Pattern of metastasis in differentiated thyroid carcinoma

Total 60 patients were selected as per described criteria from the department of Otolaryngology and head neck surgery, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from January 2005 to October 2006. In this study of 60 patients of differentiated thyroid carcinoma (DTC), majority of the patients are within 31-50 yrs age group with female predominance. Papillary carcinoma was more common in 31-40 yrs age group and follicular carcinoma was more common in 41-50 years. Thyroid swelling was the most common presenting symptom of DTC (91.66%), followed by cervical lymphadenopathy (33.33%). Among the 60 DTC patients, papillary carcinoma was commoner (73.33%) than follicular carcinoma (26.67%). Overall female-male ratio for these 60 patients of DTC was 1.72: 1, but in papillary type the ratio was 1.44:1. and for follicular carcinoma was 3:1. Out of 44 papillary carcinoma patients 18 patients had cervical lymph node metastasis (40.90%), and out of 16 follicular carcinoma patients 2 had cervical lymph node metastasis (12.50%); P < 0.05. Among the 44 papillary carcinoma patients only 1 had distant metastasis (2.27%), and among the 16 follicular carcinoma patients 4 had distant metastasis (25%); P <0.05. 85% of the patients were presented with unilateral and 15% were presented with bilateral lymph node metastasis. In this series, distant metastasis was found in bone and lung, Maximum lymph node metastasis was found in level II (42.10%), level III (57.89%) and level IV (42.10%). Finally the Chi-square (x2) significance test was performed according to above described findings and it was found that there is significant difference in the pattern of lymph node metastasis and of distant metastasis between papillary and follicular type of DTC (P<0.05).

Metastasis of differentiated thyroid carcinoma occur in two different ways lymphatic and haematogenous.Nodal metastasis occurs in 40% of papillary carcinoma and 4% of follicular carcinoma.On the other hand blood borne metastases are twice as common in follicular carcinoma then papillary group 7 .
Young patients with differentiated thyroid carcinoma typically present with regional lymph node involvement.Distant metastasis and extremes of age has poor prognosis.Distant metastasis is an aggressive with lethal consequence.Distant metastases are the principle cause of death from papillary and follicular carcinoma 1 .By multivariate analysis, any age at the time of diagnosis of distant metastasis (p < 0.0001) and involvement of multiple organ sites (p < 0.0003) were independently associated with cancer mortality.The highest risk of cancer death (92% at 5 years) was found in the 14 patients (any age), who at the time of first diagnosis of metastasis had multiple organ involvement 8 .
Lungs and bone are the commonest sites of distant metastasis 9 .At time of diagnosis of distant metastasis only lung 53%, bone 20% and multiple organ 16% were involved 10 .

Tumor Staging and Prognostic Scoring Strategies:
Several staging and clinical prognostic scoring strategies use patient age over 40 as a major feature to identify cancer mortality risk from differentiated thyroid carcinoma.When applied to the papillary carcinoma data from the Mayo Clinic, four of the schemes using age (EOTRC-European Organization for Research and Treatment of Cancer, TNM/tumor characteristics, lymph node involvement, and distant metastatic lesions, AMES/age of patient, presence of distant metastatic lesions, and extent and size of the primary cancer, and AGES/patient age and tumor grade, extent, and size), were effective in separating low-risk patients, in whom the 20 year cancer-specific mortality was 1%, from high-risk patients, in whom the 20 year cancer-specific mortality was 30% to 40%, with incrementally worsening metastasis, age, completeness of resection, invasion, and size (MACIS) scores of less than 6; 6 to 6.99; 7 to 7.99; and 8+; the 20-year survival rates were progressively lower: 99%, 86%, 59%, and 24%, respectively.
The American Joint Commission on Cancer (AJCC) TNM staging approach, which is perhaps the most widely used schemes, classifies tumors in all patient under age 45 as stage I and stage II (i.e., low risk), even those with distant metastases.Although, it has been widely verified to predict cancer mortality, TNM staging does not forecast the high number of recurrences that occur in patients diagnosed before age 20, which is true of all prognostic scoring systems that lend heavy weight to age 10  Prognostic importance of regional lymph node metastasis is controversial.In some study lymph node metastasis are not associated with worse prognosis 11 .But in others it is important especially in elderly patients.
But there are many studies where recurrence of diseases is higher in cervical lymph node metastasis that may be a marker for more aggressive differentiated thyroid carcinoma.
The associated cervical lymph node metastasis with an increase recurrence rate, a more aggressive differentiated thyroid carcinoma, low operative and radioiodine related morbidity support an aggressive approach for management of differentiated thyroid carcinoma with lymph node metastasis.
In contrast to squmaous cell carcinoma of head & neck, distant dissemination is not a death sentence for differentiated thyroid carcinoma.Long term survival of the patient with distant metastasis is quite satisfactory, in one study 43% overall survival compared with 80% survival in patient without distant metastasis 11 .
Few cases were also reported to involving brain, mediastinum, skin, liver, eye, Kidney and other organs 12 .
So pattern of metastasis is important in overall management of differentiated thyroid carcinoma.

Aims and Objectives General
To find out the relative frequency of both locoregional and distant metastasis in patients with differentiated thyroid carcinoma.

•
To find out the age and sex distribution.
• To find out the relative frequency of papillary and follicular type.
• To find out the pattern of metastasis.

Methods:
A detailed clinical history was taken from each patients about the thyroid swelling and its duration, any other neck swelling, neck pain, dysphagia, respiratory distress, cough, hoarseness of voice and any other body swellings.Any previous thyroid disease or surgery of the head neck, previous irradiation was also discussed during history taking process.A full head and neck examinations with special attention to thyroid region and cervical lymph nodes was noted.A brief general examination was also performed.A examination of larynx was also performed thoroughly with indirect or fiberoptic laryngoscopy.Then FNAC examination from the thyroid and neck node, ultrasonography, scanning examination, thyroid hormone levels were also performed.
Some of the patients were also investigated radiologicaly in the from of x-ray neck, chest, affected bones.CT scan and MRI were also performed in some of the patients for precise detection of spread of the disease.
Surgery was performed to the patients and the choice of surgery was detected by stage of the disease and others risk factors.During surgery under general anesthesia, neck palpation was also performed to detect metastatic lymph nodes.After performing surgery, the surgically excised thyroid and lymph node, some soft tissue were examined histophathologically.Most of the patients after surgery were followed up for 2/3 visit in an average of one month.Four patients with distal metastasis were treated with radio iodine ablation procedure.
Findings of every patients were documented as per data form.After compiling the results, they had been arranged and presented in various tables and figures.
On the basis of this results the significance of this study was tested statistically by using the Chi -Square test (x 2 ).x 2 value was compared with corresponding probability value.

Discussion:
Carcinoma of the thyroid gland is an uncommon Cancer, 0.6% and 1.6% of all cases of malignant neoplasia in men and women respectively 13 , but is the most common malignancy of endocrine system.Among them the differentiated tumors (papillary and follicular) are highly treatable and have a good prognosis.The incidence of this malignancy has increasing over the last decade.In a series of DTC cases in BSMMU Dhaka it has been shown that the incidence of DTC is increasing, like 3 cases in 1985 to 23 cases in 2000 1 .The cause this may be due to modern diagnostic techniques and increased cancer consciousness among the people.Yet this has been associated with a significant fall in mortality rate in some countries 1 .
The incidence of thyroid cancer in Bangladesh is not known.One study at INM & thyroid clinic in Institute of Post-graduate Medicine & Research (IPGMR) Dhaka reviewed 2629 thyroid patients from January 1994 to June 1995 and found thyroid carcinoma in 2.58% 14 .
The American cancer society estimates that 20700 new cases of thyroid cancers are diagnosed in 2002 in USA and that 1300 thyroid cancer related death occur annually 15 (AACE-2001).
In this prospective study of 60 cases of DTC we have tried to see mainly the pattern of metastasis in DTC, along with others variables like age, sex, operation findings etc.
In this series the high incidence of DTC is found in the 30 -50 years age group.This result correlates with that of Watkinson, 2000 3 where it was stated that although thyroid cancer can occur at any age, the majority of patients specially those with DTC are elderly.In adolescence and young adult thyroid cancers is predominantly of the well differentiated type.The peak incidence of the disease is in 4th decade in papillary and 5th decade in follicular.
It is predominantly a disease of women.The female to male ratio is 2.5:1 in a study 16 .In another study 17 , the female to male ratio is 3:1 and is related to patient's age.In this study shows a clear predominance of female over male in DTC.It is shown that overall female to male ratio is 1.72:1, for papillary it is 1.44:1 and for follicular it is 3:1.
In this study it is shown that out of 60 DTC cases 73.33% are of papillary & 26.67% are of follicular type, confirmed by postoperative histopathology.It shows a clear predominance of papillary over follicular carcinoma.According to the study 3 , frequency of PTC is 80% and that of FTC is 10%.Another study 16 shows that Papillary carcinoma comprises about 60% of all thyroid cancers, and follicular carcinoma comprises 18% of all malignant thyroid neoplasm 18 .Histological subtypes of both PTC and FTC were also found in this study.Out of 44 PTC patients, 40 were pure papillary, 3 were mixed papillary-follicular and 1 was follicular variant of PTC.Out of 16 FTC patients, 15 were of pure follicular variety and only 1 was Hurthle cell carcinoma.
The age distribution both for papillary and follicular variety in this study it is shown that, the peak incidence of papillary carcinoma in 31-40 years group and that of follicular in 41-50 years group.In other study 17 , it was stated that thyroid carcinoma is common in all age groups with FTC tends to occur more frequently in older adults than papillary carcinoma.
DTC may present in a variety of way, like that of primary site, local extension and that of local and distant metastasis.In this study it is shown that the main Distant metastasis to kidney, cerebellum and oesophagus have also been reported 21,22,23 .
Other reports of unusual distant metastasis also need to be express here.In one report ,24 shown unusual metastasis of papillary thyroid carcinoma to larynx and hypopharynx (not local extension).In other report 25 five documented brain metastasis with DTC out of 400 cases of thyroid cancer between 1972-1993.In another report 26 skull metastasis from thyroid follicular carcinoma with difficult diagnosis of the primary lesion.In a study 27 reported a case of solitary metastasis at right petrous apex, from occult follicular carcinoma of thyroid mimicking trigeminal neuralgia.In another study of 101 patients, has shown that the incidence of pulmonary metastasis is lowest in patient with papillary carcinoma (9%), compared with that of follicular carcinoma (13%).Involvement of recurrent laryngeal nerve, larynx, pharynx, trachea and oesophagus occur due to direct infiltration 28 .A direct associations between presence of externodal spread and occurrence of distal metastasis has also been reported in the series 29 .
In this study only 5 patients have distant metastasis out of 60 patients.This small number of patient is not enough to reflect the actual picture shown in other studies.
Up to 10% of differentiated thyroid carcinomas grow directly into surrounding tissues, increasing both morbidity and mortality.The invasion may be microscopic or gross and can occur with both papillary and follicular carcinomas.Recurrence rates are two times higher with invasive than noninvasive tumors.Up to one-third of patients with invasive tumors die of cancer within a decade 1 .
Local invasion by both type of DTC shows that structures involved by PTC are strap muscles and laryngeal extension.Structure involved by FTC are trachea, oesophagus, rec.laryngeal nerve and strap muscles.

Conclusion:
It may be concluded from the present series that proper diagnosis and accurate staging of patients of DTC should be done in a early stage, using different investigations like FNAC, histopathology, ultrasonography, CT Scan and MRI.Emphasis should also to be given in frozen section during surgery.Early and effective treatment for DTC make give good life expectancy, also in some cases reduce the mortality and morbidity.Further studies involving large number of patients and a long term follow-up are necessary to have more definite conclusion.

Table - I
Age distribution of patients of DTC (N = 60)

Table - IV
Histological type of DTC (Done by postoperative Histopathology)

Table - V
FNAC of finding of DTC (from thyroid) (N = 60)

Table - VI
FNAC Finding of neck node in DTC.(N = 60)

Table - VII
Cervical lymph node metastasis in DTC.(N = 60) Local invasion by thyroid carcinoma is a frequent finding.In this study local extension carcinoma was found in 2 PTC patients and 4 FTC patients during surgery.

Table - X
Cervical lymph node metastasis in DTC (N = 20)

Table - XIV
Local invasion findings during thyroid surgery.