Endocrine Journal 1999, 46 (1), 209-216

NOTE

Symptomatic versus Asymptomatic Papi

Microcarcinoma: A Retrospective Analy

Outcome and Prognostic Factors

Ilary Thyroid

sis of Surgical

IWAO SUGITANI AND YosHIHIDE FUJIMOTO

Division of Head and Neck, Cancer Institute Hospital, Tokyo 170-8455, Japan

Abstract. Although the mortality rate associated with papillary microcarcinoma (PMC) of the thyroid

generally is very low, some patients present with bulky nodal metastasis or distant metastasis and have an unfavorable prognosis. We retrospectively reviewed clinical aspects, surgical treatment and outcome of 178 patients with PMC in an attempt to determine the prognostic factors. The cause-specific 10-year

survival rate was 96%. Three of four patients who showed signs of distant metastasis during the

postsurgical period died of the disease, and another died of local recurrence. The most significant prognostic factors were the presence of clinically apparent lymph-node metastasis and hoarseness due to recurrent nerve palsy at the time of diagnosis. All distant metastases and cancer-specific deaths occurred in the 30 patients with symptomatic PMC who had either cervical lymphadenopathy, recurrent laryngeal nerve palsy or both. The 148 patients who had neither symptom had a distinctily favorable

outcome. Total thyroidectomy followed by radioactive iodine treatment did not improve the final outcome in patients with symptomatic PMC. We conclude that patients with asymptomatic PMC can expect a truly favorable outcome, but some of those with symptomatic PMC may fall within a high-risk

group of patients who do not benefit from aggressive treatment.

Key words: Papillary microcarcinoma of the thyroid, Prognostic factors (Endocrine Journal 46: 209-216,1999)

IN recent years ultrasonography and fine needle

aspiration biopsy cytology have made it easier to detect papillary microcarcinoma (PMC) of the

thyroid [1], but the treatment of patients with PMC remains controversial, because those minute cancers

remain harmless tumors with only a few exceptions

[2]. Several autopsy studies have revealed that more

than 10% of patients who die of diseases other than thyroid cancer have PMC, but remain

asymptomatic throughout their lives [3-8]. The outcome generally was also favorable for patients

Received: July 2, 1998 Accepted: October 16, 1998 Correspondence to: Dr. Iwao SUGITANI, Division of Head and Neck, Cancer Institute Hospital, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan

if minute cancers were found incidentally in their surgically resected thyroid specimens, even if the

cancers were associated with regional lymph node metastasis [9].

Nevertheless, occasional patients with PMC

presented with bulky nodal metastasis or with distant metastasis alone when they first visited hospitals and a minute primary cancer lesion was

detected later in the thyroid. Some of these patients clearly had an unfavorable course [10-12].

Until recently, patients with minute thyroid cancers have routinely received surgical treatment

at our institution. The purpose of this study was

to retrospectively evaluate the prognostic factors of patients who underwent surgery for PMC, and

to formulate guidelines for managing patients with this type of tumor.

210 SUGITANI et al.

Materials and Methods Results

The World Health Organization Histologic Classification published in 1988 [13] defined PMC

as a "papillary carcinoma 1.0 cm or less in diameter". During the 18-year period from 1976

through 1993, 178 patients with PMC underwent a

primary thyroid surgery at the Cancer Institute Hospital. This series comprised 25 males and 153

females. The mean age was 52 years (range, 19-79

years), and the mean duration of follow-up after surgery was 12 years (range, 5-22 years). The

prognostic factors we evaluated included: (1) sex; (2) age at primary surgery (under 50 years, 50 years or over); (3) the manifestation that led to initial

detection of PMC (cervical lymphadenopathy, hoarseness, thyroid tumor, incidental detection at

physical examination, incidental detection at

postoperative pathological examination); (4) maximum diameter of PMC (less than 0.5 cm, 0.5 cm or larger); (5) multifocality in the thyroid; (6)

lymph node metastasis; (7) extrathyroidal invasion; and (8) pathohistological appearance. To evaluate multifocality, surgical specimens

removed from 164 patients who underwent hemithyroidectomy or larger resection were studied

by routine pathological examination. Clinical

lymph node metastases 1.0 cm or larger in size were differentiated from microscopically detected metastases. As for the microscopic lymph-node

metastases, 136 patients who underwent central-zone dissection or more extensive surgery were

studied. Permanent paraffin sections from 144

patients were examined for the pathohistologic appearance of PMC in terms of the grade of

sclerosis, the grade of encapsulation and the dominant histological structure of the lesion.

Sclerosis was classified into 4 grades, (-), (±), (+) and (++), according to the amount of interstitial

connective tissue. Encapsulation was classified into 3 grades: completely encapsulated, incompletely

capsulated and non-capsulated. The dominant

structures of the lesions were classified into

papillary, follicular and mixed papillo-follicular types. The Kaplan-Meier method was used for survival-

rate analysis, and log-rank test and Fisher's exact

probability test were used for statistical analysis.

Overall outcome

The cause-specific 10-year survival rate for all 178 patients was 96%. Papillary thyroid carcinoma

recurred postoperatively in 13 patients, including regional node metastasis in 11 and distant

metastasis in four. Two of these four also had

local recurrences. Four patients had undergone two or more reoperations for local recurrences.

Three of four patients who showed distant metastasis died of the disease. The fourth patient

died of multiple, invasive local recurrences. The clinical details of the patients who died of PMC

are shown in Table 1. Eleven patients died of unrelated diseases: cerebrovascular disease (3),

myocardial infarction (1), lung cancer (2), breast cancer (2), colon cancer (1), pancreas cancer (1) and

larynx cancer (1).

Prognostic factors and outcomes

As shown in Table 2, the most significant risk factors in patients with PMC were such clues to PMC detection as the presence of clinically detected large lymph-node metastasis and hoarseness due to recurrent laryngeal nerve palsy caused by direct invasion of PMC. No patients in the present series

presented with distant metastases or extrathyroidal invasion of adjacent tissues other than the recurrent laryngeal nerve at the time of the initial surgery. The rates of tumor recurrence and those of cancer-specific death were significantly different in patients who presented with either lymphadenopathy or hoarseness from those in patients who were asymptomatic (Table 3). Postoperative occurrence of distant metastasis, repeated local recurrences, and a final outcome of cause-specific death were seen only in the 30 symptomatic PMC patients. In marked contrast, none of the 148 patients in the asymptomatic PMC group died of the disease. Furthermore, although there were four patients who required reoperation for enlarged metastatic lymph nodes later, invasive local recurrences have never occurred in the asymptomatic PMC group. Such factors as sex, age, maximum diameter of

PMC, multifocality, and pathohistologic appearance were not statistically significant as the cause of

PAPILLARY THYROID MICROCARCINOMA 211

cancer death, although some tendencies were

observed: (1) there were no PMC-related deaths in

young female patients; (2) patients with more marked lymphatic spread (intrathyroidal metastatic lesions and microscopic lymph-node metastases)

tended to have a favorable outcome; (3) patients with highly fibrotic PMC and non-capsulated PMC

tended to have a worse outcome than those with the contrary findings.

Pathologically, no poorly differentiated papillary carcinoma was seen in this series.

Therapeuetic methods for symptomatic PMC and their effects

The relationship between the various treatment methods and the outcome was studied

retrospectively in the symptomatic PMC group of

patients (Table 4). At the time of operation, several different surgeons arbitrarily determined the extent

of thyroid resection and that of nodal resection, with a general trend towards more extended

resection for more advanced lesions. Accordingly, total thyroidectomy did not improve the outcome,

and there was no definite relationship between the extent of lymph-node dissection and the curability

of the symptomatic PMC.

All of three patients given radioactive iodine therapy died of the disease, although the therapy

was done when distant metastases or severe nodal

recurrences were detected one year to four years

after the initial thyroid surgery.

Discussion

In the present study we reviewed the outcomes of 178 patients who underwent surgery for PMC.

The important prognostic factors were the presence of clinically apparent lymph-node metastasis and

hoarseness due to invasion of the recurrent laryngeal nerve at the time of diagnosis. Therefore,

patients with PMC can be classified into two groups in terms of malignancy: (1) a symptomatic PMC

group characterized either by preoperatively or intraoperatively overt lymph-node metastasis 1.0

cm or larger in size or by recurrent laryngeal nerve

palsy, and (2) an asymptomatic PMC group in which patients present with neither condition. Although none of our patients presented distant

metastasis when they first visited us, those with

hematogenous metastasis should be included in the symptomatic PMC group. When PMCs were

detected at periodical medical examinations, mass screenings, postoperative pathological exam-

inations, or found as symptomless nodules by

patients themselves, only 3% of the patients had

postoperative tumor recurrence locally and none

Table 1. Clinical details of four patients who d ied of minute papillary thy roid carcinoma

212 SUGITANI et al.

developed distant metastasis. In sharp contrast, there were several aggressive cancers among the

symptomatic PMC group: 30% of the patients with symptomatic PMC showed postoperative

recurrences and 13% of them died of the cancer

(P<0.05). With regard to the usual papillary thyroid carcinomas, which are larger than 1.0 cm in

diameter, many investigators agree that there are two distinctly different risk groups of patients [14-16]. In accordance with the AMES classification

advocated by Cady et al. [14], Sanders and

colleagues [17] concluded that patients with occult PMC who presented with cervical node disease

were classified into two risk groups defined by age and sex. They reported that neither female

Table 2. Prognostic factors and outcome of patients with papillary thyroid microcarcinoma (PMC)

PAPILLARY THYROID MICROCARCINOMA 213

patients 50 years of age or younger nor male

patients 40 years or younger died of the disease. But, in our series, although no female patient under

age 50 died of the disease, one 38-year-old male

patient died of distant metastasis. Rosen et al. [18] also pointed out that there were some aggressive

thyroid cancers in the low-risk age population

(under the age of 40). We consider that a patient with clinically apparent local cancer invasion should be classified into a high-risk group, even if

the patient belongs to the low-risk age population

[19]. Nussbaum et al. [20] suggested that papillary

thyroid cancinoma presenting with cervical

lymphadenopathy was a more aggressive disease.

In our series, a clinically detectable, 1.0 cm or larger lymph-node metastasis was an important

prognostic factor. All patients who died of the disease had nodal metastases 3.0 cm or larger. It is noteworthy that patients who had four or more

intrathyroidal minute lesions and five or more lymph nodes with microscopic metastatic lesions

were rather associated with favorable outcomes. Thus the extent of lymphatic spread of papillary

cancer cells itself proved not to be an indicator of its high malignancy.

As to the pathohistological aspects of PMC, Alto

et al. [12] reported that, although distant metastasis is uncommon and the mortality rate is low, occult

papillary carcinomas with histologically invasive lesions had a high propensity for recurrence. In

our study, patients with non-encapsulated PMC

tended to have worse outcomes. We also found that patients with primary lesions of the highly

Table 3. Comparison of postoperative courses of two groups of patients with symptomatic PMC and asymptomatic PMC

214 SUGITANI et a!.

sclerosing type had the worse outcomes. It is assumed that PMC that grows more aggressively induces a stronger fibrotic reaction around the lesion.

An appropriate treatment method should be chosen especially for patients with symptomatic PMC [21-23]. Some of them may have a high-risk cancer and others may have a low-risk cancer. The treatment of papillary thyroid cancer in general is still controversial concerning the extent of thyroidectomy, the extent of neck dissection and the need for postoperative adjuvant therapies [24]. In Western countries, total thyroidectomy followed by radioactive iodine whole body ablation and suppression of TSH secretion is widely advocated for all patients with papillary thyroid carcinoma who are classified even in a low-risk group in order to improve the prognosis [25-33]. Some authors stated, however, that patients with low-risk

papillary thyroid carcinoma have such a favorable prognosis as 98% survival in 20-year follow-up study, that further beneficial effects of those "complete" therapy have never been convincingly

shown [34, 35]. Sanders et al. [17] advocated total thyroidectomy followed by radioactive iodine whole-body ablation and TSH suppression for

patients in a high-risk age group of PMC. In our series, however, we have been accustomed to

perform lobectomy or subtotal thyroidectomy along with central zone dissection or ipsilateral modified neck dissection for a localized, non-invasive PMC lesion and total thyroidectomy along with neck dissection for a widely spread lesion or an invasive lesion. Radioactive iodine whole body ablation and TSH suppression have not routinely been carried out [24]. The use of radioactive iodine therapy was carried out for three patients with symptomatic PMC which showed severe local recurrences or distant metastases. All other trials to control locally invasive recurrences and distant metastases, such as aggressive resection including the larynx and trachea, and external irradiation did not improve the final outcomes. It is certain that, although we have to perform a prospective, large control study in order to determine the definite therapeutic guideline for this disease, our results imply that the prognosis of individual patients with PMC would be determined largely by the biological malignancy of the tumor itself, and may hardly be modified by therapeutic methods.

In 1969, Takahashi [3] reported an unexpectedly high detection rate for 13.8% of PMC in 320 unselected autopsy cases. And Sampson [4] reported that among a total of 391 autopsies from the Hiroshima-Nagasaki series, 111 cadavers had PMC. Many world-wide autopsy series have also shown a surprisingly high prevalence of PMC, ranging from 6 to 28%, without any significant differences in prevalence related to sex or age [5-8], whereas it is known that the prevalence of clinically evident thyroid cancer is only about 0.1% to 0.05% of the general population [36, 37]. As shown in the present study, all patients with an asymptomatic PMC have shown very favorable outcomes when treated by conservative surgical means. Hubert et al. [38] also showed that PMC was a nonlethal and curable disease and that nodal metastasis did not influence its outcome. It is also reported that PMCs metastasize to lymph nodes with a frequency similar to that of "clinical"

papillary carcinomas [9]. Although it is true that PMC may rarely be a source of dangerous metastatic morbidity and can be viewed as

potentially lethal [10-12], the large majority of PMCs are asymptomatic and belong to a distinctly different category of cancer- from the symptomatic PMCs in view of biological malignancy and such asymptomatic PMCs would be expected to remain harmless throughout the entire life of the patient [39]. Now particularly in Western countries, it is assumed that detection of occult, non-clinical microcarcinoma by ultrasonography and their surgical treatment have almost no effect in reducing thyroid cancer deaths in the general population, and that only palpable PMC would be treated by conservative surgery [34, 39-41]. In Japan, ultrasonography has largely been used at examinations of varied thyroid lesions including differentiation of benign and malignant nodules, because one of every six nodules is malignant, roughly 90% of all thyroid cancers are of a papillary variant, many benign nodules are cystic, and specificity and sensitivity of ultrasound in making the diagnosis of papillary carcinoma are 90% and 83% [42]. Then small incidental lesions in the thyroid can often be detected and it is possible to make a diagnosis of PMC with the aid of ultrasonography-guided fine-needle aspiration biopsy cytology [1]. PMCs are found incidentally in one of 100 to 300 people at annual medical

PAPILLARY THYROID MICROCARCINOMA 215

examinations or at mass screenings [43]. When

PMC was detected, we had routinely attempted to remove it. At our institute, our treatment method

for PMC changed in 1995 from routinely

performing surgery on all patients with PMC to conservatively follow their courses carefully, so long as the PMC is asymptomatic. Twenty-one

patients were found to have asymptomatic PMC and have been followed up until 1998. Although the duration of follow-up is short (maximum, 5

years), there have been no patients whose PMC needed surgery due to growing larger or becoming

symptomatic. It remains to be seen which non-clinical PMCs

will develop to clinical lesions with the potency to cause recurrent laryngeal nerve palsy or disease-

specific death, and how to differentiate patients

with such high-risk cancers from others [44]. We have to await the results of careful controlled trials

to corroborate a rational management of this

disease. In order to determine the potential grade of malignancy of individual PMCs, such biological

approaches as determination of expression of

growth factors and DNA content will have to be investigated [45].

Acknowledgement

The authors wish to thank Dr. Akio Yanagisawa,

Department of Pathology, Cancer Institute, for his

valuable assistance.

References

1. Yokozawa T, Miyauchi A, Kuma K, Sugawara M (1995) Accurate and simple method of diagnosing thyroid nodules by the modified technique of

ultrasound-guided fine needle aspiration biopsy. Thyroid 5:141-145. 2. Bramley MD, Harrison BJ (1996) Papillary

microcarcinoma of the thyroid gland. Br J Surg 83: 1674-1683.

3. Takahashi S (1969) Clinicopathological studies of latent carcinoma of the thyroid. Folia Endocirnol

Japon 45: 65-79 (In Japanese). 4. Sampson RJ, Oka H, Key CR, Buncher CR, Iijima S

(1970) Metastases from ocult thyroid carcinoma. An autopsy study from Hiroshima and Nagasaki, Japan. Cancer 25: 803-811.

5. Sampson RJ, Key CR, Buncher CR, Oka H, Iijima S (1970) Papillary carcinoma of the thyroid gland.

Sizes of 525 tumors found at autopsy in Hiroshima and Nagasaki. Cancer 25:1391-1393.

6. Sampson RJ, Woolnr LB, Bahn RC, Kurland LT (1974) Occult thyroid carcinoma in Olmsted County,

Minnesota: Prevalence at autopsy compared with that in Hiroshima and Nagasaki, Japan. Cancer 34: 2072-2076.

7. Fukunaga FH, Yatani R (1975) Geographic

pathology of ocult thyroid carcinomas. Cancer 36: 1095-1099.

8. Bondeson L, Ljungberg 0 (1981) Occult thyroid carcinoma at atuopsy in Malmo, Sweden. Cancer 47: 319-323.

9. Aiyoshi Y, Ishikawa T, Morishima I, Yashiro T, Hara H, Nakamura Y, Yamashita K (1995) Regional

lymph node metastases from differentiated thyroid carcinomas smaller than 1 cm. Endocrine Surg 12:

43-49 (In Japanese). 10. Yamashita H, Noguchi S, Murakami N, Mochizuki Y, Nakayama I (1986) Prognosis of minute

carcinoma of thyroid. Follow-up study of 49

patients. Acta Pathol Jpn 36:1469-1475. 11. Strate M, Lee EL, Childers JH (1984) Occult

papillary carcinoma of the thyroid with distant metastases. Cancer 54:1093-1100.

12. Allo MD, Christianson W, Koivunen D (1988) Not all "occult" papillary carcinomas are "minimal". Surgery 104: 971-976.

13. Hedinger C, Williams ED, Sobin LH (1988) Histologic typing of thyroid tumors. In:

International Histological Classification of Tumors. 2nd ed, World Health Organization. Springer-

Verlag, New York, No. 11, 9-10. 14. Cady B, Rossi RL (1988) An expanded view of risk-

group definition in differentiated thyroid carcinoma. Surgery 104: 947-953.

15. Hay ID, Grant CS, Taylor WF, McConahey WM (1987) Ipsilateral lobectomy versus bilateral lobe resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a

novel prognostic scoring system. Surgery 102:1088- 1095.

16. Byar DP, Green SB, Dor P, Williams ED, Colon J, van Gilse HA, Mayer M, Sylverster RJ, Glabbeke

MV (1979) A prognostic index for thyroid carcinoma. A study of E.O.R.T.C. thyroid cancer cooperative group. Eur J Cancer 15:1033-1041.

17. Sanders LE, Rossi RL (1995) Occult well differentiated thyroid carcinoma presenting as cervical node disease. World J Surg 19: 642-647.

18. Rosen IB, Bowden J, Luk SC, Simpson JA (1987)

216 SUGITANI et al.

Aggressive thyroid cancer in low-risk age

population. Surgery 102:1075-1080. 19. Fujimoto Y, Sugitani I (1998) Postoperative

prognosis of intrathyroidal papillary thyroid carcinoma: Long-term (35-45 year) follow-up study.

Endocr J 45: 475-484. 20. Nussbaum M, Bukachevsky R (1990) Thyroid carcinoma presenting as a regional neck mass. Head

& Neck 12:114-117. 21. De Jong SA, Demeter JG, Jarosz H, Lawrence AM, Paloyan E (1993) Primary papillary thyroid carcinoma presenting as cervical lymphadenopathy:

The operative approach to the "lateral aberrant thyroid". Ann Surg 59:172-177.

22. Noguchi S, Yamasahita H, Murakami N, Nakayama I, Toda M, Kawamoto H (1996) Small carcinomas

of the thyroid: A long-term follow-up of 867 patients. Arch Surg 131:187-191. 23. Rodriguetz JM, Moreno A, Parrilla P, Sola J, Soria

Y, Tebar FJ, Aranda F (1997) Papillary thyroid microcarcinoma: Clinical study and prognosis. Eur

J Surg 163: 255-259. 24. Fujimoto Y, Obara T, Yamashita T (1997) Papillary

thyroid carcinoma: Rationale for hemithyroid- ectomy and regional node dissection. In: Clark OH,

Duh QY (eds) Textbook of Endocrine Surgery. WB Saunders, Philadelphia, 82-89. 25. Thompson NW, Nishiyama RH, Harness JK (1978)

Thyroid carcinoma: Current controversies. Curr Probl Surg 15:1-67.

26. Mazzaferri EL, Young RL (1981) Papillary thyroid carcinoma: A 10 year follow-up report of the impact of therapy in 576 patients. Am J Med 70: 511-518.

27. Clark OH (1982) Total thyroidectomy: The treatment of choice for patients with differentiated thyroid cancer. Ann Surg 196: 361-370.

28. Samaan NA, Maheshwari YK, Nader S, Hill CS, Shultz PN, Haynie TP, Hickey RC, Clark RL,

Goepfert H, Ibanez ML, Litton CE (1983) Impact of therapy for differentiated carcinoma of the thyroid:

An analysis of 706 cases. J Clin Endocrinol Metab 56: 1131-1138.

29. Van De Velde CJH, Hamming JF, Goslings BM, Schelfhout LJDM, Clark OH, Smeds S, Bruining HA,

Krenning EP, Cady B (1988) Report of the consensus development conference on the management of differentiated thyroid cancer in Netherlands. Eur J

Cancer Clin Oncol 24: 287-292. 30. Beenken S, Guillamondegui 0, Shallenberger R, Knapp C, Ritter D, Goepfert H (1989) Prognostic

factors in patients dying of well-differentiated thyroid cancer. Arch Otolaryngol Head Neck Surg 115:

326-330. 31. DeGroot LJ, Kaplan EL, McCormick M, Straus FH

(1990) Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 71: 414-424.

32. Frankenthaler RA, Sellin RV, Cangir A, Goepfert H (1990) Lymph node metastasis from papillary-

follicular thyroid carcinoma in young patients. Am J Surg 160: 341-343.

33. Solomon BL, Wartofsky L, Burman KD (1996) Current trends in the management of well differentiated papillary thyroid carcinoma. J Clin Endocrinol Metab 81: 333-339. 34. Cady B (1981) Surgery of thyroid cancer. World J Surg 5: 3-14.

35. Vickery AL, Wang CA, Walker AM (1987) Treatment of intrathyroidal papillary carcinoma of

the thyroid. Cancer 60: 2587-2595. 36. Maruchi N, Furihata R, Makiuchi M (1971) Population surveys on the prevalence of thyroid cancer in a non-endemic region, Nagano, Japan. Int. J Cancer 7: 575-583.

37. Pelizzo MR, Piotto A, Rubello D, Casara D, Fassina A, Busnardo B (1990) High prevalence of occult

papillary thyroid carcinoma in a surgical series for benign thyroid disease. Tumori 76: 255-257. 38. Hubert JP Jr, Kiernan PD, Beahrs OH, McConahey

WM, Woolner LB (1980) Occult papillary carcinoma of the thyroid. Arch Surg 115: 394-398.

39. Hay ID, Grant CS, van Heerden JA, Goellner JR. Ebersold JR. Bergstralh EJ (1992) Papillary thyroid

microcarcinoma: A study of 535 cases observed in a 50-year period. Surgery 112:1139-1147.

40. Woolner LB, Lemmon ML, Beahrs OH, Black BM, Keating FR Jr (1960) Occult papillary carcinoma of

the thyroid gland: A study of 140 cases observed in a 30-year period. J Clin Endocrinol Metab 20: 89-

105. 41. McConahey WM (1989) Thyroidology: Past, present and future. In: van Heerden JA (ed) Common

Problems in Endocrine Surgery. Year Book Medical Publishers, Chicago, 132-140. 42. Okamoto K, Yamashita T, Harasawa A, Kanamuro

T, Aiba M, kawakami M, Ito Y, Murakami M, Fujimoto Y, Obara T (1994) Test performances of three diagnostic procedures in evaluating thyroid

nodules: Physical examination, ultrasonography and fine needle aspiration cytology. Endocr J 41: 243-247.

43. Takebe K, Date M, Yamamoto Y, Ogino T (1996) The detection of minimal thyroid cancer in mass

screening with ultrasonography. Geka (Surgery) 58: 651-654 (In Japanese).

44. Rosen IB, Azadian A, Walfish PG (1995) Adverse aspects of small thyroid cancer and need for treatment. Head & Neck 17: 373-376.

45. Sugitani I, Yanagisawa A, Shimizu A, Kato M, Fujimoto Y (1998) Clinicopathological and

immunohistochemical studies of papillary thyroid microcarcinoma with cervical lymphadenopathy. World J Surg 22: 731-737.