Dec 4, 2001 - follicular carcinoma (FTC), 4 cases had papillary thyroid cancer (PTC). ... poorly differentiated carcinoma in 32.1%, 50.0%, and 17.9% of cases,.
World J. Surg. 26, 153–157, 2002 DOI: 10.1007/s00268-001-0198-x
WORLD Journal of
SURGERY © 2001 by the Socie´te´ Internationale de Chirurgie
Metastatic Differentiated Thyroid Carcinoma: Clinicopathological Profile and Outcome in an Iodine Deficient Area Anjali Mishra, M.S.,1 Saroj Kanta Mishra, M.S., D.N.B.,1 Amit Agarwal, M.S.,1 Birendra Kishore Das, M.D., A.N.M.,2 Gaurav Agarwal, M.S., D.N.B.,2 Sanjay Gambhir, D.R.M., D.N.B.2 1 2
Department of Endocrine Surgery, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, India 226014 Department of Nuclear Medicine, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, India 226014
Published Online: December 4, 2001 Abstract. Reports on metastatic differentiated carcinoma in endemic goiter regions are scarce. The aim of this study was to look into the clinicopathological profile and outcome of patients with metastatic differentiated thyroid carcinoma (DTC) of endemic origin. This was a retrospective study of 28 cases of metastatic DTC out of a total of 140 DTC patients managed between 1990 and June 1999. Demographic data, clinicopathological profile, operative and radioiodine ablation therapy details, and follow-up findings were noted. The overall incidence of distant metastases in our series was 20%. Mean age was 48.5 ⴞ 12.8 years (32.1% patients were < 45 years). Most metastases were detected synchronously (85.7%) and were multiple, with the skeletal system being the commonly affected site. Out of 22 cases having skeletal metastases, 6 patients were young (< 45 years). Though most patients with skeletal metastases had follicular carcinoma (FTC), 4 cases had papillary thyroid cancer (PTC). Near total or total thyroidectomy was done in 26 cases. Sixteen patients required regional lymph node dissection. Resection of metastases was performed in 9 cases. Histopathological diagnosis was PTC, FTC, and poorly differentiated carcinoma in 32.1%, 50.0%, and 17.9% of cases, respectively. Most patients had good symptomatic palliation following administration of I131 therapy. In 17.9% of cases there were locoregional recurrences. There was an overall 28.6% mortality. Two patients expired in the perioperative period. Six others died in follow-up (all within 3–9 months). In contrast to iodine sufficient regions, the incidence of metastases was high; the majority of cases had synchronous, symptomatic skeletal metastases. Skeletal metastases were not infrequent even in cases of PTC and in young patients. One-third of the cases were young. Though survival was poor despite aggressive management, significant symptomatic palliation could be achieved in most cases.
Distant metastases have variously been reported to occur between 4% and 20% of cases of differentiated thyroid cancer [1, 2]. The incidences vary considerably between papillary and follicular carcinoma [3]. In the absence of distant metastases differentiated thyroid carcinoma (DTC) is indolent malignancy. However, once metastasis is detected, the mortality rate becomes very high [3– 8]. Though radioiodine has been considered to be the preferred modality of treatment in such cases, the cure rate ranges between 30% and 40% [9 –13]. Surgical removal of metastases wherever feasible facilitates radioiodine therapy and complete cure can be Correspondence to: S.K. Mishra, M.S., D.N.B., e-mail: skmishra@ sgpgi.ac.in
achieved in few [3, 14, 15]. Though we have abundant literature from developed countries addressing this issue, not much information is available from endemically iodine deficient regions. In this study we have analyzed our data to document the clinicopathological profile and outcome of metastatic DTC and tried to look for significant differences from nonendemic regions.
Materials and Methods Out of 140 cases of DTC managed between 1990 and June 1999, there were 28 cases of metastatic DTC. Medical records of these cases were reviewed. Demographic data, clinicopathological profile of distribution of metastases, operative and radioiodine ablation therapy details, and follow-up findings were noted. The protocol followed for thyroid cancer management at our center is total thyroidectomy. In cases of preoperative cytologically confirmed lymph node metastasis, we perform lymph node dissection. Where lymph nodes are clinically negative and we find a lymph node more than 0.5 cm in the central compartment, we perform a central compartment lymph node dissection and sample the midjugular region. If a jugular lymph node is found positive (frozen section) then, we perform a lateral neck dissection. If the frozen section facility is not available, then we defer lateral compartment neck dissection until the final histopathology report is available. This is followed by a whole body radioiodine scan (WBRI) 6 weeks after surgery to detect residual and/or metastatic disease. Thyroxine suppression is given to all patients to keep serum TSH to undetectable levels. Radioiodine ablation is given when residual or metastatic disease is found. The dosages of radioiodine for ablation are 30 –50 mCi for thyroid remnant, 100 mCi for regional lymph nodes, and 150 –200 mCi for distant metastases. The scans are repeated at 6-month intervals and further radioiodine ablation is given as required. However, in the initial phase of this study four patients received multiple low dose radioiodine therapy as facilities for patient isolation following high dose radioiodine therapy were not available.
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Table 1. Clinical profile of metastases. Characteristic Detection Clinically symptomatic Detected on routine chest X-ray On first postoperative WBRI scan On subsequent WBRI scan Symptoms related to metastases (n ⫽ 20) Bone pain Swelling Pathological fracture Compressive myelopathy Site Lungs Skeleton Lungs ⫹ skeleton Brain secondary Skin Axillary lymph nodes
Table 2. Pathological features of primary tumor. n (%) 20 (71.4) 2 (07.1) 2 (07.1) 4 (14.3) 4 (14.3) 10 (35.7) 5 (17.9) 2 (07.1) 6 (21.4) 14 (50.0) 8 (28.6) 2 (07.1) 1 (03.6) 1 (03.6)
WBRI: whole body radioiodine.
Results The overall prevalence of distant metastases in our series was 20% (28/140 cases). The prevalence of metastases in papillary, follicular, and poorly differentiated carcinoma was 9.5%, 40%, and 50%, respectively. Twenty-three cases presented primarily at our institute, while 5 patients were referred from outside (1 after total thyroidectomy and 4 after less than total thyroidectomy procedures). Mean age of the patients was 48.5 ⫾ 12.8 years (range, 23–70 years). Nine patients (32.1%) were ⬍ 45 years of age and 17 (67.9%) were ⬎ 45 years of age. M:F ratio was 1:2.1. The mean duration of illness was 89.3 ⫾ 129.8 months (1 month–50 years). All the patients were clinically and biochemically euthyroid. Twenty-four patients presented with thyromegaly. Twelve (42.9%) patients had clinically palpable cervical lymph nodes. Metastases were synchronous in 24 (85.7%) and metachronous in 4 (14.3%) cases. Of the 20 cases (71.4%) having one or more symptoms related to metastases at the time of admission, 3 presented with symptoms primarily related to metastases. Two of them had skull secondaries that were excised outside (excised twice in one case). The third case presented with paraplegia due to metastatic follicular carcinoma. Pulmonary metastases were present in 14 cases, and skeletal metastases were present in 22 cases. Most of the cases had widespread metastases. Out of 6 cases, who had solitary metastases on preoperative evaluation, we could document the solitary nature of metastases in only 4 cases, because 2 patients did not report for postoperative WBRI scan. Some other important characteristics of metastases are summarized in Table 1. Histopathological findings and histopathological correlations are given in Table 2 and 3, respectively. The striking finding is that skeletal metastases were not so infrequent in young patients and in patients having papillary carcinoma. Besides primary surgery directed at achieving locoregional control of thyroid cancer, resection of metastases was done in 9 cases. The indication for resection of metastatic lesions was curative intent (3 cases of solitary metastases), symptomatic palliation (1 patient with paraplegia), and facilitation of radioiodine therapy (3 patients). Two patients who presented primarily with skull swelling had already had resected metastatic lesions. Details of operative procedures are summarized in Table 4.
n (%)
Feature Tumor characteristic Tx T1 T2 T3 T4a Histopathology Papillary carcinoma Follicular carcinoma Poorly differentiated carcinoma Other features Mean tumor diameter (cm) Bilateral tumors Multicentricity a
1 (3.6) Nil 5 (17.9) 7 (25.0) 15 (53.6) 9 (32.1) 14 (50.0) 5 (17.9) 6.4 ⫾ 3.5 6 (21.5) 5 (17.9)
Extrathyroidal invasion.
Table 3. Clinicopathological correlation of metastases. Site
Total no.
Median age
⬍ 45 years
PTC
FTC
Poorly diff. Ca.
Lungs Skeleton Lungs ⫹ skeleton Total
6 14 8 28
45 50.5 45.5
3 4 2 9
5 3 1 9
— 9 5 14
1 2 2 5
PTC: papillary thyroid carcinoma; FTC: follicular thyroid carcinoma; diff. Ca.: differentiated carcinoma. Table 4. Operative details. Operative procedure Thyroid surgery (n ⫽ 27) Total thyroidectomy Near total thyroidectomy Completion thyroidectomy Subtotal thyroidectomy Incisional biopsy Lymph node dissection (n ⫽ 16) Modified radical neck dissectiona Radical neck dissectionb Superior mediastinal lymph node dissection Metastasectomy (n ⫽ 9) Partial sternal excision Hemimandiblectomy Clavical excision Excision of skull secondary Excision of axillary lymph node Laminectomy
No. 16 5 4 1 1 10 6 5 2 2 1 2 1 1
a Lymph node dissection leading to preservation of at least one of three vital structures in the neck (spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle). b Lymph node dissection leading to sacrifice of all the three vital structures in the neck (as above).
Two patients expired in the postoperative period: 1 patient on the 4th postoperative day due to compressive cervical myelopathy secondarily to metastases in the cervical vertebrae resulting in paralysis of the diaphragm and respiratory failure. The second case, who had a low tracheostomy, had an accidental dislodgement of the tracheal tube followed by cardiac arrest. All the surviving patients received thyroxine suppressive ther-
Mishra et al.: Metastatic Thyroid Cancer
apy. Mean duration of follow-up was 23.9 ⫾ 21.4 months (3–74 months). Five patients refused adjuvant radioiodine therapy and were lost to early follow-up. Later on 2 of these were reported dead by their relatives. One more presented 6 months after surgery with widespread painful skeletal metastases. As this patient refused radioiodine ablation, he was referred for palliative radiotherapy. He was subsequently lost to follow-up. Twenty-one patients received radioiodine therapy. Mean dose of I131 received by the patients was 377 ⫾ 248 (70 –903) mCi. Though no patient could be rendered disease-free, all except 1 had significant symptomatic improvement. Five (17.9%) patients developed locoregional recurrence within the follow-up period ranging from 2 months to 48 months (median 12 months). Out of these, 2 recurred in the thyroid bed and 3 in the cervical lymph nodes. Reexcision was done in 4 cases. One patient had inoperable local recurrence in the thyroid bed and refused to undergo further treatment. Six patients expired during follow-up within 3–9 months; all had skeletal metastases. Two of these had refused radioiodine ablation. All the rest were alive with disease at their last follow-up. Even the cases who had metastases detected on postoperative iodine scan had progression of disease. But significant symptomatic palliation was achieved in most of the cases after radical surgery followed by TSH suppressive therapy and radioiodine ablation. Discussion In cases of well-differentiated thyroid carcinoma, 4%–20% develop distant metastases [1, 2]. Less than 1% of all patients with papillary carcinoma and 3%– 4% of patients with follicular carcinoma have distant metastases at the time of diagnosis [13, 16, 17]. Seventy-five percent of patients who develop distant metastases do so within 5 years. The prevalence of distant metastases in our series was 20%. Whether this high prevalence is due to delay in seeking medical advice (mean duration of illness 89.3 ⫾ 129.8 months) or is the true high incidence is difficult to say. Similar to other series the incidence of distant metastases was higher in follicular carcinoma as compared to papillary carcinoma [3]. Distant metastasis is associated with advanced clinical stage of disease, male sex, and old age; however, the conditions are not determinants for distant metastases [18]. Similar findings were present in our series, but one-third of our cases were less than 45 years of age. The mean age in our series at 48.5 ⫾ 12.8 years is considerably lower than other series [3]. Metastases diagnosed before surgery have a more negative effect on survival as compared to those cases diagnosed on follow-up [9]. In our study, 85.7% of our cases were diagnosed before surgery. Despite the indolent behavior of DTC, the appearance of distant metastases significantly worsens the prognosis [3– 8]. However, the prognosis is still better as compared to other carcinomas. The 5-year survival in patients with lung metastasis from DTC was at worst 29% if the metastases did not show radioiodine uptake and as high as 61% if I131 uptake was seen [19]. The fractional and cumulative dosages used for radioiodine ablation in our series are comparable to other groups [3, 5, 9, 14, 20]. Cumulative survival in patients having resectable lesions has been reported as high as 44.8%– 67% at 5 years [14, 15]. According to Wood et al. [15], factors that may be associated with less favorable outcome are multiple sites of metastasis and an interval of less than 5 years between treatment of the primary tumor and discovery of the first
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metastasis. Other bad prognostic factors are extensive metastases, greater age at discovery of metastasis, absence of radioactive iodine uptake, and moderately differentiated follicular cell type [4]. As soon as metastases develop there is no prognostic difference between papillary and follicular carcinoma. Lung metastases are common in young patients with papillary carcinoma, while bone metastases are common in older patients with follicular carcinoma. Bone metastases were never found in young patients in most previous series [3, 6, 7, 21]. Lung metastases are favorably affected by radioiodine. The occurrence of bone metastases alone or in combination with other sites significantly worsens the prognosis [3]. As also reported previously by Wood et al. [14], many of our primary tumors were in an advanced stage with features of extracapsular extension (76%), large tumors (76% ⬎ 3 cm), multifocality, and positive lymph nodes (62%). The tumor diameter in our series was considerably larger than previously reported [14] (Table 5). Poorly differentiated cancer cells have been reported as an important finding in predicting pulmonary metastasis in differentiated carcinoma of the thyroid [21]. However, most series have not addressed the issue of poorly differentiated thyroid carcinoma in detail. For metastatic DTC, preferred therapy is consistent repetitive treatment with radioiodine. Samaan et al. [19] have reported survival benefits in patients treated with radioiodine as compared to those not treated. Though survival benefit could not be shown, others have also demonstrated that treatment with I131 is one of the factors that account for survival. Patients whose metastases concentrate I131 and who could be treated with radioiodine had higher survival rates [20]. The cure rate ranges between 30% and 40% [4, 9 –13]. The efficacy of radioiodine therapy depends on the size, location, and number of distant metastatic lesions. Micronodular diffuse lung metastases, revealed by whole body scan in the absence of significant radiographic changes, have the greatest chance of favorable response to I131, and complete remission is achieved in most cases [9, 10, 21]. Complete remission is also reported in some isolated bone metastases of small size, detectable by whole body iodine scan, but not by radiography [3, 4, 9, 11]. However, in our series even the cases who had metastases detected on postoperative iodine scan had progression of disease, and we did not have a single case of minimal skeletal metastases. Considering the radioiodine insensitivity of bone metastases, surgical treatment has been recommended by many workers [3, 9, 14, 15]. Niederle et al. [14] have recommended even complicated surgical treatment, because it has a favorable effect on prognosis and the patient’s quality of life. In our series also, patients had improved quality of life and significant palliation even in the face of widespread metastases. The clinical presentation and biological behavior of metastatic DTC in an endemically iodine deficient area seem significantly different from that of an iodine sufficient area (Table 5), although, considering the retrospective nature and different patient selection criteria in the available literature, a definite conclusion cannot be reached. However, with our experience we wish to emphasize certain findings. Though DTC is believed to be an indolent tumor, one-third of our patients with metastatic DTC were young and were otherwise in a low risk group. The overall incidence of metastases was high. Second, the incidence of metastases in papillary thyroid cancers was also high as compared to other series. In contrast to iodine sufficient regions, the majority of cases had
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Table 5. Comparison of clinicopathological profiles of SGPGI patients with literature from industrialized countries.
Characteristics
SGPGI (India) (n ⫽ 28)
Niederle [14]a (Austria) (n ⫽ 45)
Wood [15] (USA) (n ⫽ 56)
Ozaki [22]b (Japan) (n ⫽ 59)
Hoie [23]c (Norway) (n ⫽ 91)
Mean age (years)
48.5
56
40.5
—
Prevalence (%) Synchronous Skeletal Distribution (%) T0 Tx T1 T2 T3 T4 Other features Tumor diameter (cm) Extrathyroidal invasion (%) Bilateral tumors (%) Lymph nodes ⫹ (%) Histopathology Papillary (%) Follicular (%) Poorly differentiated (%)
20.0 85.7 78.6
56.9 (M) 59.2 (F) — 64.5 91.1
— — 43.0
10.0 — —
— 3.6 — 17.9 25.0 53.6
— — — — — —
— — — — — —
— — — — — —
12.4 34.1 18.7 (n ⫽ 82) 8.5 (7) — 40.2 (33) 17.1 (14) 24.4 (20) 9.3 (8)
6.4 53.6 21.5 53.6
— 22.0 13.0 18.0
24% ⬍ 3 cm 76 (19/25) — 62 (10/16)
4.8 56.0 — 71.0
— 33.0 (30/91) 52.0 (27/52) 92.5 (62/67)
32.1 50.0 17.9
9 91
51 44
71.2 28.8
100
SGPGI: Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow. Series consist exclusively of: asurgical resection of metastases; bpulmonary metastases; and cpapillary carcinoma.
synchronous, symptomatic metastases with the skeletal system being the commonest affected site. Similar to other series, incidence of distant metastases was high in follicular carcinoma and poorly differentiated carcinoma. Despite aggressive management the outcome was poor in terms of survival, with one-third of cases already dead with a mean follow-up of only 23.9 ⫾ 21.4 months. Considering the available literature, we believe our survival rate at 5 years might be lower. However, significant symptomatic palliation was achieved in most cases. Whether the explanation for such poor outcome is the advanced stage at presentation or inherent aggressive biological behavior needs to be explored further. Résumé. On connat peu de publications concernant le cancer métastatique différencié dans les régions de goitre endémique. Le but de cette étude a été d’analyser le profile clinico-pathologique et l’évolution des patients porteurs d’un cancer différencié de la thyroïde (CDT) métastatique d’origine endémique. On rapporte ici les résultats de 28 cas de CDT métastatique sur un total de 140 patients porteurs d’un CDT, traités entre juin 1990 et juin 1999. Les caractéristiques, le profile clinicopathologique, les données de l’exérèse chirurgicale et de la radio-ablation ainsi que du suivi ont été enregistrées. L’incidence globale de métastases à distance dans notre série a été de 20%. L’âge moyen des patients a été de 48.5 ⴞ 12.8 ans (32.1% patients avaient plus de 45 ans). La plupart des métastases étaient multiples et ont été détectées de façon synchrone (85.7%): le squelette a été le site le plus fréquemment intéressé. Parmi les 22 patients porteurs des métastases squelettiques, six étaient jeunes (< 45 ans). Bien que la plupart des patients ayant des métastases squelettiques sont porteurs d’un cancer folliculaire (CTF), il s’agissait dans quatre cas d’un cancer papillaire (CTP). On a réalisé une thyroïdectomie totale ou presque totale dans 26 cas. Seize patients ont nécessité un curage loco-régional et neuf patients ont eu une résection de métastases. Le diagnostic histologique a été un CTP dans 32.1%, un CTF dans 50.0% et un cancer indifférencié dans 17.9% des cas. La palliation symptomatique a été satisfaisante chez la plupart des patients après administration d’I131. Des récidives loco-régionales ont été constatées dans 17.9% des cas. La mortalité globale a été de 28.6%. Deux patients se sont éteints en période post-opératoire. Six autres sont décédés pendant le suivi (tous avant 3–9 mois). Au contraire de ce qui se passe en régions
normalement pourvues en iode, l’incidence de métastases était élevée, la majorité des patients avait des métastases du squelette synchrones, symptomatiques. Les métastases du squelette ne sont pas rares même en cas de CTP et chez les patients jeunes (un tiers des cas). Bien que la survie soit médiocre malgré un traitement agressif, on a pu obtenir une palliation symptomatique dans la plupart des cas.
Resumen. Los informes sobre carcinoma diferenciado metastásico en regiones geográficas de bocio endémico son escasos. El propósito del presente estudio fue investigar el perfil clínico-patológico y el resultado final en pacientes con carcinoma diferenciado metastásico (CDT) de origen en regiones endémicas mediante el estudio retrospectivo de 28 casos de CDT metastásico entre 140 pacientes con CDT manejado entre 1990 y junio de 1999. Se registraron los datos demográficos, el perfil clínico-patológico, los detalles de la terapia de ablación mediante yodo radioactivo y los hallazgos durante el período de seguimiento. La tasa global de metástasis fue 20%. La edad promedio fue 48.5 ⴞ 12.8 años (32.1% de los pacientes fueron mayores de 45 años). La mayoría de las metástasis (85.7%) fue detectada sincrónicamente y éstas fueron múltiples, con el esqueleto como la ubicación más frecuente. De 22 casos con metástasis esqueléticas, seis eran personas jóvenes (< 45 años). Aunque la mayoría de los pacientes con metástasis esqueléticas tenía carcinoma folicular (CFT), 4 presentaron cáncer papilar (CPT). Se practicó tiroidectomía casi total o total en 26 pacientes, y 16 requirieron disección ganglionar regional. La resección de metástasis fue realizada en 9 casos. El diagnóstico histopatológico fue CPT, CFT y carcinoma pobremente diferenciado en 32.1%, 50% y 17.9%, respectivamente. La mayoría de los pacientes obtuvo buena paliación sintomática luego de terapia con I131; 17.9% exhibieron recurrencias loco-regionales y se registró mortalidad de 28.6%; dos pacientes expiraron en la etapa perioperatoria y ostros 6 lo hicieron en el curso del seguimiento (todos dentro de los primeros 3–9 meses). Contrario a lo que ocurre en regiones con suficiencia de yodo, la incidencia de metástasis fue elevada y la mayoría de los pacientes presentó metástasis esqueléticas sintomáticas sincrónicas. Las metástasis esqueléticas fueron comunes, aun en casos de CPT en pacientes jóvenes. Un tercio de los pacientes eran jóvenes. Aunque la supervivencia fue pobre a pesar de un manejo agresivo, se logro mejoría sintomática en la mayoría de los pacientes.
Mishra et al.: Metastatic Thyroid Cancer
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