Castillo, MD, FACS[*]; Samuel Sostre, MD, Ph D[*], FACP; Luz Alicea, MD[dagger]

[*] San Juan Bautista School of Medicine and San Juan Bautista Medical Center Caguas, Puerto Rico, [dagger] ACP Student Member, IACP Associate

This case report was awarded the First Prize in the Poster Division of the Clinical Vignette Competition at the American College of Physicians, Puerto Rico Chapter, held on October 10, 2008 at Restaurant Los Chavales Convention Center.

Address correspondence to: Call Box 4964 Caguas, Puerto Rico 00726-4964. Tel. (787) 653-0550 ext. 6030 * Email: m.interna@yahoo.com
Table 1. Laboratory results pre-operatively

                           Patient Results        Normal Values

TSH                        0.010 IU/mL            0.47 - 5.04 IU/mL
TSH                        0.0004 IU/mL           0.47 - 5.04 IU/mL
Free T3                    3.4 pg/mL              1.5 - 3.5 pg/mL
T4                         13.52 mg/dL            4.5 - 12.0 mg/dL
Thyroglobulin              124.0 ng/mL            0.5 - 5.5ng/mL
Thyroid Stimulating        211%                   0 - 125%
Immunoglobulin
Microsomal Antibodies      16.77 IU/mL            Negative less than 40
Thyroglobulin Antibodies   Less than 33.3 IU/mL   Negative less than 79

Table 2. Pathology results from specimen biopsy post-thyroidectomy

Right Thyroid Lobe       Right Thyroid Lobe       Left thyroid Lobe

The tumor measured 6     It was at 0.2 mm of      Tumor measured 2 mm
mm in diameter. It       the nearest inked        in diameter and
showed cystic            margins.                 appears totally
degeneration and                                  excised.
psammoma bodies.

Micropapillary           Microfollicular          Micropapillary
Carcinoma                Adenoma                  Carcinoma,
                                                  Follicular -Variant.
                                                  "Incidentaloma"
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