Risk group-based management of differentiated thyroid carcinoma

*Division of Head and Neck Surgery and Oncology, Department of Otolaryngology, and †Department of Pathology, New York University School of Medicine, New York, New York, #Division of Head and Neck Surgery and Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA

A number of controversies exist in the treatment of differentiated thyroid carcinoma with respect to the extent of surgery, use of radioactive iodine and post-operative thyroxine suppression. Recent recognition of prognostic factors has helped to assign patients, based on their risk profile, as being at high risk of developing recurrence. This has facilitated the development of a selective approach to therapy, thus, avoiding unnecessary treatment and reducing morbidity without compromising treatment outcome. This review attempts to evaluate the current concepts of management of differentiated thyroid carcinoma in the light of these new developments.

Key words: Follicular thyroid cancer, papillary thyroid cancer, prognosis, risk factors, thyroid neoplasm

The term ‘differentiated thyroid carcinoma’ includes papillary and follicular carcinoma with all its histological variants. The histopathologic characterists are summarised in Figures 1-4. The differentiated thyroid cancer represents 98% of all thyroid cancers. Despite the low mortality from thyroid cancer treatment remains controversial. Most important is the appropriate selection of the type and extent of treatment. Although thyroid cancer has a relatively indolent clinical course, a subset of these tumours is clinically aggressive and, in some patients, fatal. Recent recognition of prognostic factors and validation in large series of patients has helped to identify the patients at high risk of developing recurrence and to initiate treatments which are appropriate to the risk profile of an individual patient. This has facilitated the development of a selective approach to therapy, thus, avoiding unnecessary treatment and reducing morbidity without compromising the treatment outcome. This review attempts to evaluate the current concepts and controversies of management of patients with differentiated thyroid carcinoma

Several controversies currently exist regarding the management of differentiated thyroid cancer. These include the extent of surgical resection, role of radioiodine treatment, thyroxine suppression and treatment of the lymphatic drainage to the neck.

Whether a patient with differentiated thyroid carcinoma should undergo total thyroidectomy or thyroid lobectomy and isthmusectomy (limited thyroid surgery) is one of the most contested treatment issues.

Proponents of total thyroidectomy for all patients with differentiated thyroid carcinoma argue the need based on the following reasons: (1) high incidence of microscopic multi-focal disease, (2) to facilitate radioactive iodine for the detection and treatment of residual disease, (3) to allow the use of thyroglobulin as a marker for recurrent disease, and (4) possibility of anaplastic transformation of any microscopic foci of carcinoma.

Those who propose limited thyroid resection (lobectomy with isthmus resection) argue that without documented benefit of total thyroidectomy in low-risk patients, even the small increased risk of permanent hypoparathyroidism (4% to 9%) and recurrent nerve damage (1% to 8%) is not justifiable. ^1,2Limited thyroid resection may avoid life-long thyroid hormone replacement, a legitimate concern especially in patients with limited compliance. The presence of microscopic multifocal disease has no clinical importance, as shown by the very low incidence of recurrence in the residual thyroid lobe following thyroid lobectomy. The incidence of anaplastic carcinoma from potential residual microscopic disease is extremely rare.

Among the patients presenting with differentiated thyroid cancer about 75% will lie in the low-risk group. They have a low recurrence rate (<5%) and excellent survival rate (>98%). In this group of patients, extent of thyroidectomy has no impact on the outcome. The multivariate analysis by Cunningham et al. (1990) failed to show any advantage of total thyroidectomy over lesser procedures.3 The retrospective matched pair analysis by Shah et al (1993) also has concurred with this finding.4 Thus, there is good clinical evidence to support limited thyroid surgery in patients presenting with low-risk differentiated thyroid cancer.

The current clinical evidence suggests that patients with high-risk differentiated thyroid cancer would benefit from total thyroidectomy for maximum local control and the ability to treat metastatic foci with radioiodine treatment. Total thyroidectomy is also generally accepted for patients with a prior history of head and neck irradiation and clinically abnormal contralateral thyroid lobe. The intermediate-risk group requires an individualised treatment policy based on the prognostic factor profile.

Figure 1: Follicular Carcinoma. H and E staining showing characteristic features for follicular carcinoma. a) (3.76X magnification) Thyroid nodule showing thickened capsule and a nodule composed of small thyroid follicles. Notice that the edges of the follicle are irregular and appear to infiltrate into the fibrous capsule. b) (9.4X magnification) and d) (37.6X magnification) Tumour cells within the vascular space confirming vascular invasion. c) (56.4X magnification) Shows the morphology of the carcinoma of relatively small follicular architecture with somewhat enlarged cells.

Radioiodine is used in the management of differentiated thyroid carcinoma based on the premise that normal, as well as malignant thyroid tissues, have selective uptake of radioactive iodine. It is used in various situations including screening for distant metastases, ablative treatment of residual normal thyroid tissue and treatment of distant metastases. Whether all patients with differentiated thyroid cancer should be reviewed and treated is controversial. In a recent survey of 233 thyroid experts 61% advised routine postoperative radioiodine treatment.⁵

Two recent retrospective studies have demonstrated that adjuvant radioiodine treatment reduces recurrence in patients with differentiated thyroid cancer. ^6,7 One of these studies also has found a significant advantage for survival in the radioiodine treated group.6 No other studies have confirmed these findings. Several independent investigators have reported no significant advantage of using radioiodine in preventing disease recurrence of differentiated thyroid carcinoma. ^8,9,10 Also, no obvious correlation has been found with respect to the survival rate of patients with differentiated thyroid carcinomas, even in high-risk cases, treated by adjuvant radioiodine. ^10-14

One of the major arguments for the routine use of radioiodine is to eliminate possible microscopic multifocal disease. As discussed in the previous section, however, multifocal microscopic disease does not have any prognostic significance in differentiated thyroid carcinomas. The debate of radioiodine treatment and the extent of thyroid surgery are inseparable. If routine adjuvant radioiodine treatment is recommended then all patients should undergo total thyroidectomy, as presence of normal thyroid tissue negates the efficacy of radioiodine treatment.

The controversy of radioiodine treatment can be effectively addressed with the application of prognostic factors and risk group analysis. Based on the available clinical evidence it can be said that patients with low-risk differentiated thyroid cancer can be managed effectively by limited thyroid surgery without adjuvant radioiodine treatment. As the incidence of distant metastases in this group of patients is very low (1 to 7%) they also do not need to undergo surveillance using radioiodine scanning.^2,15-17

The patients with distant metastases clearly need total thyroidectomy and postoperative radioiodine treatment. It is recognised that in about 25% of patients with distant metastases fail to concentrate radioiodine. ¹⁸ The patients with high-risk tumours may also benefit from having a radioiodine scan, ablation (if uptake is >1-2%), and follow-up screening. Treatment of the patients in the intermediate risk group should be individualised based on the risk factor profile.

Figure 2: Follicular adenoma with H¸rthle cell change. b) (3.76X magnification): Shows a follicular adenoma (right) and thyroid tissue with H¸rthle cell change (left). a) Shows the H¸rthle cell change in which each of the thyroid cells is enlarged with eosinophilic cytoplasm and variably sized nucleus. Some of these cells may show aneuploidy, however, this is not a definite diagnostic criteria for malignancy. The adenoma is composed of small thyroid follicle (d) with minimal cellular pleomorphism (c).

Adjuvant thyroxin treatment is given to maintain a low thyroid stimulating hormone level so as to suppress the activity of thyroid tissue through the thyroid-hypothalamus-pituitary negative feedback axis. Cunningham et al (1990) in a multi-variate analysis of differentiated thyroid carcinoma reported its effectiveness in improving survival rate in patients over 50,3 a finding others have confirmed. ^19,20 The current literature is in agreement that all patients with differentiated thyroid carcinoma will benefit from thyroxin suppression treatment. A thyroid-stimulating hormone level which is below normal but easily detectable has been shown to be equally effective as a nondetectable thyroid stimulating hormone level. ²¹ Despite concurrence about the detrimental effect of thyroxine suppressive therapy on bone density, Marcocci et al (1994) demonstrated that carefully monitored suppressive therapy is not associated with bone loss in pre-menopausal women.²²

Unlike other mucosal malignancies, overall, cervical nodal metastasis has no prognostic significance in differentiated thyroid carcinoma. This supports the general practice of not performing elective neck dissection, despite the estimated 50% incidence of occult metastases. In patients over 45 years of age, cervical nodal metastases is a poor prognostic factor. ¹⁵ It is not certain whether these patients will benefit from elective neck dissection, node sampling or routine radioiodine treatment.

The patients with palpable nodal disease should undergo modified comprehensive neck dissection covering levels I to VI. As the common site of nodal metastases is to the central compartment nodes (para and pre-tracheal group), this should be included in the procedure.²³ In the case of incidental metastatic cervical lymph node metastases without a clinically detectable thyroid abnormality, an expectant follow-up with thyroxine suppression is acceptable. ^24,25

Figure 3: ‘Tall Cell’ follicular variant of papillary carcinoma. This variant of papillary carcinoma may be difficult to distinguish from follicular adenoma. a) A nodule within a follicular adenoma. This nodule consists of larger cells with large and pale nuclei, making the nodule appear pale at low magnification compared with the surrounding thyroid follicles. This lesion is considered a variant of papillary carcinoma because it shares virtually all of the cytologic features of a papillary carcinoma and having papillary structure. b-d) Show a neoplastic follicle composed of large cells and pale nuclei. Nuclear grooving, cellular crowding, cellular enlargement and nuclear inclusions are identified.

Although the majority of patients with differentiated thyroid cancer have a favourable prognosis, it has a poor outcome in a subset of patients. In the recent past, several large retrospective studies have identified various patient and tumour-related factors with prognostic significance in differentiated thyroid cancer.^2,3,15,26,27 These studies have further stratified patients into well-defined risk groups and have helped to develop a rationale treatment policy. ^17,28,29,30Recognition of this risk group has helped clinicians to institute a selective treatment approach.

Different prognostic factors evaluated in these studies are age, primary tumour size, extrathyroidal extension, distant metastases at presentation, histology, gender, nodal status and focality of the tumour.

Since first recognised by Craver (1925), age has been identified as an important predictive factor by many independent investigators, with the younger age group of patients showing a favourable prognosis. ^17,30-33 The cut off age used by different studies varies from 40 to 50 years. Fifty years was used by Cunningham et al (1990), 40 years for men and 50 years for women by the Lahey Clinic and 45 years by the Memorial Sloan-Kettering study. ^3,15,26 It was initially thought that the age of the tumour was more important than the age of the patient. No biological evidence for this notion is currently available. There is no real evidence that the aggressiveness of thyroid carcinoma increases with time. The histological features remain the same irrespective of the age. There are only a few reports of anaplastic carcinoma arising from a preexisting differentiated thyroid carcinoma. ³⁴

Gender only has a weak prognostic significance, with women showing a better survival advantage than men.3 However, on detailed analysis of the data this result appears to be related to a younger age distribution among women. So if age is also taken into account gender does not have prognostic significance. ¹⁵

Figure 4: Papillary carcinoma. This is a classical papillary carcinoma with focal psammona bodies (laminated calcification), papillary structures and cells with nuclear grooving, cellular crowding, cellular enlargement and nuclear inclusions.

All the large clinical series are in agreement that a tumour size over 4 cm and clinical evidence of extrathyroidal extension are poor independent prognostic factors. ^3,15,26,27 Both univariant and multivariant analysis of these studies have concurred that distant metastases, at the time of presentation, is an ominous sign.³⁵

Histology of the tumour as a prognostic factor is controversial. Though the Lahey Clinic and Sloan-Kettering studies have suggested that the histology of the tumour has prognostic significance, both these studies have significant flaws in their methodology. Even though these studies attempted to differentiate papillary from follicular tumours, H¸rthle cell tumours were grouped under follicular lesions and mixed papillary-follicular growths with the papillary lesions. Further reports from the Sloan-Kettering series have shown that there is a significant difference in survival between H¸rthle cell and non-H¸rthle cell tumours (69% vs. 85%). ³⁶ There was no difference, however, in survival of patients having pure papillary or mixed papillary-follicular lesions. ³⁷ None of the large published series have addressed the rare histological variants; tall cell type of papillary thyroid carcinoma and insular or oxyphilic variants. The tall cell variant of papillary thyroid carcinoma is generally considered to have a poor prognoisis. ³⁸

Unlike other malignant tumours, presence of lymph node metastases, in general, is not regarded as an unfavourable prognostic factor in thyroid carcinoma. ^3,15,26 This is primarily because of the close association of nodal metastases with younger patients, a strong favourable prognostic factor.3 Further detailed analysis was carried out by Hughes et al (1994), using match-pair analysis of a large group of patients with differentiated thyroid carcinoma. ³⁹ This has shown that though the patients with nodal metastases had a higher incidence of recurrence the overall survival rate was not influenced by this sign. But when age of the patient also was taken into account nodal metastases in older patients with thyroid cancer was found to be an unfavourable prognostic factor. In younger patients, however, the nodal metastases was found to be a favourable feature. The reported incidence of occult metastases in clinically N0 patients with differentiated thyroid carcinoma is 50%. ⁴⁰ Even with this high incidence cervical nodal progression and recurrence is an uncommon event. ⁴¹

The reported incidence of multifocal tumours varies from 17% to 37%. ^2,17,41 Serial sectioning of the thyroid gland with differentiated thyroid carcinoma has shown evidence of multifocal disease, in up to 87.5% of glands. 42 Even with this high incidence of multifocal disease the incidence of recurrence of cancer in the unresected lobes is only 4.6% to 8%. ^34,43,44 Results from several large series are in agreement that multifocal disease does not adversely influence the survival rate. ^3,26 The differentiated thyroid carcinoma is quite unique in that the presence of microscopic and multicentric disease has minimal clinical significance.

In the recent past, many groups have developed a system of assigning patients with differentiated thyroid carcinoma into well-defined risk groups. This has enabled clinicians to develop a rationale treatment policy with predictable outcome.

Cadey and Rossai (1988), from the Lahey Clinic, identified age, distant metastases at the time of presentation, extra-thyroidal extension, gender and histology as significant prognostic factors (AMES). ³² Based on these factors, they assigned patients into low-risk and high-risk groups. According to this system, patients younger than 40 years (men) or 50 years (women) of age without distant metastases and patients (regardless of age) with cancers less than 5 cm, no extrathyroidal extension and no micro-invasive follicular histology are assigned to the low-risk group. The rest of the patients were grouped in the high-risk category. Of the 821 patients analysed in this study, 89% of the patients had low-risk and 11% had high-risk cancers. The disease-free survival rates were 98.2% and 54% for low- and high-risk patients, respectively. The recurrence rates were 5% and 55% for lowand high-risk groups, respectively.

The Mayo Clinic investigators developed an elegant scoring system, based on their review of 858 patients with papillary thyroid carcinoma. ²⁷ This incorporates age, tumour grade, extent of disease and tumour size (AGES). A score of less than 6 constituted a low-risk and had a 25-year survival rate of 87%. Patients with a score of more than 6 constituted a high-risk and had a 25-year survival rate of 35%. This system was further modified by removing tumour grade; a feature difficult to duplicate by other centers. This modified system is based on distant metastases, age, tumour size and extra-thyroidal extension (MACIS). ⁴⁵

A retrospective multivariate analysis of 1355 patients at Ohio State University have identified age, time to treatment, extrathyroidal extension, lymph-node metastases, extent of surgery, radioactive iodine treatment and gender as independent prognostic factors.6 Based on these risk factors patients were grouped into four stages. Stage 1 and 2 consisted of all patients with growths less than 4.5 cm, with or without cervical nodal metastases, without extrathyroidal extension or distant metastases. This group had 83% of the patients and had a survival rate of 97%. Stage 3 and 4 tumours include all growths larger than 4.5 cm, with extrathyroidal extension, with or without distant metastases. This group accounted for 17% of the cases and had a survival rate of 79%.

The Memorial Sloan-Kettering Cancer Institute series consisted of 1038 patients. Mutivariant analysis of these patients identified age, tumour size, extrathyroidal extension, distant metastases and histology as significant prognostic factor. 15 They introduced a third, intermediate-risk group. ¹⁷ This consisted of low-risk patients (<45 years) with high-risk tumours and high-risk patients (>45 years) with low-risk tumours (Figure 5). Forty-five per cent of the patients were in the low-risk group and the 20-year disease free survival of these patients were 90%. Thirty-three per cent of the intermediate-risk group of patients had a 20-year survival rate of 85% and 22% of the high-risk group of patients had a survival rate of 57%. Introduction of a third group has increased the discriminatory power of the risk groups.

The identification of prognostic factors and risk group assignment of differentiated thyroid carcinoma has helped to formulate a selective treatment approach (Figure 5). Such a treatment policy can spare many patients the morbidity of unnecessary treatment, in a cost-effective manner without compromising treatment outcome. In spite of the vast body of literature to support this treatment approach, controversy and inconsistency of treatment still persists. It is hoped that the risk group assignment will serve as a staging system for the differentiated thyroid carcinoma and will provide a rationale and selective treatment approach.

During the past years advances have been made in the understanding of the molecular mechanisms involved in the initiation and progression of thyroid carcinoma. With the better understanding of the genetic basis of thyroid carcinoma, it is quite likely that molecular prognostic markers will converge, which may prove to have a better prognostic significance that the current risk-group assignment based on the demographic and morphologic profile.

Key mutations of both oncogenes and tumour suppressor genes have been identified during thyroid cancer development. Mutations of gsp and TSHR genes have been recognised during the process of transformation of toxic nodules to adenoma; ras and probably gsp gene mutations have been observed during the transformation of follicular adenoma to follicular carcinoma. As in medullary thyroid carcinoma and MEN syndrome, ret proto-oncogene mutations is now established as a significant finding in radiation-induced papillary thyroid carcinoma.⁴⁶ This mutation is observed in as high as 50% of papillary cancers. This consists of juxtaposition of the 3’ or tyrosine kinase domain of the RET gene (which codes for a receptor protein not normally expressed in follicular thyroid cells) with the 5’ domain of ubiquitously expressed genes, which provide the promoter and dimerization functions, necessary for the constitutive activation of RET/PTC proteins.⁴⁷ The p53 mutation has been implicated in dedifferentiation of thyroid carcinoma and in anaplastic thyroid carcinomas.⁴⁸

The clinical significance of these genetic markers is not well established. The presence of the mutation does not seem to influence the biological behavior of the tumour or its response to conventional treatment modalities. ⁴⁹ In the future, integration of these discoveries into a prognostic staging scheme may allow us to better predict the biological behavior of cancers in individual patients.

	Low-risk	Intermediate-risk	High-risk
Criteria
Age:	<45 years	>45 years <45 years	>45 years
Tumour size	<4cm	<4cm >4cm	>4cm
Histology:	favourable	favourable unfavourable*	unfavourable*
Extrathyroidal extension:	No	No Yes	Yes
Distant metastases:	No	No Yes	Yes
Nodal metastases:	+/-	- +/-	+
Treatment
Therapy options
Thyroid surgery:	Limited	Individualised	Total
Thyroxine:	Yes	Yes	Yes
Radioiodine	No	+/-	Yes

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Copyright date: 12th June 2001
Correspondence: M Abraham Kuriakose, School of Medicine, Suite 7U, Skirball Building, 530 First Avenue, New York, NY 10016, USA