31

Papillary Microcarcinoma of the Thyroid—Prognostic

Significance of Lymph Node Metastasis
and Multifocality

Sin-Ming Chow, M.B.B.S1 BACKGROUND. It is known that patients with papillary microcarcinoma (PMC) of
Stephen C. K. Law, M.B.B.S1 the thyroid gland have a very favorable prognosis. The rising incidence of PMC
John K. C. Chan, M.B.B.S2 among papillary thyroid carcinoma (PTC) necessitates the identification of prog-
Siu-Kie Au, M.B.B.S1 nostic factors and the formulation of treatment protocols.
Stephen Yau, M.B.B.S.1 METHODS. The authors conducted a retrospective analysis of 203 patients with
Wai-Hon Lau, M.B.B.S.1 PMC who were diagnosed on or before 1999 and were treated at the Department
of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong.
1
Department of Clinical Oncology, Queen Eliza- RESULTS. The cause specific survival, locoregional (LR) failure free survival, and
beth Hospital, Hong Kong, People’s Republic of distant metastases failure free survival rates at 10 years were 100%, 92.1%, and
China. 97.1%, respectively. Five patients had lung metastases; 2 patients died of their
2
Department of Pathology, Queen Elizabeth Hos- metastases 12.9 years and 14.8 years after diagnosis, and 3 patients achieved
pital, Hong Kong, People’s Republic of China. clinical remission after radioiodine (RAI) treatment. Twelve patients had LR recur-
rences. Patients with LR recurrence were highly salvageable with a combination of
surgery, RAI treatment, and external radiotherapy; all but one (who refused treat-
ment) were alive without disease at last follow-up. Multivariate analyses did not
reveal any independent prognostic factor for survival. The risk of cervical lymph
node (LN) recurrence increased 6.2-fold (P ⫽ 0.01) and 5.6-fold (P ⫽ 0.02) when LN
metastases and multifocal disease were present at diagnosis. RAI ablation reduced
the LN recurrence rate to 0.27 (P ⫽ 0.04). The presence of LN metastasis increased
the rate of distant metastasis 11.2-fold (P ⫽ 0.03). Age was not a significant factor
in predicting disease recurrence or survival. Subdivision by tumor sizes ⱕ 5 mm
and ⬎ 5 mm did not affect the outcome, but no patient with tumors ⱕ 5 mm had
mortality related to PMC.
CONCLUSIONS. Despite the overall excellent prognosis for patients with PMC, PMC
was associated with a 1.0% disease-related mortality rate, a 5.0% LN recurrence
rate, and a 2.5% distant metastasis rate. Therefore, the treatment of patients with
PMC should be no different from the treatment of patients with conventional PTC:
i.e., complete surgery with consideration for RAI and/or external radiation therapy
if poor prognostic factors are present. Cancer 2003;98:31– 40.
© 2003 American Cancer Society.

The authors thank Mr. Oscar Mang of the Hong KEYWORDS: differentiated thyroid carcinoma, papillary carcinoma, microcarcinoma,
Kong Cancer Registry for his generous support in radioiodine, lymph node metastasis.
providing mortality data for analysis.

Address for reprints: Sin-Ming Chow, M.B.B.S, De-

partment of Clinical Oncology, Block R, Queen
Elizabeth Hospital, 30 Gascoigne Road, Kowloon,
P apillary microcarcinoma of the thyroid (PMC) is defined as pap-
illary carcinoma measuring ⱕ 1 cm in greatest dimension accord-
ing to the World Health Organization classification system for thyroid
Hong Kong; Fax: (011) 852 23594782; E-mail:
tumors.1 Before this definition was introduced, confusion in termi-
chowsm@ha.org.hk
nology and definitions rendered comparing data a difficult task.
Received January 6, 2003; revision received These included small papillary carcinomas (e.g., tumors measuring
March 11, 2003; accepted March 18, 2003. ⱕ 1.5 cm2– 4) and the descriptive terms occult papillary carcinoma and

© 2003 American Cancer Society

DOI 10.1002/cncr.11442
32 CANCER July 1, 2003 / Volume 98 / Number 1

incidentaloma, which were used to describe incidental beth Hospital from 1960 to 1999 were reviewed retro-
finding at autopsy or in thyroidectomy specimens of spectively. Our department is a tertiary referral center
small papillary carcinoma with no clinical suspicion of for the management of patients with malignant dis-
malignancy. Some authors included both papillary ease. Tumors were classified histologically according
carcinoma and follicular carcinoma as occult thyroid to the World Health Organization criteria.1 Of 997
carcinoma. To avoid confusion, this discussion is re- patients, 110 patients with missing information on the
stricted to papillary thyroid carcinoma (PTC) because size of their primary thyroid tumor and 3 patients with
of the distinctive difference in clinical features and no primary tumor found in resected thyroidectomy
outcomes of patients with papillary carcinoma and specimen were excluded (either PTC found in ectopic
follicular carcinoma.5 The discussion on thyroidec- sites or metastasis proven by pathologic examination).
tomy series is limited herein to reports on tumors Among the remaining 884 patients, 203 patients (23%)
measuring ⱕ 1 cm. The prognoses for patients in were diagnosed with papillary microcarcinoma
thyroidectomy series are excellent.6 –11 Some reports (PMC). In the whole group of 997 patients, a temporal
revealed zero mortality;7,9 –11 whereas, in other re- trend toward decreasing mean tumor size was noted:
ports, a very low mortality rate of 0.25– 0.4%6,8 was Before 1980, the mean tumor size was 3.25 cm; during
found. PMC can be lethal, because small numbers of 1980 –1989, the mean tumor size was 2.45 cm; and,
patients develop locoregional (LR) recurrences6 – 8 and during 1990 –1999, the mean tumor size was 2.25 cm
distant metastases (DM).8,11 One study reported a (P ⫽ 0.001). The percentage of PMC in patients with
long-term recurrence rate of 6% at 20 years.6 PTC during these 3 periods increased progressively
In autopsy studies, the incidence of small PTC from 11.9%, to 21.6%, and to 24.5%.
varied from 1.0% to 35.6%,12–15 depending on the thor-
oughness of examination (e.g., the number of section- Management Strategy
ing levels) and diagnostic criteria.16 Lymph node (LN) The management of patients with PTC consisted ba-
metastases were detected in 3.1–18.2% of patients.14,15 sically of primary surgery followed by evaluation for
Marked geographic differences in incidence rates were radioiodine (RAI) treatment and external radiother-
noted: 1% in Brazil,12 13% in Hong Kong (unpublished apy, as described previously.25 In general, we prefer
data from Queen Elizabeth Hospital), 11.3–28.4% in bilateral thyroidectomy for patients with PTC, because
Japan,4,13,17 1.5% in Greece,18 and 35.6% in Finland.15 total or near-total thyroidectomy results in fewer re-
Based on the high incidence in autopsy studies in currences compared with unilateral surgical proce-
Finland, this common incidental finding was viewed dures. For incidental finding of PTC, we would discuss
as a normal finding, and tumors that measured ⱕ 5 with patients the options of completion thyroidec-
mm were considered tumor instead of carcinoma to tomy and RAI ablation. If patients underwent con-
avoid unnecessary surgeries.15 Most of the autopsy tralateral completion thyroidectomy within 6 months
series did not reveal differences in incidence with of their initial thyroid surgery, then it was considered
respect to gender,15,19 age,15,20 thyroid size,14 or mul- part of initial surgery. If patients underwent contralat-
tifocality.14 Further subdivision of tumors by size (ⱕ 5 eral surgery after 6 months postdiagnosis, after which
mm vs. ⬎ 5 mm) was suggested by Kasai and Saka- tumor in the opposite lobe was confirmed, then it was
moto because of the lower frequency of LN metastasis considered local recurrence. Our criteria for RAI abla-
and extrathyroid extension in the subgroup of patients tion in patients with PTC was tumor size ⬎ 1cm, LN
with smaller tumors.19 metastasis, age older than 40 years, presence of extra-
Studies in our hospital21 and in Japan22 revealed a thyroid extension, macroscopic postoperative residual
temporal trend toward decreasing tumor size of PTC. disease in the neck, and/or DM. The usual dose for
With advances in ultrasonography and fine-needle as- patients with or without distant metastasis was 2.96
piration biopsies, especially in mass screening pro- gigabecquerel (GBq) (80 mCi) and 5.55 GBq (150 mCi),
grams, PMC can be diagnosed before surgery.23,24 respectively. External radiotherapy to the thyroid bed
Controversies arise because of conflicting reports in and cervical lymphatics was given to patients with
management policies. By analyzing 203 patients with macroscopic postoperative LR disease, extensive ex-
PMC who were seen at a single institute, we have trathyroid extension, and LN metastasis. Sometimes,
attempted to identify the prognostic factors and opti- protocol violations happened because of the prefer-
mal treatment for this group of patients. ences of individual physicians or patients. After pri-
mary treatment, all patients received thyroxin in sup-
MATERIALS AND METHODS pressive or replacement doses. After 1998, the thyroid-
The records of 997 patients with PTC who were treated stimulating hormone (TSH) level was kept in the
at the Department of Clinical Oncology, Queen Eliza- normal range for low-risk patients. Serum thyroglob-
 Papillary Microcarcinoma of Thyroid/Chow et al. 33

ulin monitoring was available after January, 1989. Hu- were considered inoperable. A lower percentage of
man recombinant TSH was not available in our hos- patients with PMC received RAI treatment (67.5% vs.
pital. The International Union Against Cancer26/ 80.9%) and external radiotherapy (3.4% vs. 16.3%).
American Joint Committee on Cancer27 TNM staging Lower rates of LR recurrence (10.3% vs. 16%) and DM
system was used for the classification of prognoses. (2.5% vs. 7.6%) were found in the PMC group. A
greater proportion of patients had Stage I disease in
Statistical Analysis the PMC group (81.8% vs. 52.4%). CSS, LRFFS, and
We analyzed the clinical, pathologic, and treatment DMFFS rates were significantly better in the patients
factors in relation to the following outcome parame- with PMC.
ters: cause specific survival (CSS), LR failure free sur-
vival (LRFFS), and DM failure free survival (DMFFS). Prognostic Factors
LR failure was defined as clinically or radiologically Multivariate analysis did not reveal any prognostic
detectable recurrences in the thyroid bed or cervical factors for CSS. Table 2 summarizes the LR and LN
LNs. DM was clinically or radiologically detectable recurrence analyses. Higher LR recurrence rates were
disease outside the neck. All CSS, LRFFS, and DMFFS found in patients with LN metastasis at presentation
curves were generated by the Kaplan–Meier method. (relative risk [RR], 4.2; 95% confidence interval
Log-rank tests were used to compare prognostic fac- [95%CI], 1.3–13.6; P ⫽ 0.019) and in patients who had
tors. Differences in clinical parameters were analyzed no RAI ablation (RR, 0.2; 95%CI, 0.07– 0.7; P ⫽ 0.01).
with chi-square tests, t tests, or Fisher exact tests, as Multifocal disease (defined as ⬎ 1 foci of PTC in the
appropriate. Relevant variables were entered into thyroidectomy specimen) was marginally insignificant
multivariate analyses using a Cox regression model.28 (P ⫽ 0.07). LN recurrence increased in patients with
SPSS software (version 10.0; SPSS, Inc., Chicago, IL) cervical LN metastasis at presentation, multifocal dis-
was used in the data analyses. Significance levels were ease, and the absence of RAI ablation. The LN recur-
presented as P values. It was assumed that the ob- rence rate increased 6.2-fold when there was positive
served differences were statistically significant at the P LN metastasis at presentation (95%CI, 1.6 –24.4; P
ⱕ 0.05 level. Subgroup analyses were performed in ⫽ 0.01) and increased 5.6-fold when multifocal tumor
relevant circumstances. was found in thyroidectomy specimen (95%CI, 1.3–
23.4; P ⫽ 0.02). RAI ablation reduced the relative risk of
RESULTS LN recurrence to 0.27 (95%CI, 0.08 – 0.93; P ⫽ 0.04). For
The mean follow-up for the 203 patients with PMC DMFFS, LN metastasis was the only prognostic factor,
was 8.4 ⫾ 5.5 years. Thirty-three patients (16.3%) were and the presence of LN metastasis increased the relative
lost to follow-up after a mean of 4.9 years. The major- risk of DM to 11.2 (95%CI, 1.3–100.7; P ⫽ 0.03).
ity of patients were ethnic Chinese (97%). The CSS, The significance of LN metastasis at diagnosis is
LRFFS, and DMFFS rates at 10 years were 100%, illustrated in Table 3. The increased in LR recurrence
92.1%, and 97.1%, respectively. Two patients died of rate was accounted for by the increase in LN recurrence
disease after 10 years; the 15-year CSS rate was 95%. rather than local thyroid bed recurrence. Among 50 pa-
Most patients presented with Stage I disease (81.8%). tients who had LN metastasis at presentation, 14.0% of
Two patients had DM in the lungs at presentation, patients developed LN recurrences and 8.0% of patients
and 3 patients developed DM in the lungs (with addi- had DM, compared with only 2.0% and 0.65%, respec-
tional bone metastasis in 1 patient) as recurrent dis- tively, in patients without LN metastasis. The incidence
ease at 0.6 years, 9.7 years, and 10.8 years after diag- of LN metastasis increased with the presence of multi-
nosis. LR recurrences occurred in 12 patients (in LN in focal disease in primary thyroid tumors (34.9% vs. 20%;
10 patients and in the thyroid bed in 2 patients). All LR P ⫽ 0.034). Figure 1 depicts the LN recurrence rate with
recurrences occurred within 8 years after diagnosis respect to surgery, initial LN metastasis status, and RAI
(mean, 3.1 years). treatment. RAI ablation in patients with LN negative
disease, after undergoing bilateral surgery, resulted in a
Comparison of Patient Characteristics and Outcome lower rate of LN recurrence: 7.1% (3 of 42 patients)
among Patients With and Without PMC versus 0% (0 of 95 patients; P ⫽ 0.03). In the cohort of 42
The basic demographic data on patients with and patients with N0 disease, the LN recurrence rate was
without PMC and are compared in Table 1. At presen- 7.1% after thyroidectomy alone. For those 95 patients
tation, patients with PMC had a higher female-to-male who had the same staging but received RAI after surgery,
ratio (6.5 vs. 4.2) and had lower rates of extrathyroid no patient had a recurrence. For patients with N1 dis-
extension (20.7% vs. 31.3%), LN metastasis (24.5% vs. ease, the overall LN recurrence rate after RAI ablation
33.3%), and DM (1% vs. 4%). No patients with PMC was not significantly different (P ⫽ 0.6). Age, gender,
34 CANCER July 1, 2003 / Volume 98 / Number 1

TABLE 1
Patient Characteristics and Treatment for Papillary Microcarcinoma (PMC) Compared with Patients
in the Non-PMC Group

No. of patients (%)

Patient characteristic PMC Non-PMC P value

Total patients 203 681 —

Age (yrs)
Mean ⫾ SD 46.8 ⫾ 13.4 45 ⫾ 16.7 0.17
Range 7.7–77.2 10.5–91.6 —
Gender (female:male ratio) 6.5 4.2 0.048
Female 176 (86.7) 549 (80.6) —
Male 27 (13.3) 132 (19.4) —
Mean size ⫾ SD (cm) 0.7 ⫾ 0.28 2.9 ⫾ 1.7 —
Multifocal disease
No 140 (69.0) 440 (64.6) NS
Yes 63 (31.0) 213 (31.3) —
Not stated 0 (0.0) 28 (4.1) —
Extrathyroidal extension
No 161 (79.3) 346 (50.8) ⬍ 0.001
Yes 42 (20.7) 323 (47.4) —
Not stated 0 (0.0) 12 (1.8) —
Lymph node metastases
No 153 (75.4) 450 (66.1) 0.028
Yes 50 (24.6) 226 (33.2) —
Not stated 0 (0.0) 5 (0.7) —
Distant metastasis at presentation 2 (1.0) 27 (4.0) 0.036
Type of thyroid surgery
Total or near-total thyroidectomy 187 (92.1) 632 (92.8) 0.01
Lobectomy 16 (7.9) 30 (4.4) —
Biopsy/no surgery 0 (0.0) 19 (2.8) —
Lymph node surgery
None resected 148 (72.9) 455 (66.8) 0.2
Excision/sampling 35 (17.2) 157 (23.1) —
Neck dissection 20 (9.9) 64 (9.4) —
Not stated 0 (0.0) 5 (0.7) —
Radioiodine treatment 137 (67.5) 551 (80.9) ⬍ 0.001
External radiotherapy 7 (3.4) 111 (16.3) ⬍ 0.001
Locoregional recurrence 12 (10.3) 109 (16.0) ⬍ 0.001
Distant metastasis 5 (2.5) 52 (7.6) 0.008
Lung metastasis during the course of disease (total) 5 (2.5) 39 (5.7) 0.06
At presentation 2 (1.0) 20 (2.9) 0.1
As recurrence 3 (1.5) 19 (2.8) 0.4
UICC/AJCC TNM staging
Stage I 166 (81.8) 357 (52.4) ⬍ 0.001
Stage II 0 (0.0) 95 (14.0) —
Stage III 35 (17.2) 207 (30.4) —
Stage IV 2 (1.0) 20 (2.9) —
Undetermined 0 (0.0) 2 (0.3) —
Ten yr survival (%)
CSS 100 92 0.002
LRFFS 92.1 81.9 0.004
DMFFS 97.1 91.9 0.0089

PMC: papillary microcarcinoma; SD: standard deviation; NS: nonsignificant; UICC: International Union Against Cancer; AJCC: American Joint Committee on Cancer;
CSS: cause-specific survival; LRFFS: local-regional failure–free survival; DMFFS: distant metastasis failure-free survival.
 Papillary Microcarcinoma of Thyroid/Chow et al. 35

TABLE 2
Locoregional Failure-Free Survival and Lymph Node Recurrence Analyses According to Prognostic Factors

Patients with locoregional recurrence Patients with LN recurrence

Multivariate analysis Multivariate analysis

Univariate Univariate
Characteristic No. (%) P value RR (95% CI) P value No. (%) P value RR (95% CI) P value

Age
ⱕ 45 yrs 7/100 (7.0) 0.52 — NS 6/100 (6.0) 0.55 — NS
ⱖ 45 yrs 5/103 (4.9) — — — 4/103 (3.6) — — —
Gender
Female 11/176 (6.3) 0.58 — NS 9/176 (5.1) 0.79 — NS
Male 1/27 (3.7) — — — 1/27 (3.7) — — —
Cervical LN metastases
No 5/153 (3.3) 0.01 1.0 0.019 3/153 (2.0) 0.0014 1.0 0.01
Yes 7/50 (14.0) — 4.2 (1.3–13.6) — 7/50 (14.0) — 6.2 (1.6–24.4) —
Size of primary thyroid tumor
ⱕ 0.5 cm 4/70 (5.7) 0.97 — NS 8/133 (7.0) 0.37 — NS
⬎ 0.5 cm 8/133 (6.0) — — — 2/70 (2.9) — — —
Multifocal disease
No 5/140 (3.6) 0.05 1.0 0.07 3/140 (2.1) 0.005 1.0 0.02
Yes 7/63 (11.1) — 3.0 (0.9–9.6) — 7/63 (11.1) — 5.6 (1.3–23.4) —
Extrathyroidal extension
No 101/161 (6.2) 0.78 — NS 8/161 (5.0) 0.92 — NS
Yes 2/42 (4.8) — — — 2/42 (4.8) — — —
Type of thyroid surgery
10/187
Total/near total thyroidectomy 10/187 (5.3) 0.21 — NS (5.3) 0.35 — NS
Lobectomy 2/16 (12.5) — — — 0/16 (0.0) — — —
Type of LN surgery
Excision 5/35 (14.3) 0.048 — NS 5/35 (14.3) 0.0059 — NS
Neck dissection 2/20 (10.0) — — — 2/20 (10.0) — — —
No LN excised 5/148 (3.6) — — — 3/148 (2.0) — — —
Radioiodine treatment
No 7/66 (11.4) 0.035 1.0 0.01 5/66 (7.6) 0.19 1.0 0.04
Yes 5/137 (3.6) — 0.2 (0.07–0.7) — 5/137 (3.6) — 0.27 (0.08–0.93) —
External radiotherapy
No 10/196 (5.1) 0.007 — NS 8/198 (4.1) 0.0012 — NS
Yes 2/7 (28.6) — — — 2/7 (28.6) — — —

LN: lymph node; RR: relative risk; 95% CI: 95% confidence interval; NS: not significant.

extrathyroid extension, type of thyroid surgery, and LN

surgery were not distinguished as significant factors in
any of the analyses, univariate or multivariate, of CSS, LR
control, or DM. TABLE 3
Lymph Node Metastasis and Outcome
Patients Without DM at Presentation
No. of patients with lymph
For the 201 patients without DM at presentation, the node metastases at
findings were similar to those for whole group of 203 presentation (%)
patients. No single, independent prognostic factor
could be found for CSS. The LR recurrence rate was Status Absence Presence P value
increased 4.5-fold by the presence of LN metastasis at
Total patients 153 50 —
presentation (RR, 4.5; 95%CI, 1.4 –15.2; P ⫽ 0.014) and Locoregional recurrence 5 (3.3) 7 (14.0) 0.01
was reduced to 20% by RAI ablation (RR, 0.2; 95%CI, Local 2 (1.3) 0 (0.0) 1.0
0.06 – 0.7; P ⫽ 0.011). Multivariate analysis showed Lymph node 3 (2.0) 7 (14.0) 0.002
that the prognostic factors for LN recurrence were the Distant metastasis (all) 1 (0.65) 4 (8.0) 0.006
At presentation 0 (0.0) 2 (4.0) 0.006
same as the factors for whole group of patients with
At recurrence 1 (0.7) 2 (4.0) 0.15
PTC, i.e., multifocal disease (RR, 5; 95%CI, 1.1–22.3; P
36 CANCER July 1, 2003 / Volume 98 / Number 1

TABLE 4
Comparison of Clinical Characteristics and Outcome of Patients with
Papillary Microcarcinoma, Based on the Size of Primary Tumors

No. of patients (%)

Tumor size Tumor size

Clinical feature or outcome < 5 mm > 5 mm P value

Total patients 70 133 —

Mean ⫾ SD
Age (yrs) 49.6 ⫾ 13 45.3 ⫾ 13.4 0.03
Tumor size (mm) 0.38 ⫾ 0.1 0.89 ⫾ 0.14 ⬍ 0.001
Follow-up (yrs) 8.2 ⫾ 5.6 8.5 ⫾ 5.3 0.7
Gender
Female 60 (85.7) 116 (87.2) 0.8
Male 10 (14.3) 17 (12.8) —
FIGURE 1. Lymph node (LN) recurrence with respect to treatment, initial LN
Extrathyroidal extension 3 (4.3) 39 (29.3) ⬍ 0.001
node status, and radioiodine (RAI) treatment. The number of patients in each Lymph node metastasis 18 (25.7) 32 (24.1) 0.8
group is shown in parentheses. NS: not significant; ⫹ve: positive; ⫺ve: Multifocal disease 18 (25.7) 45 (33.8) 0.27
negative. DM at presentation 1 (1.4) 1 (0.8) 1.0
Thyroid surgery
Total thyroidectomy 60 (85.7) 127 (95.5) 0.025
Lobectomy 10 (14.3) 6 (4.5) —
⫽ 0.03), LN at presentation (RR, 5.5; 95%CI, 1.3–22.6; Lymph node surgery
P ⫽ 0.02), and RAI ablation (RR, 0.2; 95%CI, 0.06 – 0.9; No LN excised 54 (77.1) 94 (70.7) 0.5
P ⫽ 0.03). Excision/sampling 7 (10) 26 (19.5) —
Neck dissection 9 (12.9) 13 (9.8) —
Radioactive iodine 41 (58.6) 96 (72.2) 0.06
Subdivision of Tumors According to Size External radiotherapy 3 (4.3) 4 (3.0) 0.7
The subdivision of primary tumors according to size Recurrences
(ⱕ 5 mm vs. ⬎ 5 mm) did not have significant LR 4 (5.7) 8 (6.0) 1.0
Thyroid bed 2 (2.9) 0 (0.0) 0.12
impact on patient outcome (Table 4). Seventy pa-
LN 2 (2.9) 8 (6.0) 0.5
tients had tumors that measured ⱕ 5 mm in greatest DM 0 (0.0) 3 (2.3) 0.55
dimension: They presented at a younger mean age Status at last follow-up
(45.3 years vs. 49.6 years for patients with tumors Alive with no disease 66 (94.3) 129 (97) 0.1
that measured ⬎ 5 mm) and had lower frequency of Alive with disease 0 (0.0) 1 (0.8) —
LR 0 (0.0) 1 (0.8) —
extrathyroid extension (4.3% vs. 29.3%). No differ-
DM 0 (0.0) 0 (0.0) —
ence was found in the frequency of LN metastasis or Died of disease 0 (0.0) 2 (1.5) —
multifocality. These patients also had a higher rate Died of other disease 4 (5.7) 1 (0.8) —
of lobectomy (14.3% vs. 4.5%) compared with total Ten yr survival (%)
thyroidectomy (85.7% vs. 95.5%), and they received CSS 100.0 100.0 0.35
LRFFS 91.9 92.3 0.97
RAI ablation less frequently (58.6% vs. 72.2%; P
DMFFS 100.0 96.2 0.47
⫽ 0.06).
With regard to the outcome parameters of LR SD: standard deviation; DM: distant metastases; LR: locoregional; CSS: cause-specific survival; LRFFS:
failure and DM, there was no significant difference. local-regional failure-free survival; DMFFS: distant metastasis failure-free survival.
Incorporation of the tumor size variable into multivar-
iate analyses did not alter the results in terms of prog-
nostic factor identification.
Nonetheless, none of patients in the group with dence of a thyroid nodule in the remaining lobe,
small tumors died of disease. Two patients decided to whereas the other patient had no evidence suspicious
undergo completion thyroidectomy at 1.2 years and of recurrence. These two patients may have consid-
7.6 years after lobectomy, after which, contralateral ered undergoing completion thyroidectomy years later
thyroid bed tumor (0.4 cm and 0.3 cm respectively) that revealed multifocal contralateral disease rather
was confirmed by pathology. Both of those patients than developing a clinical recurrence. However, we
belonged to the group with smaller primary tumors. still included them with the patients who developed
Before their second surgery, they were followed regu- local thyroid bed recurrence. Furthermore, 12 patients
larly by clinical examination and thyroid bed ultra- had tumors that measured ⬍ 1–2 mm, and none of
sonography. One patient had ultrasonographic evi- them developed recurrent disease.
 Papillary Microcarcinoma of Thyroid/Chow et al. 37

Patients who Died of Disease DISCUSSION

Two patients died of disease, both from respiratory According to the Hong Kong Cancer Registry data in
failure related to lung metastases. The first patient was 1998 –1999,29 thyroid carcinoma contributed to 15.7%
a lady who was diagnosed with a unifocal, 6 mm PMC of the incidence of malignancies among females in the
at age 74 years. Neither extrathyroid extension nor LN age range 15–34 years, ranking second to breast car-
metastasis was present. She underwent subtotal thy- cinoma. Our data show that PMC contributes to 20%
roidectomy. Lung and bone metastases were detected of all patients with PTC seen in our department in the
at 10.8 years. The patient died 12.9 years after diagno- past decade. PMC, as a specific subgroup of PTC,
sis. Another patient was a man age 44 years with a 1 deserves attention because of its increasing frequency
cm PMC. He had LN metastasis and multifocal disease among patients with PTC in clinical practice and the
at presentation. He underwent total thyroidectomy implications for patient management among young
and unilateral LN dissection. Resection margins were adults.
negative. Lung metastasis was found 9.7 years after The pattern of practice in treatment varies widely
diagnosis, which led to his death at 14.8 years. for patients with PTC. The lack of randomized trials,
temporal changes in presentation and practice, and
conflicting reports on treatment modalities (especially
Patients with LR Recurrence
on RAI) all confuse practitioners about what consti-
Two patients had local thyroid bed recurrences: They
tutes the optimal treatment for this subgroup of pa-
both had primary tumors that measured ⱕ 5 mm, as
tients. This study showed that PMC was capable of
discussed above (see Subdivision of Tumors Accord-
causing mortality (2 of 203 patients; 1%), despite the
ing to Size). Both patients underwent initial lobectomy
overall excellent prognosis for these patients. This
and had their thyroid bed tumors discovered after
concurs with studies that included large numbers of
undergoing completion thyroidectomy years later. It is
patients (178 –1628 patients).6,8,30 The series that re-
arguable whether this represents natural multifocal
ported zero mortality mostly included smaller num-
disease or an actual recurrence. Both patients were
bers of patients (90 –120 patients).9 –11 The recurrence
treated successfully with completion thyroidectomy
rates were remarkably lower for patients who had
and RAI ablation, and both were alive with no disease
small tumors compared with their counterparts who
at the last follow-up.
had larger tumors (⬎ 1 cm). Disease mortality was
Ten patients developed LN recurrences. One pa-
attributed to lung metastasis, whereas patients with
tient had lung metastasis at diagnosis. All but one
LR recurrence were amenable to treatment with com-
patient remained alive with no disease after treat-
binations of surgery, RAI, and EXT. The LN recurrence
ment, which included surgery alone in two patients,
rate was low (5%), comparable to the reported 1.7–
surgery and RAI in five patients, surgery and external
6.2% rate in the literature.6,9,30
radiation therapy (EXT) in one patient, and EXT alone
in one patient. One patient refused treatment and was
Prognostic Factors
alive with a palpable cervical LN at last follow-up.
Prognostic factor analyses revealed that LN disease at
presentation predicted a higher rate of LR recurrence
Patients with Lung Metastasis and DM. Although its significance in predicting sur-
Two of five patients with lung metastasis died of re- vival is disputed, the prognostic value of LN status
spiratory failure. Both had recurrent, bilateral, ma- with regard to recurrent disease has been well docu-
cronodular lung metastases. The other 3 patients were mented in studies of patients with PTC25,31 and
alive with no evidence of disease at last follow-up (at PMC.6,8,30
3.7 years, 6.8 years, and 8.9 years). Two of those pa- The subdivision of tumors according to size did
tients had lung metastases that were detected at diag- not show a significant difference in outcome, although
nosis, and the other patient had lung metastases de- patients in the group with small tumors did not have
tected at recurrence. The chest X-ray findings showed disease-related deaths. The 2 patients who had con-
an either normal or faint reticulonodular (micronodu- tralateral disease at completion thyroidectomy (⬎ 1
lar) pattern. Two patients were diagnosed with a pos- year after primary surgery) may have harbored multi-
itive RAI scan, although their chest X-rays were nor- focal disease rather than true local recurrence. The
mal. These 3 patients were categorized with clinical clinical significance, judged by the small number of
complete remissions (negative serum thyroglobulin events, is difficult to ascertain. Furthermore, 12 pa-
levels and RAI scans and no radiologic evidence of tients who had tumors that measured ⬍ 1–2 mm did
disease) after treatment with RAI doses of 450 mCi, not develop any recurrence. This group of patients
380 mCi, and 200 mCi. had tiny tumors that may be considered innocuous.
38 CANCER July 1, 2003 / Volume 98 / Number 1

Among the patients who developed LR recur- finding at presentation, varying from ⬇ 50% to 80%.46
rence, tumors were as small as 0.3 cm. Most LR recur- To date, the recommendation for LN surgery is not
rences (10 of 12 patients), in fact, were LN recurrences. unified. In Hong Kong, the current approach for LN
Whether this is related to the lack of central compart- surgery is excision for enlarged LNs, with formal neck
mental lymphadenectomy is a matter of concern. dissection reserved for patients with extensive LN me-
We found that multifocality was correlated with tastasis. The sensitivity of LN metastasis detection,
LN metastasis at presentation, which also was noticed apart from more extensive surgery, can be increased
in an autopsy study by Sampson et al.4 We also con- by special immunohistochemical methods. Microme-
firmed that multifocality predicted for LR recurrence, tastases in cervical LNs were detected in 27% of pa-
as reported by Baudin et al.7 tients who had PMC with pN0 by immunohistochem-
Older age at presentation is a universally identi- ical methods.47 It is not surprising that central
fied poor prognostic factor for patients with PTC.32–38 compartmental LN dissection was advocated as part
However, we found that older age did not affect the of surgery in guidelines for the treatment of patients
outcome of patients with PMC adversely, as also ob- with PTC.47– 49 However, dissection should be per-
served in the study by Yamashita et al.8 Whether this is formed very carefully to avoid damaging the recurrent
related to intrinsic biologic differences or to the over- laryngeal nerves and the parathyroid glands. Our data
whelming importance of other factors, like LN status, from Figure 1 revealed that RAI decreased the LN
multifocality, and treatment factors, remains an open recurrence rate from 7.1% to 0.0% in patients with
question for further studies. who were negative for LN metastasis at presentation.
It is tempting to speculate that RAI may eradicate
Treatment of Patients with PMC microscopic metastasis in LNs. If a central compart-
Total thyroidectomy (or bilateral resection) is the pre- mental lymphadenectomy is not performed routinely,
ferred treatment for patients with PTC if their diagno- which is the current scenario in our locality, then the
sis of PTC is made before surgery, based on the high expected incidence of microscopic LN metastasis after
rate of multifocal disease (28.3%) and bilateral disease thyroidectomy would be high. The clinical signifi-
(about 20% at our center). Currently, bilateral surgery cance of these micrometastases is difficult to predict.
is a safe procedure in expert hands. Bilateral lobec- With this caveat in mind, it may be a good policy to
tomy resulted in a reduction of tumor recurrence rates support the use of RAI ablation in regions where
and cause specific mortality in high-risk patients.39 In lymphadenectomy is not a routine practice. Undoubt-
low-risk patients, bilateral lobectomy also reduced the edly, this speculation requires proof in large-scale,
recurrence rate.39 Whether completion thyroidectomy systematic studies. To date, the contemporary litera-
is indicated when a lobectomy specimen reveals an ture on LN surgery and its implications for recur-
incidental PMC should be subjected to individual con- rences do not provide sufficient evidence to guide the
sideration. The management of patients with PTC var- best surgical approach.
ies from completion thyroidectomy (with or without
RAI) to observation, sometimes with follow-up imag- Role of RAI
ing studies (i.e., ultrasonography). In the current study, RAI reduced the LN recurrence
Despite the documented effectiveness of RAI for rate, especially in patients with pT1N0 disease. It is
the treatment of patients with differentiated thyroid possible, as discussed above, that this reduction was
carcinoma, such as reductions in recurrence related to the bulk of disease. In this group of patients
rates,25,32,35–38 the regression of DM,40 – 43 and im- who did not undergo formal LN dissection, the bulk of
provements in survival,25,32,35,36,44 a recently published micrometastases may have been small. In this situa-
study of 2444 patients from a single institute refuted tion, the effect of RAI in eradicating the disease may
these findings.45 The possible reasons for this dis- be demonstrated more easily.
agreement may be related to the bulk or volume of For patients who were diagnosed with DM, the
tumor left after surgery. If surgery can remove all or response to RAI was good. Among the five patients
most of the tumors, then the effect of RAI in eradicat- who had DM, three patients achieved a complete clin-
ing microscopic foci in thyroid remnants or LN me- ical remission with negative serum thyroglobulin lev-
tastasis may be difficult to detect, leading to nonsig- els at last follow-up. It is interesting to note that two
nificant findings. As a result, one expert in endocrine patients were diagnosed with DM during the initial
surgery mentioned that RAI remnant ablation did not postoperative period by posttherapy scans, when DM
improve the already excellent rates of outcome in was not noticeable or was present faintly as reticu-
patients with small PTC.11 lonodular shadows on chest X-rays. Posttherapy scans
For patients with PTC, LN metastasis is a common show greater sensitivity for detecting DM compared
 Papillary Microcarcinoma of Thyroid/Chow et al. 39

with diagnostic scans, because the dose of RAI is carcinoma in a single institute. Head Neck. 2002;24:670 –
higher. Without these scans, diagnosis might have 677.
6. Hay ID, Grant CS, van Heerden JA, Goellner JR, Ebersold JR,
been delayed for these patients. The chance of a cure
Bergstralh EJ. Papillary thyroid microcarcinoma: a study of
is greatest when DM was are RAI avid and while the
535 cases observed in a 50-year period [see discussion].
volume of disease is low (i.e., radiolologically unde- Surgery. 1992;112:1139 –1147.
tectable by chest X-rays and computed tomography 7. Baudin E, Travagli JP, Ropers J, et al. Microcarcinoma of the
scans). With the observation of two fatalities from lung thyroid gland: the Gustave-Roussy Institute experience.
metastases as macronodular recurrences and the suc- Cancer. 1998;83:553–559.
cess with treating early lung metastasis, it is logical to 8. Yamashita H, Noguchi S, Murakami N, et al. Extracapsular
invasion of lymph node metastasis. A good indicator of
suggest that early postoperative RAI can detect early
disease recurrence and poor prognosis in patients with thy-
DM and successfully treat or even cure the DM. roid microcarcinoma. Cancer. 1999;86:842– 849.
9. Appetecchia M, Scarcello G, Pucci E, Procaccini A. Outcome
CONCLUSIONS after treatment of papillary thyroid microcarcinoma. J Exp
The treatment of patients with PMC is controversial. Clin Cancer Res. 2002;21:159 –164.
We believe that tumor size should not be the only 10. Rassael H, Thompson LD, Heffess CS. A rationale for con-
servative management of microscopic papillary carcinoma
factor considered. Although total or near-total thy-
of the thyroid gland: a clinicopathologic correlation of 90
roidectomy was considered the surgical treatment of cases. Eur Arch Otorhinolaryngol. 1998;255:462– 467.
choice in some centers,11 observation was adopted as 11. Furlan JC, Bedard Y, Rosen IB. Biologic basis for the treat-
the protocol at the other extreme.30 We are looking ment of microscopic, occult well-differentiated thyroid can-
forward to the long-term results from Sugitani et al., cer. Surgery. 2001;130:1050 –1054.
who observed the clinical course of patients with 12. Bisi H, Fernandes VS, de Camargo RY, Koch L, Abdo AH, de
asymptomatic PMC without proceeding to any treat- Brito T. The prevalence of unsuspected thyroid pathology in
300 sequential autopsies, with special reference to the inci-
ment.50 Their new protocol of conservative treatment
dental carcinoma. Cancer. 1989;64:1888 –1893.
started in 1995. Twenty-one patients were followed 13. Yamamoto Y, Maeda T, Izumi K, Otsuka H. Occult papillary
without disease progression until 1998.30 However, the carcinoma of the thyroid. A study of 408 autopsy cases.
surveillance policy for patients with PMC is difficult to Cancer. 1990;65:1173–1179.
implement, because our patients have trouble accept- 14. Bramley MD, Harrison BJ. Papillary microcarcinoma of the
ing no treatment for malignant disease in which re- thyroid gland. Br J Surg. 1996;83:1674 –1683.
currence and mortality definitely are observed, which 15. Harach HR, Franssila KO, Wasenius VM. Occult papillary
carcinoma of the thyroid. A “normal” finding in Finland. A
was as long as ⬎ 10 years in this study.
systematic autopsy study. Cancer. 1985;56:531–538.
In conclusion, we advise bilateral thyroidectomy if 16. Fink A, Tomlinson G, Freeman JL, Rosen IB, Asa SL. Occult
patients who have PTC are diagnosed before surgery, micropapillary carcinoma associated with benign follicular
irrespective of tumor size. If poor prognostic factors, thyroid disease and unrelated thyroid neoplasms. Mod
such as LN metastasis or multifocality, are present, Pathol. 1996;9:816 – 820.
then RAI may be a good option to reduce the risk of 17. Fukunaga FH, Yatani R. Geographic pathology of occult
thyroid carcinomas. Cancer. 1975;36:1095–1099.
recurrence. Furthermore, the use of RAI during the
18. Delides GS, Elemenoglou J, Lekkas J, Kittas C, Evthimiou C.
postoperative period has a dual benefit of diagnosing Occult thyroid carcinoma in a Greek population. Neo-
early DM and treating these micrometastases. plasma. 1987;34:119 –125.
Whether the early application of RAI as ablation may 19. Kasai N, Sakamoto A. New subgrouping of small thyroid
improve patient outcome is a matter of debate, and carcinomas. Cancer. 1987;60:1767–1770.
further studies are encouraged. 20. Bondeson L, Ljungberg O. Occult thyroid carcinoma at au-
topsy in Malmo, Sweden. Cancer. 1981;47:319 –323.
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