Hyperfunctioning thyroid carcinoma: A systematic review.

Hyperthyroidism may be caused by the development of primary or metastatic thyroid carcinoma. The aim of the present study was to collect recently reported cases of hyperfunctioning thyroid carcinoma in order to analyze its pathological characteristics, diagnostic procedures and treatment strategies. A PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) search was performed for studies published between January 1990 and July 2017. Full-text articles were identified using the terms, 'hyperfunctioning thyroid carcinoma/cancer', 'malignant hot/toxic thyroid nodule', or 'hyperfunctioning papillary/follicular/Hürthle thyroid carcinoma'. Original research papers, case reports and review articles were included. Among all thyroid carcinoma cases included in the present study, the prevalence of follicular thyroid carcinoma (FTC) was ~10%; however, the prevalence of FTC among hyperfunctioning thyroid carcinomas was markedly higher (46.5% in primary and 71.4% in metastatic disease). The size of hyperfunctioning thyroid tumors was considerably larger compared with that of non-hyperfunctioning thyroid tumors, with a mean size of 4.25±2.12 cm in primary hyperfunctioning thyroid carcinomas. In addition, in cases of metastatic hyperfunctioning thyroid carcinoma, tumor metastases were widespread or large in size. The diagnosis of primary hyperfunctioning thyroid carcinoma is based on the following criteria: i) No improvement in thyrotoxicosis following radioactive iodine (RAI) treatment; ii) development of hypoechoic solid nodules with microcalcifications on ultrasound examination; iii) increase in tumor size over a short time period; iv) fixation of the tumor to adjacent structures; and v) signs/symptoms of tumor invasion. The diagnosis of metastatic hyperfunctioning thyroid carcinoma should be considered in patients suffering from thyrotoxicosis who present with a high number of metastatic lesions (as determined by whole-body scanning), or a history of total thyroidectomy. Surgery is the first-line treatment option for patients with primary hyperfunctioning thyroid carcinoma, as it does not only confirm the diagnosis following pathological examination, but also resolves thyrotoxicosis and is a curative cancer treatment. RAI is a suitable treatment option for patients with hyperfunctioning thyroid carcinoma who present with metastatic lesions. Copyright: © Liu et al.

Introduction

Thyroid carcinoma coexisting with hyperthyroidism is an uncommon occurrence (1), as low thyroid-stimulating hormone (TSH) levels can suppress the development and growth of differentiated thyroid carcinoma cells. The majority of nodules in patients with low TSH levels are considered to be benign (NCCN, British Thyroid Association) (1); however, an increasing number of thyroid carcinoma cases are diagnosed in patients with Graves' disease, toxic goiter and functioning thyroid adenoma (2). These thyroid carcinomas may be embedded in or adjacent to a larger hot nodule, and the majority are non-functional. However, previous studies have reported that hyperfunctioning thyroid carcinoma may present as autonomous functioning thyroid nodules (AFTN) within the thyroid gland, or as functioning lesions in metastatic foci (3–5). In addition, Als et al (3) identified 19 patients with toxic thyroid carcinoma in 2002, while Mirfakhraee et al (5) identified a solitary hyperfunctioning thyroid nodule harboring thyroid carcinoma and reported 76 cases of malignant hot thyroid nodules based on a literature search. Hyperfunctioning thyroid carcinomas are capable of absorbing iodine, as well as synthesizing and releasing thyroxine. Patients with hyperfunctioning thyroid carcinomas may therefore present with clinical thyrotoxicosis. It is considered that this type of hyperthyroidism may be caused by hyperfunctioning thyroid carcinoma. However, as the incidence of hyperfunctioning thyroid carcinoma is very low, diagnosis may be delayed and the subsequent choice of treatment may be unsuitable. Therefore, the aim of the present study was to improve our understanding of hyperfunctioning thyroid carcinoma in order to prevent misdiagnosis and to identify the most effective treatment strategies.

Materials and methods

Search strategy and selection criteria

A literature search of PubMed for studies published in English between January 1990 and July 2017 was performed using the terms, ‘hyperfunctioning thyroid carcinoma/cancer’, ‘malignant hot/toxic thyroid nodule’, or ‘hyperfunctioning papillary/follicular/Hürthle cell thyroid carcinoma’, followed by a review of the identified articles. Hyperfunctioning thyroid carcinoma was divided into primary and metastatic. The inclusion criteria for studies involving primary hyperfunctioning thyroid carcinoma were as follows: i) Thyroid carcinoma, papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC) or Hürthle cell carcinoma (HCC); ii) clinical hyperthyroidism with symptomatically or biochemically diagnosed thyrotoxicosis; iii) AFTN, hot or warm nodules (as determined by scintigraphy) and other thyroid tissues with suppressed uptake (99mTc, and/or 131I or 123I); iv) thyroid carcinomas of an identical size to hot or warm nodules, or the absence of hyperplasia in non-cancerous thyroid tissues on pathological analysis. Studies involving cases where the size of the thyroid carcinoma was not identical to that of the hot or warm nodules on scintigraphy, or those where this information was not included, were excluded from the present study, as these tumors may be embedded in hot benign nodules and be non-functional. The inclusion criteria for studies involving metastatic hyperfunctioning thyroid carcinoma were required to meet aforementioned points i, ii and iii; or i, ii and iv; or a minimum of points i, ii and vi of the following: i) Thyroid carcinoma, PTC, FTC or HCC confirmed by bioptic analysis of the metastatic lesions or thyroid nodule; ii) clinical hyperthyroidism; iii) hyperthyroidism that persists or develops following total thyroidectomy; iv) increased 99mTc, and/or 131I or 123I uptake in the metastatic lesion as determined by scintigraphy. Studies involving cases of persistent euthyroidism following total thyroidectomy were also excluded, as this may indicate functioning but not hyperfunctioning thyroid carcinoma.

Study selection

Since the incidence of hyperfunctioning thyroid carcinoma is very low, the number of cases found on PubMed was small, and the majority of the cases had incomplete data. Of the 763 articles retrieved from PubMed using our search strategy, 397 were duplicated and 324 did not meet the inclusion criteria. Finally, the remaining 42 articles were included in the present study. A detailed flowchart of the study selection process is presented in Fig. 1.

Figure 1.

Flow diagram of the screening process for study selection.

Results

Primary hyperfunctioning thyroid carcinoma

The literature search identified 43 cases of primary hyperfunctioning thyroid carcinoma between 1998 and 2017 (Table I) that fulfilled the inclusion criteria (3,5–28); the full-text versions of the majority of articles published before 1998 were unavailable. The mean age of patients was 50.1±19.0 years (range, 11–79 years) and the female:male ratio was 2.31 (30:13). All patients presented with clinical hyperthyroidism. Biochemical thyrotoxicosis was confirmed in all patients, apart from 11 cases, 5 of which presented with low TSH and normal T3 and T4 levels, and 6 cases with incomplete information. Thyroid scintigraphy analysis (99mTc and/or 131I or 123I) was performed in all but 2 patients, and indicated the presence of hot or warm nodules with suppressed uptake in the remainder of the thyroid gland as AFTN. All 43 cases presented with at least one of the following characteristics, indicating that the hyperfunctioning nodule was in fact the thyroid carcinoma: i) Pathological tumor size identical to the size of the nodule as determined by preoperative thyroid scintigraphy analysis; or ii) the thyroid tissue adjacent to the carcinoma was atrophic or normal. The majority of the cases presented with a single hyperfunctioning thyroid carcinoma, apart from 2 cases; patient 23 presented with two hyperfunctioning FTCs, and patient 31 presented with 4 hyperfunctioning PTCs. The mean tumor size was 4.25±2.12 cm. A total of 4.7% of the tumors were ≤1.0 cm in size, 11.6% were >1 to ≤2.0 cm, 39.5% were >2 to ≤4.0 cm and 44.2% were >4.0 cm. Details on the preoperative ultrasound parameters were mostly unavailable; however, based on the available information, there were no characteristic findings indicative of thyroid carcinoma (Table I). The results of fine-needle aspiration (FNA) of the thyroid performed on 15 patients identified differentiated thyroid carcinoma (DTC) or suspected DTC in 10 cases, no diagnosis by cytology in 4 cases, and no malignant characteristics in 1 case. In terms of histological subtype, 20 cases (46.5%) were FTC, 21 cases were PTC [including 7 follicular variant PTC (FVPTC)] and 2 cases were HCC.

Table I.

Reported cases of primary hyperfunctioning thyroid carcinoma.

A, Study ID, patient characteristics and findings on examination
No.	First author	Year	Age, years	Sex	Tumor growth	Pertechnetate	Chemical thyrotoxicosis	FT3 (pmol/l)	FT4 (pmol/l)	TSH (uIU/ml)	AFTN size (cm)	Tumor size (cm)	US	FNA	Pathology	(Refs.)
1	Appetecchia	1998	23	F	3.5→ 4.0 cm	AFTN	Chemical	11.55↑	25.52↑	0.11↓	3.5/4	4	Inhomogeneous nodule		Gross PTC, 4 PTC, 3 microfoci PTC	(6)
2	Mircescu	2000	11	F		Yes, hyperfunctioning nodule	Chemical		75↑	0.03↓	4.5	4	Enlarged with numerous cystic lesions		PTC 4.0 cm, cystic	(7)
3	Bourasseau	2000	47	M		Yes, hot, solitary	Chemical	↑	N	0.05↓	3.5	3.5	Solitary	Suspicious	PTC	(8)
4	Bourasseau	2000	36	M		Yes, hot, solitary	No	N	N	0.025↓	2.5	2.5	Solitary	No diagnostic	FTC	(8)
5	Bourasseau	2000	56	M		Yes, hot, solitary	Chemical		↑	0.03↓	5.5	5.5	Solitary	No	FTC	(8)
6	Bourasseau	2000	39	F		Yes, warm	Chemical	↑	↑	0.004↓	1	1	Multinodular	Suspicious	PTC	(8)
7	Bourasseau	2000	33	F		Yes, hot	No	N		0.005↓	3	3	Multinodular	Not diagnostic	PTC	(8)
8	Camacho	2000	49	F		Yes, Hot, AFTN	Chemical		15.7↑	0.04↓	3.5	3.5		No	FTC with hemorrhagic central portion	(9)
9	Als	2002	54	M		Hot, AFTN	Uncertain				8.5	8.5		No	FTC	(3)
10	Als	2002	62	F		Uncertain	Uncertain							No	PTC	(3)
11	Als	2002	50	M		Hot, AFTN	Uncertain				10	10		No	FTC	(3)
12	Als	2002	62	M		Hot, AFTN	Chemical	↑	N	↓	8	8		No	FTC	(3)
13	Als	2002	71	F		Hot, AFTN	Chemical	↑	↑	↓	4	4		No	FTC	(3)
14	Als	2002	69	F		Hot, AFTN	Chemical	↑	N	↓	6	6		No	FTC	(3)
15	Als	2002	55	F		Hot, AFTN	Uncertain			↓	5.5	5.5		No	FTC	(3)
16	Als	2002	79	F		Hot, AFTN (suppression)	Chemical	↑	↑	↓				No	FTC	(3)
17	Als	2002	65	M		Hot, AFTN	Chemical	↑	N	↓	6.5	6.5		No	FTC	(3)
18	Als	2002	56	M		Hot, AFTN	Chemical	↑	N					No	FVPTC	(3)
19	Als	2002	75	M		Hot, AFTN	Chemical	↑	N	↓	5.5	5.5		No	FTC	(3)
20	Als	2002	77	F		Hot, AFTN	Chemical	↑	N	↓	4	4		No	PTC	(3)
21	Als	2002	71	F		Hot, AFTN	Chemical	↑		↓	6	6		No	FTC	(3)
22	Als	2002	74	F		Hot, AFTN	Chemical	↑	↑	↓	7	7		No	FTC	(3)
23	Fuhrer	2003	59	M		Hot, AFTN right, WBS: no uptake in lung	No	N	N	0.01↓	3.5	3.5	One solid with calcification, one solid	Lung FNA: FTC	FTC ×2	(10)
24	Wong	2003	67	F		Yes, hot, AFTN	Chemical		↑	↓	2.5	3		No feature of carcinoma	Hürthle cell carcinoma	(11)
25	Gozu	2004		F		Yes, hot 5.0 cm, 2.0 cm hypoactive	Chemical	9.11↑	1.89↑	0.005↓	5	5		No	PTC (intracystic)	(12)
26	Majima	2005	59	F		AFTN	Chemical	4.4↑	2.7↑	0.01↓	1.5	1.5	Hypoechoic with cystic degeneration, calcification	PTC	PTC	(13)
27	Bitterman	2006	57	F		Hot in right, cold in left	Possibly	?	?	?	6	6	Multinodular	Not diagnostic	FTC	(14)
28	Bitterman	2006	59	F		Hot, 5 cm AFTN	Possibly	?	?	?	5	5	Solitary nodule	No	FTC	(14)
29	Niepomniszcze	2006	64	F		Yes, AFTN	Chemical			0.02↓	6	6		no	FTC	(15)
30	Uludag	2008	36	M	1.4→ 1.8 cm (11 months)	AFTN	No	N	N	0.05↓	1.4	1.5	Hypoechoic nodule	PTC	PTC	(16)
31	Nishida	2008	62	F		4 hot AFTN in both lobes	Chemical	5.2↑	2.39↑	0.007↓	2.0, 1.5, 0.6,1.5	2.0	Multinodular	PTC	PTC ×4	(17)
32	Bommired-dipalli	2010	63	M	Enlarging (5 months)	Yes, AFTN right	Chemical	N	2.1↑	0.01↓	4	4	Solid mass	FVPTC?	FVPTC, LN, FVPTC	(18)
33	Azevedo	2010	47	F	Enlarging (2 years)	Yes, high iodine uptake AFTN	Chemical		2.75↑	0.05↓	2.6	3	Solid nodule	PTC suggestive	FVPTC	(19)
34	Giovanella	2010	68	F		AFTN, no cold area in nodule	Chemical	7.6↑	N	0.006↓	5.3	5.3	Hypoechoic nodule	No	FTC	(20)
35	Tfayli	2010	11	F		Yes, predominant AFTN	Chemical		1.14	↓	3.5	3	Non-homogenous nodule	Not, diagnostic TC not excluded	PTC	(21)
36	Karanchi	2012	43	F		AFTN	Chemical	12.7↑	3.1↑	0.01↓	6.5		Solid nodule	No	Hürthle cell carcinoma	(22)
37	Nair	2012	38	M		Hot, AFTN right lobe whole	Chemical	6.12↑	2.9↑	0.003↓	3.8	3	Hypoechoic with scattered microcalcification	NO	PTC with multifocal microPTC	(23)
38	Ruggeri	2013	15	F	2.5→ 3.5 cm (6 months)	Yes, AFTN	Chemical	5.0↑	20.15↑	0.001↓	3.5	3.5	Isoechoic, peripheral halo, blood flow, regular margin	No	FVPTC	(24)
39	Mirfakhraee	2013	29	F	2.4→ 2.7 cm (2 years)	Yes, AFTN	No	N	N	0.005↓	2.7	2.5	Solid, isoechoic, internal Hypervascularity	No	FTC	(5)
40	Gabalec	2014	15	F		Hot, AFTN	Chemical		30.4↑	0.01↓	4.5	4	Heterogenous, well-demarcated nodule	Follicular neoplasia?	FVPTC	(25)
41	Kuan	2014	60	F	No mention	Hot, AFTN right lobe whole	Chemical	7.71↑	7.75↓	0.005↓	8	8	Hypoechoic, avascular, nodule	Follicular neoplasia, FTC?	FVPTC	(26)
42	Rees	2015	16	F		Yes, 2.6 cm uptake	Chemical	14.3↑	39.4↑	0.03↓	4	4	Hyperechoic, hypervascular nodule	DTC?	FVPTC	(27)
43	Kadia	2016	37	F	Enlarging (3 months)	–	Chemical		23.3↑	0.13↓	3.6	3	Isoechoic, well-defined homogeneous solid nodule	NO	PTC encapsulated variant	(28)
B, Treatment and outcome
No.	First author		Treatment			Pretreatment effect			Surgery outcome		RAI effect and prognosis			Metastatic		(Refs.)
1	Appetecchia		Thyroidectomy + bilateral neck dissection + RAI			Triamazole to euthyroid			Hypothyroid, but anterior cervical tumor residual		No thyrotoxicosis or recurrence					(6)
2	Mircescu		Right loboisthmectomy/total (2 months) + RAI			Methimazole + blocker			No mention		8 months, no residual uptake					(7)
3	Bourasseau		Thyroidectomy			No mention			No mention		No					(8)
4	Bourasseau		Thyroidectomy			No mention			No mention		No					(8)
5	Bourasseau		Thyroidectomy			No mention			No mention		No					(8)
6	Bourasseau		Thyroidectomy			No mention			No mention		No					(8)
7	Bourasseau		Thyroidectomy			No mention			No mention		No					(8)
8	Camacho		Thyroidectomy + RAI			No mention			No mention		3 years, no thyrotoxicosis or recurrence					(9)
9	Als		Surgery + RAI			Uncertain			Uncertain		117 months			Yes		(3)
10	Als		Surgery + RAI + PR			Uncertain			Uncertain		82 months			Yes		(3)
11	Als		Surgery + RAI + PR			carbimazole			Uncertain		18 months			Yes		(3)
12	Als		Surgery + RAI			Uncertain			Uncertain		190 months			Yes		(3)
13	Als		RAI + surgery + RAI			Uncertain			Uncertain		68 months			Yes		(3)
14	Als		Surgery + RAI + PR			Uncertain			Uncertain		28 months			Yes		(3)
15	Als		Surgery + RAI + PR			Uncertain			Uncertain		93 months			Yes		(3)
16	Als		RAI + surgery + RAI			Uncertain			Uncertain		46 months			Liver and sacrum		(3)
17	Als		Surgery + RAI + PR			Uncertain			Uncertain		107 months			Yes		(3)
18	Als		Surgery + RAI			Uncertain			Uncertain		208 months alive			No		(3)
19	Als		Surgery + RAI			Uncertain			Uncertain		181 months			No		(3)
20	Als		Surgery + RAI			Uncertain			Uncertain		45 months			Uncertain		(3)
21	Als		Surgery + RAI + PR			Uncertain			Uncertain		44 months			Yes		(3)
22	Als		Surgery + RAI			Uncertain			Uncertain		76 months alive			Yes		(3)
23	Fuhrer		Total thyroidectomy + RAI - thoracic surgery (8 months)			Euthyroid			Hypothyroid with RAI		Hypothyroid, 8 months thyrotoxicosis control good			Yes		(10)
24	Wong		Lobectomy/total thyroidectomy + RAI			No mention			No mention		No mention					(11)
25	Gozu		Lobectomy/total thyroidectomy + RAI			Euthyroid			Hypothyroid (6 weeks)		1 year, no thyrotoxicosis or recurrence					(12)
26	Majima		Lobectomy			No mention			Hypothyroid (3 months)		No					(13)
27	Bitterman		Loboisthmectomy + nodule excision/total thyroidectomy			PTU, no clinical improve			Disease-free 1.5 years		No					(14)
28	Bitterman		Left lobectomy			PTU, intolerance several months			No mention		No					(14)
29	Niepomniszcze		Lobectomy/total thyroidectomy + RAI			No mention			No mention		6 months, no thyrotoxicosis or recurrence					(15)
30	Yazici		RAI→total thyroidectomy + CND			No mention			No recurrence or residual disease		Thyrotoxicosis control, but size increase					(16)
31	Nishida		Total thyroidectomy			Thiamazole, 5 months to euthyroid			No recurrence and residual disease (1 year)		No					(17)
32	Bommireddipalli		Total thyroidectomy + RAI			No			No mention		1 year, TG↑LN +, 1.5 year, LN biopsy +			Yes		(18)
33	Azevedo		Total thyroidectomy + RAI			Methimazole 2 months to euthyroid			True hypothyroidism (2 months) then RAI		3 years + 2 years no thyrotoxicosis or recurrence					(19)
34	Giovanella		Right loboisthmectomy + RAI			No			Hypothyroid		3.4 years, negative					(20)
35	Tfayli		Lobectomy/total thyroidectomy + RAI			No mention			No mention		1 year, no thyrotoxicosis or recurrence					(21)
36	Karanchi		Hemithyroidectomy/total thyroidectomy (1 year) + RAI			No control			Euthyroid (2 weeks)		No					(22)
37	Nair		Total thyroidectomy + CND + LND + RAI (4 weeks + 6 months)			Carbimazole to euthyroid			No mention		TG 1 year high, LN metastases			Yes		(23)
38	Ruggeri		Surgery			Methimazole to euthyroid			No mention		No					(24)
39	Mirfakhraee		Left lobectomy			No mention			Euthyroid (6 months) with no recurrence of cancer		No					(5)
40	Gabalec		Hemithyroidectomy/total thyroidectomy + CND + RAI			Triamazole			No mention		To hypothyroid state					(25)
41	Kuan		Total thyroidectomy			No mention			No mention		No					(26)
42	Rees		Left lobectomy + RAI			Carbimazole to euthyroid			No mention		Wel-controlled					(27)
43	Kadia		Left lobectomy			methimazole + blocker			Euthyroid (2–4 weeks)		No					(28)

M, male; F, female; AFTN, autonomous functioning thyroid nodule; US, ultrasound; FNA, fine-needle aspiration; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; FVPTC, follicular variant papillary thyroid carcinoma; LN, lymph node; RAI, radioactive iodine; PR, preoperative radioactive iodine; CND, central neck dissection; LND, lateral neck dissection; TG, thyroglobulin; WBS, whole-body scanning.

Of the 15 patients pretreated with anti-thyroid drugs, the results indicated disease control to euthyroid in 8 patients, unknown outcome for 4 patients, no disease control in 2 patients and drug intolerance in 1 patient. Thyroid surgery was performed in all patients. In all patients with available information on disease outcome (n=9), thyrotoxicosis was well-controlled by surgery. Radioactive iodine (RAI) treatment was performed preoperatively in 3 patients who had been initially diagnosed with benign AFTN, and postoperatively in 20 patients. As long-term follow-up data were absent for the majority of the patients, and as patients were treated with RAI within a short time period following surgery, it was difficult to evaluate the effect of RAI alone on those patients. However, the available data indicated that only few (14 cases in 43 cases) suffered recurrence of thyrotoxicosis or carcinoma within a short follow-up period [44.5 months (6–208 months)] following thyroid surgery and RAI.

Metastatic hyperfunctioning thyroid carcinoma

Following a literature search, a total of 28 cases of metastatic hyperfunctioning thyroid cancer were identified (Table II) (3,4,29–44) according to the aforementioned inclusion criteria. All patients had either clinical thyrotoxicosis with biochemical data indicating hyperthyroidism, or been diagnosed as thyrotoxicosis. In addition, all cases (apart from case 56) had a high 99mTc, and/or 131I or 123I uptake in distant lesions, as demonstrated by whole-body scanning. All patients presented with multiple or large metastases to the bone, lungs, liver or mediastinum. The largest metastatic lesion was observed in the liver of patient 62 (17.0 cm). The mean patient age was 61.2±10.8 years, and the female:male ratio was 1.8 (18:10). Histopathological examination revealed that 20 cases were FTC, 5 cases were PTC (including 1 FVPTC), 1 case was insular TC, and 1 case was an unknown type of DTC. A total of 14 patients with metastatic hyperfunctioning thyroid carcinoma had undergone thyroidectomy, while the remaining 14 patients had no history of thyroidectomy. Thyroid scans were performed in 13 of the 14 cases with no thyroidectomy history, and the results of 6 cases indicated none to normal uptake, cold regions in the thyroid gland and the presence or absence of cold nodules. The remaining 7 cases were diagnosed with AFTN. Thyroid FNAs were performed in 5 cases with no history of thyroidectomy: DTC (1 PTC and 1 FTC) was diagnosed in 2 cases, follicular cells were identified in another 2 cases, and no malignant cells were detected in the remaining case. Biopsies of the metastatic lesions were performed in 3 cases, and the results indicated metastatic DTC. Therefore, of the 14 patients without thyroidectomy, 4 were diagnosed with metastatic hyperfunctioning thyroid cancer, 2 as suspicious and 8 as uncertain.

Table II.

Reported cases of metastatic hyperfunctioning thyroid carcinoma.

A, Study ID, patient characteristics and findings on examination
No.	First author	Year	Age, years	Sex	Thyroid-ectomy history	Thyroid scan	Whole body scan	Thyroto-xicosis	FT3 (pmol/l)	FT4 (pmol/l)	TSH (uIU/ml)	TG (ng/ml)	Metastatic location	Thyroid FNA	Biopsy on metastasis	Pathology	(Refs.)
44	Girelli	1990	66	F	No	Normal, uptake cold nodules	High uptake in distant lesions	Clinical			0.01↓	5,300	Bone	PTC	Metastatic	PTC PTC	(29)
45	Mizukami	1994	64	F	No	Hot AFTN 4.0	High uptake in distant lesions	Clinical			↓		Bone	Microfo-llicular	No	FTC	(30)
46	Russo	1997	60	F	No	Hot AFTN two	High uptake in distant lesions (after surgery)	Clinical	2.8↑	N	0.06↓	513	Lung	No	No	Insular TC	(31)
47	Salvatori	1993	79	F	No	Cold areas	High uptake in distant lesions	Clinical	10.4↑	3.8↑	0.06↓	382	Lung	FTC	No	FTC	(32)
48	Als	2002	61	M	No	Hot AFTN	High uptake in distant lesions	Clinical					Uncertain	No	No	FTC	(3)
49	Als	2002	65	F	No	Hot AFTN	High uptake in distant lesions	Clinical					Uncertain	No	No	FTC	(3)
50	Als	2002	71	F	No	Hot AFTN	High uptake in distant lesions	Clinical		↑	↓		Uncertain	No	No	FTC	(3)
51	Als	2002	62	F	No	Hot AFTN	High uptake in distant lesions	Clinical			↓		Uncertain	No	No	FTC	(3)
52	Als	2002	63	M	No	Hot AFTN	High uptake in distant lesions	Clinical		N	↓		Uncertain	No	No	PTC	(3)
53	Sundaraiya	2009	68	M	No	Cold nodule	High uptake in distant lesions	Clinical	42.6↑	100↑	↓		Rib	No	Rib FTC	FTC multifocal	(33)
54	Damle	2012	65	M	No	–	High uptake in distant lesions	Clinical			0.03↓	300	Lung, bone	Follicular neoplasm	No	FTC	(34)
55	Damle	2012	62	M	No	No uptake	High uptake in distant lesions	Clinical	↑	↑	↓	300	Bone	No	Metastatic FTC		(34)
56	Gardner	2014	66	F	No	Diffuse reduction	No WBS	Clinical	25.1↑	37.9↑	0.006↓		Lung, bone	No malignant cells		FVPTV	(35)
57	Kunawudhi	2016	43	F	No	Cold	High uptake in distant lesions	Clinical	32.55↑	6.34↑	0.026↓		Bone, liver	No	No	FTC	(36)
58	Abs	1991	57	F	Partial thyroid-ectomy	Normal	High uptake in distant lesions	Clinical			0.6↓	640	Mediasti-num			FTC	(37)
59	Lorberb-oym	1996	67	F	Total thyroid-ectomy		High uptake in distant lesions	Clinical	273↑	15.7↑	0.1↓		Hemipelvis			FTC	(38)
60	Yoshimura	1997	61	M	Total thyroidectomy + RAI + hip replacement		High uptake in distant lesions	Clinical	46.1↑	105.3↑	0.05↓	329	Pelvis			FTC	(39)
61	Salvatori	1993	69	F	Partial thyroidectomy	Low uptake	High uptake in distant lesions	Clinical	3.8↑	10.4↑	0.06↓	48,680	Lung			DTC	(32)
62	Guglielmi	1999	58	F	Subtotal thyroidectomy		High uptake in distant lesions	Clinical	18.4↑	44.5↑	0.1↓	3,686	Liver, lung		Liver FTC	FTC	(40)
63	Basaria	2002	74	M	Total thyroidectomy 8 years		High uptake in distant lesions	Clinical	↑	↑	↓	2,280	Mediastinum and lung			PTC	(41)
64	Orsolon	2008	66	M	Total thyroidectomy		High uptake in distant lesions	Clinical	4.5↑	1.6	<0.1↓	>10,000	Bone, lung			FTC	(42)
65	Tan	2009	39	F	Total thyroidectomy + hip replacement + RAI		High uptake in distant lesions (FDG)	Clinical	27.9↑	4.41↑	0.01↓	1,000	Pelvic mass			FTC	(43)
66	Nishihara	2010	59	F	Total thyroidectomy + EBRT		High uptake in distant lesions	Clinical	↑	↑	0.01↓	8,000	Multiple bone and lung			FTC	(44)
67	Qiu	2015	45	M	Total thyroidectomy		High uptake in distant lesions	Clinical	13.42↑	33.9↑	0.04↓		Bone			FTC	(4)
68	Qiu	2015	75	M	Total thyroidectomy		High uptake in distant lesions	Clinical	9.35↑	27.18↑	0.24↓		Lung			PTC	(4)
69	Qiu	2015	43	F	Total thyroidectomy		High uptake in distant lesions	Clinical	7.23↑	29.14↑	0.22↓		Bone			FTC	(4)
70	Qiu	2015	51	F	Total thyroidectomy		High uptake in distant lesions	Clinical	9.51↑	31.73↑	0.02↓		Bone, lung			FTC	(4)
71	Qiu	2015	54	F	Total thyroidectomy		High uptake in distant lesions	Clinical	7.83↑	32.15↑	0.01↓		Bone			FTC	(4)
B, Treatment and outcome
No.	First author		Pretreatment antithyroid drug			Treatment			Surgery outcome				Response to RAI				(Refs.)
44	Girelli		Thyrotoxicosis to subhyperthyroidism			Total thyroidectomy + RAI			Persistent				Hyperthyroidism persisting 6 months after RAI				(29)
45	Mizukami		Unknown			RAI			–				Persistent after 2 RAI				(30)
46	Russo		Unknown			Subtotal thyroidectomy/1 year total + RAI 2			Mild hyperthyroidism				Hypothyroid, TG remains high (2 years)				(31)
47	Salvatori		Effect not shown			Total thyroidectomy + RAI			Improved only 1 month				Hyperthyroidism persisting 4 months after RAI				(32)
48	Als		Unknown			RAI + surgery + RAI			Persistent				27 months, died				(3)
49	Als		Unknown			RAI + surgery + RAI			Persistent				39 months, died				(3)
50	Als		Unknown			Surgery + RAI			Persistent				229 months, died				(3)
51	Als		Unknown			Surgery + RAI			Persistent, possible improvement				10 months, died				(3)
52	Als		Unknown			Surgery + RAI			Persistent				71 months, died				(3)
53	Sundaraiya		Effect not shown			Total thyroidectomy + RAI			Persistent				3 months RAI hypothyroid with tumor control				(33)
54	Damle		Thyrotoxicosis difficult to control			Subtotal thyroidectomy + RAI			Improved only 2 months				5 years of no recurrence of thyrotoxicosis				(34)
55	Damle		Thyrotoxicosis difficult to control			RAI			–				3 years of no recurrence of thyrotoxicosis				(34)
56	Gardner		Thyrotoxicosis difficult to control			Total thyroidectomy + RAI			Died of thyroid storm 12 days postoperatively				–				(35)
57	Kunawudhi		Effect not shown			Total thyroidectomy + right LND + RAI + EBRT			Persistent				2 years, progressive disease				(36)
58	Abs		Thyrotoxicosis difficult to control			Rib biopsy + RAI, good							RAI 9 years, no metastases				(37)
59	Lorberboym		Pretreatment to euthyroid +EBRT to hypothyroid			Pretreatment + EBRT + RAI							4 weeks RAI hypothyroid				(38)
60	Yoshimura		No mention			RAI + pretreatment							Rapid improvement 1.5 years survival				(39)
61	Salvatori		Effect not shown			RAI							Hyperthyroidism persisting 6 months after RAI				(32)
62	Guglielmi		Failure to control thyrotoxicosis			ILP + RAI							1.5 years good control				(40)
63	Basaria		Good control			Pretreatment + RAI							3 months hypothyroid				(41)
64	Orsolon		Unknown			Unknown							Unknown				(42)
65	Tan		Worsening			Removal of pelvis mass and partial bone			Thyrotoxicosis disappeared				Resistant to RAI				(43)
66	Nishihara		Unknown			RAI low multiple							10 months after RAI, toxicosis control, but tumor progression, 8 years of survival				(44)
67	Qiu		Unknown			RAI + palliative resection							Effect not clearly shown
68	Qiu		Unknown			RAI							Effect not clearly shown				(4)
69	Qiu		Unknown			RAI + palliative resection							Effect not clearly shown				(4)
70	Qiu		Unknown			RAI + palliative resection							Effect not clearly shown				(4)
71	Qiu		Unknown			RAI							Effect not clearly shown				(4)

M, male; F, female; RAI, radioactive iodine; EBRT, external beam radiation therapy; AFTN, autonomous functioning thyroid nodule; FNA, fine-needle aspiration; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; FVPTC, follicular variant papillary thyroid carcinoma; TC, thyroid carcinoma; DTC, differentiated thyroid carcinoma; LND, lateral neck dissection; ILP, interstitial laser photocoagulation; TG, thyroglobulin; LN, lymph node.

The results demonstrated that, of the 13 patients who underwent pretreatment with anti-thyroid medication, 6 experienced difficulties or were unable to control thyrotoxicosis, while only 3 patients became euthyroid. The outcome of thyrotoxicosis in the remaining 4 patients was uncertain. Total or subtotal thyroidectomy was performed in 12 of 14 cases without a history of thyroidectomy. One patient succumbed to thyroid crisis at 12 days post-surgery. Following surgery, thyrotoxicosis persisted in 8 patients, while a transient improvement was observed in 3 patients. All patients underwent multi-dose RAI, apart from 2 patients (patient 56 succumbed to the disease and the outcome of patient 64 is unknown). Following RAI, the majority of the patients exhibited a significant improvement in hyperthyroidism and good cancer control; however, thyrotoxicosis in patient 44 persisted for up to 6 months. Patients 55 and 58 experienced no recurrence of thyrotoxicosis or cancer during a follow-up period of 3 or 9 years, respectively following RAI treatment. Of particular note, patient 65 developed RAI resistance 4 years after the first dose of RAI. This patient's thyrotoxicosis was caused by pelvic metastasis, which was cleared following surgical removal of the pelvic mass.

Discussion

Thyroid carcinoma coexisting with hyperthyroidism is rare and is more commonly encountered among younger, female patients (5). Diagnosis relies on clinical and histopathological correlation. On histopathological examination, the lack of hyperplastic thyroid tissue often suggests a hyperfunctioning thyroid cancer (28).

The results of the present study have several implications, as discussed below. First, the prevalence of different histological subtypes of hyperfunctioning thyroid carcinoma was investigated in the present study. The results indicated that 46.5% of primary hyperfunctioning thyroid carcinomas and 71.4% (20/28) of metastatic hyperfunctioning thyroid carcinomas were of the FTC subtype. Mirfakhraee et al (5) reported that 36.4% (28/77) of solitary hyperfunctioning thyroid nodules harboring a thyroid carcinoma, in which the majority are primary hyperfunctioning thyroid carcinomas, were of the FTC subtype. Qiu et al (4) reported that the prevalence of FTC in functioning metastatic thyroid carcinoma was 60.5% (23/38), of which 5 cases were hyperfunctioning. By comparison, the Surveillance, Epidemiology and End Results (SEER) cancer registry program (1974–2013) (45), which records all histological thyroid cancer cases as a single group, indicates that the prevalence of FTC is 10.8% and that of PTC is 83.6%. Therefore, there appears to be a higher prevalence of FTC among patients with hyperfunctioning thyroid carcinoma, and a particularly high prevalence among patients with metastatic disease. This suggests that hyperfunctioning thyroid carcinoma may be more likely to occur in either primary or metastatic FTC when compared with PTC. The reason for this is unknown. The results presented by Qiu et al (4) indicate that the prognosis of patients with metastatic hyperfunctioning FTC is worse compared with that for patients with PTC.

Tumor size is an additional important factor to consider for hyperfunctioning thyroid carcinoma. In the present study, the mean tumor size of primary hyperfunctioning thyroid carcinoma was observed to be 4.25±2.12 cm. These results are consistent with those presented by Mirfakhraee et al (5), who reported a mean tumor size of 4.13±1.68 cm in malignant hot nodules (the majority of which were hyperfunctioning thyroid carcinomas). By comparison, the SEER cancer registry program (1974–2013) (45) reports that 28.6% of thyroid carcinomas are ≤1.0 cm in size, 26.0% are >1.0 to ≤2.0 cm, 23.0% are >2.0 to ≤4.0 cm, 9.6% are >4.0 cm and 13.0% are unknown. Pazaitou-Panayiotou et al (2) conducted a well-organized review, which demonstrated that the majority of non-functioning thyroid carcinomas that coexist with Graves' disease, toxic nodule goiter or hyperfunctioning adenoma, are microcarcinomas (35.0–88.0%). In addition, similar characteristics were observed in these metastatic hyperfunctioning thyroid carcinoma patients. It is considered that large primary or metastatic tumors may synthesize excessive thyroid hormones more readily, which may cause hyperthyroidism. Somatic mutations in TSH receptor genes may explain the hyperthyroidism caused by thyroid cancer. These mutations activate the intracellular cAMP cascade, induce hormone production and, ultimately, lead to hyperthyroidism (28,46). Pringle et al (47) observed that thyroid-specific knockout of PrkarIa leads to hyperthyroidism and thyroid cancer in mice. Moreover, they suggested that another genetic mutation may be implicated in metastasis, apart from PrkarIa mutation in the thyroid (47). As DTC cells have similar functions to normal thyroid follicular cells, such as TSH-dependence, absorption of iodine and secretion of thyroglobulin, DTC cells may also secrete thyroxine. When autoregulation mechanisms are impeded, such as in Graves' disease, large DTCs may secrete excessive amounts of thyroxine resulting in hyperthyroidism. These results also indicate that debulking surgery may play a key role in the treatment of this rare disease.

As regards the diagnosis of hyperfunctioning thyroid carcinoma, it is difficult to distinguish malignant from benign AFTN, as they share common characteristics, such clinical thyrotoxicosis with hot nodules on thyroid scintigraphy. However, the following factors may help determine whether thyrotoxicosis is the result of primary hyperfunctioning thyroid carcinoma: i) No improvement in thyrotoxicosis following RAI treatment (patient 30 in the present systematic review) (16); ii) ultrasound results indicating the presence of hypoechoic solid nodules with microcalcifications (patients 23 and 37 in the present systematic review) (10,23); and iii) tumor growth over a short time period (patient 32 and 43 in the present systematic review) (18,28). Additional risk factors for malignancy were also reported, such as age (<20 or >60 years), male sex, a family history of DTC, a previous history of head or neck irradiation, tumor fixation to adjacent structures and symptoms of tumor invasion (3,5). Most importantly, AFTN should not be considered to rule out the possibility of malignant thyroid tumor. The applicability of thyroid FNA in differentiating malignant from benign AFTN is limited. This is because ~50% of primary hyperfunctioning thyroid carcinomas are FTCs, which are difficult to distinguish from follicular adenoma by FNA. However, if follicular neoplasms in the thyroid nodule are detected by FNA, combined with high uptake in distant lesions on whole-body scan images and thyrotoxicosis, a diagnosis of metastatic hyperfunctioning thyroid carcinoma, FTC or FVPTC should be considered. Of the 5 metastatic hyperfunctioning thyroid carcinoma patients who underwent FNA, 2 cases were DTC (1 PTC and 1 FTC) and 2 cases were follicular neoplasms; therefore, these 4 patients were diagnosed with metastatic hyperfunctioning thyroid carcinoma. FNA may therefore facilitate the diagnosis of hyperfunctioning metastatic thyroid carcinoma. In 13 of 14 patients with no history of thyroidectomy who underwent thyroid scans, 6 cases demonstrated no increased uptake in the thyroid gland. For these patients, and for patients who develop thyrotoxicosis following total/subtotal thyroidectomy, a diagnosis of metastatic hyperfunctioning thyroid carcinoma should be considered and a whole-body scan should be performed with other additional imaging methods in order to identify metastatic lesions. Core needle aspiration and pathological analysis by H&E staining may also facilitate the diagnosis of primary or metastatic thyroid carcinoma. Hyperfunctioning thyroid carcinoma will require diagnosis by FNA or core needle aspiration and whole-body scanning, as well as confirmation of clinical thyrotoxicosis.

Drug management is considered more suitable for primary hyperthyroidism with Graves' disease. However, based on our clinical experience, favorable clinical benefits may be achieved with early surgery in cases with secondary hyperthyroidism caused by nodular goiter or thyroid adenoma. Furthermore, surgery can effectively cure patients with hyperthyroidism with non-functioning thyroid carcinomas. For the treatment of hyperfunctioning thyroid carcinoma, the primary aim is to control hyperthyroidism, as well as the cancer itself. Therefore, surgery, particularly total thyroidectomy, is the first-line treatment option for patients with primary hyperfunctioning thyroid carcinoma, as it does not only confirm the diagnosis following pathological examination, but also resolves thyrotoxicosis and cures the cancer. Of the 43 patients in the present study, all except 4 patients diagnosed preoperatively by FNA, were diagnosed with thyroid carcinoma following thyroid surgery. In addition, all 43 patients developed euthyroidism/hypothyroidism within a short time-period following surgery. However, total thyroidectomy may not be the optimal first-line treatment option for patients with hyperfunctioning metastatic lesions with non-functioning primary thyroid carcinoma (as indicated by no increased uptake on thyroid scintigraphy). This is because a total thyroidectomy is unable to control thyrotoxicosis and may even lead to deterioration, as the majority of hormones are produced by metastatic lesions. Of the 5 cases who had undergone total or subtotal thyroidectomy, postoperative thyrotoxicosis persisted in 3 patients, transient improvements were observed in 1 patient, and the remaining patient succumbed to thyroid crisis 12 days after surgery. In addition, the significance of total thyroidectomy in terms of 131I therapy was markedly lower in patients with low thyroid bed 131I uptake and intense 131I uptake in distant metastatic lesions. However, for patients with functional primary and metastatic tumors, total thyroidectomy may be the optimal primary treatment option, as it eliminates the hot primary thyroid carcinoma, which produces a certain amount of thyroid hormones, removes the thyroid gland and reduces the 131I dose required to treat the metastatic lesions. In addition, total thyroidectomy and subsequent pathological diagnosis may be particularly useful for patients who have not undergone a preoperative FNA.

RAI is necessary for treating hyperfunctioning metastatic lesions in patients with thyroid carcinoma (4); it is a first-line treatment option for patients with a history of thyroidectomy or for those with no increased uptake in the thyroid gland. To avoid a possible thyroid storm, pretreatment with antithyroid medication is required. Fractionated RAI (as for patient 66 in the present systematic review) (44), or minimal invasive local ablation may also be considered (as for patient 62 in the present systematic review) (40). If the metastatic lesion is resistant to RAI and the functioning lesion resectable, surgery may be considered as a treatment option. This was demonstrated in patient 65 (43), whose thyrotoxicosis disappeared following surgical removal of the functioning pelvic mass. However, it is difficult to evaluate the efficiency of RAI following surgery in patients with primary functioning thyroid carcinoma without metastasis. As the majority of primary hyperfunctioning thyroid tumors were large, and metastasis was reported during follow-up post-surgery, RAI was considered as a treatment option following surgery in patients with primary hyperfunctioning thyroid carcinoma (12,19).

In conclusion, the results of the present study indicated that the size of hyperfunctioning thyroid tumors is markedly larger, and primary or metastatic FTC is more commonly hyperfunctioning compared with PTC. FNA or core needle aspiration together with whole-body scanning may play a key role in the diagnosis of clinical thyrotoxicosis. In addition, surgery and RAI are the preferred treatments for primary and metastatic hyperfunctioning thyroid carcinoma, respectively. However, there were certain limitations to the present study: We evaluated studies using the Newcastle-Ottawa Scale and the scores of the studies ranged 2–4. Considering that the number of hyperfunctioning thyroid carcinomas is small and most studies are published as case reports, a risk of bias may exist and the results must be interpreted with caution.