Diagnostic items and treatment of Plummer's disease: a study on 180 patients.

La Clinica Terapeutica 149, 191, 1998

Introduction

Henry Plummer in 1913 was the first to describe the differences between the hyperthyroidism of

Graves’ disease and the hyperthyroidism in single and multinodular goiter

Plummer disease (PD) is a disorder where a part of the thyroid tissue is functioning autonomously

whereas the normal feedback mechanism is operative in the rest of the gland.

In fact, the PD is characterized by the presence of an autonomous hyperfunctioning “hot” nodule

(AHN) within a normal thyroid gland. The incidence of AHN is higher in areas of iodine deficiency

(endemic goiter) than in iodine-replete regions. AHN represent five to ten per cent of all solitary

nodules and 28% of all hyperthyroidism syndroms. It occur predominantly in women and it develop

more commonly in older age groups. The function and growth of AHN are not dependent on

pituitary stimulation. Histopathologically, the nodules are well circumscribed and most are

encapsulated. The diagnosis of AHN is readly established by combining the results of isotope scan,

inhibition test using thyroid hormones, and stimulation test using thyroid stimulating hormone

(TSH). The clinical and laboratory findings of the nodules have been clarified by the accumulation

of many cases, although the histopathologic findings of AHN are still unclear and little information is

available in standard pathology textbooks.

The diagnosis of AHN is established by a 131I thyroid scintigraphy demonstrating an increased

radionuclide uptake as:

1. a warm (isoactive) nodule with an intensity of activity comparable to that of the remaining

extranodular parenchyma and an euthyroid state;

2. a hyperfunctioning (“hot”) nodule with incomplete suppression of remaining thyroid parenchyma

and an euthyroid state;

3. a “hot” nodule with complete suppression of uptake in the remaining thyroid tissue and an

euthyroid state;

4. a “hot” nodule with complete suppression of remaining thyroid parenchyma and thyrotoxicosis.

The autonomous function of the nodule is characterized by the persistence of radioactive iodine

uptake, despite suppressive doses of thyroid hormone. Other criteria include a flat TSH response

to TRH-test.

The clinical manifestations of the associated hyperthyroxinemia are usually milder than those of

Graves’ disease. Cardiovascular manifestations are predominant and they have a subtle onset that

may be associated with tachycardia, atrial fibrillation, and congestive heart failure. Weakness,

muscle wasting, and emotional lability are common. Eye signs characteristically do not occur.

The aim of this study was to evaluate clinical data of patients who have been undergone to

medical, radionuclide, surgical and percutaneous ethanol injection (PEI) treatment of AHN, to

establish the real value of these therapeutical strategies.

Materials and methods

We examined 180 patients with AHN (146 females, 81.1%, mean of age = 55; 34 males, 18.9%,

mean of age = 56; F/M ratio = 4.3/1) arrived to our observation from January 1990 to December

1997. Five patients studied during 1997 were not included because the period of observation was
less than one year.

125 patients (69.4%) have been undergone medical treatment, 24 surgery (13.3%), 19 radioiodine

therapy (10.6%), and 12 PEI (6.7%).

The diagnosis of autonomous activity of the nodule has been confirmed by thyroid scintigraphy
(131I) with radioactive iodine uptake (RAIU) usually followed by scintigraphy after T3 suppression
testing (T3 administration for 3 to 7 days) (Werner test) or, in some cases, after stimulation with

TRH-test. Thyroid scans have been classified as “compensated” (normal or slightly decreased
paranodular uptake), “borderline” (markedly decreased paranodular uptake) or
“decompensated” (no paranodular activity). The TRH-test has been done by intravenous

stimulation (200 mg, sampling at 0, 15, 30, 45 and 60 min) in 80 out of 180 patients (44.4%). The

goiters have been classified, in according to the amount of autonomous thyroid hormone secretion,
into 3 categories: euthyroid autonomous nodule (normal FT3, FT4 and TSH blood levels; normal

response to TRH-test); autonomous nodule with subclinical hyperthyroidism (euthyroid; TRH-test

unresponsiveness); and autonomous nodule in toxic phase (TRH-test unresponsiveness with

abnormal values of serum free T4 and/or free T3). TRH-test unresponsiveness has been defined

as absence of plasma-TSH (< 0.5 mU/L) 30 minutes after intravenous TRH injection, whereas

subclinical hyperthyroidism has been defined as TRH-resistant suppression of TSH blood levels in

presence of normal range of circulating thyroid hormone concentrations.

The ultrasonographic (US) examination has been performed in all patients. We used a Toshiba
SSH 140-A “HG” (Tokyo, Japan) with a real-time sonographic scanner (7.5 MHz linear probe). Six

sonographic items have been examined: volume of nodules, anechoic intranodular component,

calcification, hypoechogenicity, inhomogeneity of the internal echo pattern and presence or

absence of “halo sign”. From September 1992, the ultrasonography has been integrate with a

qualitative and quantitative evaluation of the vascularization (parenchymal flow and peak systolic

velocity (Vp) evaluated on inferior thyroid artery) by Color Flow Duplex Doppler (CFDD) in 27 out

of 180 patients (15%). The CFDD pattern has been classified under four different types: 1) nodules

without internal or perinodular vascularization; 2) nodules with moderate vascularization confined to

the extranodular tissue; 3) nodules with significant intra and perinodular vascularization; 4) nodules

with an abundant internal vascularization (thyroid inferno).

Furthermore, 49 (27.2%) out of 180 AHN have been studied by US-guided fine needle aspiration

(FNA) cytology, using a 23 and/or 25 Gauge needle.

The cytosmear has been treated with Papanicolau and May-Grünwald-Giemsa (MGG) stains and

immediately studied by the cytopathologist.

We selected the ANH that may be undergone to PEI treatment on the grounds of these clinical-
semeiological features: volume of the lesions (< 4 cm) (volume of the nodule has been calculated

using this formula: lenght x width x depth x 0.52 = volume in ml); US and CFDD pattern; function of
the nodule (euthyroidism, subclinical hyperthyroidism or toxic phase); TSH, FT3, FT4, circulating

anti-thyroglobulin (Tg-Ab) and anti-thyroid peroxidase (TPO-Ab) antibodies and thyroglobulin blood

levels; thyroid scintigraphy with RAIU and Werner test. All patients have been followed-up from 12

to 65 months (mean: 38.5).

Results

In our study we found 47 patients (26.1%) affected by an euthyroid autonomous nodule; 98

patients (54.5%) had an autonomous nodule with subclinical hyperthyroidism and 35 patients

(19.4%) were affected by a toxic autonomous nodule. The Table 1 shows the relationship between

the volume of the lesion (US evaluated) and his function.

The most frequent US aspect was the solid nodular lesion (87 cases = 48.3%); we observed mixed

nodules in 82 out of 180 cases (45.6%), whereas the nodules with anechoic US features were very

rare (11 = 6.1%).

The table 2 shows the relationship between the anechoic thyroid lesion and his function.

We observed that all patients < 20 years old, had a no-colliquative nodules, whereas 75.1% of solid

nodules were present in patients 20-29 years old and 24.9% had colliquative phenomena.

In patients 30-39 years old the frequence of mixed lesions was smaller (13.4%) than the frequence

of solid lesions (86.6%).

We found the smaller percentage of colliquative phenomena in patients 40-49 years old (6.2%)

compared with the percentage of no-colliquative nodules (93.8%).

In 12.3% patients 50-59 years old, the nodules had anechoic areas, whereas 87.7% of the lesions

were solid. Furthermore, patients over 60 years old had no colliquative nodules.

The US study of calcifications, related with thyroid function, showed a frequence like 4.2% in partial

autonomous nodule, 4.1% in pretoxic and 8.5% in toxic nodule (Table 3).

The CFDD evaluation showed nodules with significant intra and perinodular vascularization (type
III) in 3 out of 27 patients (11.1%) and nodules with an abundant internal vascularization (type VI)

in 24 out of 27 patients (88.9%). In our study the cytological evaluation has been performed in 49

patients by FNA (15 partially autonomous nodules, 30.7%; 28 pretoxic nodules, 57.1%; 6 toxic

nodules, 12.2%).

The most frequent cytologic feature was the simple hyperplasia (36 cases = 73.5%); in 6 patients

(12.2%) was present the hemorrhagic aspect; 4 patients (8.2%) had colloid lesions and 3 have not

been cytologically well defined (1 follicular proliferation and 2 hematic swabs).

The table 4 shows the relationship between the cytologic features of the nodular lesions and their

function.

The FNA has been a useful therapeutical method to treat the autonomous colliquative nodule. In

fact, in 6 nodules undergone to withdrawal, we observed a partial or complete regression of lesions

in 40% of the cases; we found an increase of regression percentage (60%) when the sclerotherapy

followed the FNA.

Medical therapy by methimazole (10-20 mg/day per 30-90 days) and propanolol (20 mg every 8 h)

was able to control the thyrotoxicosis in 71.2% of the cases (Table 5).

In 19 patients treated by radionuclide therapy (131I; 2-12 mCi) we observed the successful in
73.7% and relapses of thyrotoxicosis in 10.5% of the cases. As to surgical therapy, we observed

the relapse of the lesion in 4.2% and a real or subclinical hypothyroidism in 37,5% of the patients.

The table 5 shows, also, 12 patients (10 affected by thyrotoxicosis, 2 with subclinical hyperthyroid

state) undergone to PEI and followed-up through-out 12 months. In these subjects the volume of

the lesion was 6-35 ml and the ethanol amount was from 0.5 to 2 times the dimension of the nodule

and inspected in 4-7 times; 4 patients have been treated two times.

The US follow-up showed a significant reduction of the dimensions of the nodule. It has not been

recognized any relapse or hypothyroidism symptoms; the only collateral effects have been a light

pain, a transitory dysphonia and a moderate increase of the temperature.

 Discussion

In adult patients, the decision to treat the autonomous nodule depends upon the size and the

degree of function of the nodule and the age of the patient.

It is very important to confirm the diagnose of Plummer disease evaluating FT3-FT4-TSH blood

levels before the begin of the treatment.

The initial treatment of PD is surely medical: in fact, since 50 years, from the initial application of

Astwood, the use of thionamides has been an efficient strategy to get a permanent remission of

the disease.

Particularly these kind of drugs can inhibit specific steps in thyroid hormone biosyntesis, organ
function and coupling within the thyroid gland.

Furtheremore, the thionamides are useful to prepare patients to thyroidectomy. The indications to

perform in these patients the surgical treatment are now well standardizes. There are some

peculiar and well defined conditions: thyrotoxicosis, pregnancy, inefficacious medical and

radionuclide therapy, suspect of malignant lesion and compressive phenomena.

Radioiodine has been used to treat hyperthyroid disease since almost 50 years. This therapy has a

considerable appeal for the elderly patients with small thyroid nodules, in which the surgical risk is

higher.

Livraghi and others began to apply the percutaneous ultrasound-guided ethanol injection to PD. In

fact this therapeutical strategy is supported by the benign nature of the lesion and by the presence

of the capsule that can avoid the ethanol shedding out of the nodule.

Preliminary results showed that this tecnique may be an important alternative to surgical and

radionuclide therapy, but associated with medical treatment (13, 14).

In our experience we observed that the autonomous nodule is frequent and prevalent in female

sex; furthermore, his hyperfunction is related with old age of the patients and with the volume of the
lesion.
As to US evaluation, it is possible to recognize many different features of the PD. In fact, in 48.3%

of our patients was present a solid nodular lesion with abundant intra- and perilesional

vascularization evaluated by CFDD; in 8.6% of the cases we observed a multinodular goiter, while

45.6% were anechoic areas within the lesions. Furthermore, the colliquative phenomenon was

more frequent in the fourth decade of life and his presence may means the resolution of the lesion.

Moreover, by the US evaluation it is possible identify the calcification phenomena more frequently

in toxic (8.5%), than non-toxic nodules.

As to cytologic features of the PD, the nodular lesion is characterized by colloid lesion, hyperplasia

phenomena and hemorrhagic pseudocysts. Moreover, could be observed an important cellular

hypeactivity with cytoplasmatic vacuoles, thickened chromatin and, by an ultrastructure approach,

an amount of number and volume of mithocondria could be recognized.

The solid nodule presented, instead, a simple hyperplasia-like aspect.

Furthermore it has been possible to recognize the cytologic diagnosis of hemorrhagic pseudocysts

in case of anechoic or mixed lesions, only.

FNA can resolve the colliquative phenomenon in 40% of the cases, and we observed the healing of

60% of hemorrhagic lesions after sclerotherapy. In 71.2% of the patients, by medical therapy, it has

been possible to reach a new state of euthyroidism (the relapse of thyrotoxicosis has been

observed in 6.4% only).

In our study the radionuclide therapy got to clinical hypothyroidism (89.5%), but in 10.5% of

patients it has been inefficacious.

The surgical therapy has been cause of real or subclinical hypothyroidism (37.5%); particulary, we

observed a relapse of PD after lobectomy (26%). Furthermore in 12.5% of the cases some post-

surgical complications have been observed: hypoparathyroidism and vocal cord paralysis.

After PEI, instead, we observed euthyroidism in 75% of patients, without any hypothyroidism or
relapse cases.
The incidence of transitory and exiguous complications (8.3%), may be drasticly cut down

improving the method. All these results are like those reported in the international literature.

So, it doesn’t exist a single therapy to treat the PD because of the great variability of thyroid

function, the frequent post-surgical relapses, the possible spontaneous resolution of the lesion after

the colliquative event, the dimension and the compressive phenomena of the nodular lesions.

On the grounds of our studies, we think that a careful clinical control, associated with a medical

therapy in case of thyrotoxicosis, may be the mainly therapeutic option for patients affected by PD.

So, the surgical or radionuclide treatment could be addressed to the big or toxic nodules insensible

to pharmacological therapy. The PEI represent a new method to treat the PD because of

efficacious, harmless, cheap and practical too.

Volume Euthyroid autonomous nodule Preclinical hyperthyroidism Toxic nodule

(cm)
0-1 3/47 (6.4%) 8/98 (8.1%) 0/35 (0%)

1-2 15/47 (31.9%) 25/98 (25.6%) 6/35 (17.2%)

2-3 20/47 (42.6%) 31/98 (31.6%) 13/35 (37.1%)
>4 9/47 (19.1%) 34/98 (34.7%) 16/35 (45.7%)
Total 47/47 (100%) 98/98 (100%) 35/35 (100%)

Table 1: Volume of the nodules in Plummer disease: relationship between the volume of the lesion
(US evaluated) and his function.

Function Number Percentage

Euthyroid autonomous nodule 3/47 6.4
Preclinical hyperthyroidism 5/98 5.1
Toxic nodule 2/35 5.7
Total 10/180 5.5

Table 2: Relationship between nodules with anechoic US features and their function in Plummer
disease.

Function Number Percentage

Euthyroid autonomous nodule 2/47 4.2
Preclinical hyperthyroidism 4/98 4.1
Toxic nodule 3/35 8.5
Total 9/180 5

Table 3: frequency of the calcifications related with the function of the nodule.
 Function Simple Colloid hemorrhagic not well
hyperplasia lesion cyst defined
Euthyroid 11/36 2/4 1/6 0/3
autonomous
nodule (30.6%) (50%) (16.7%) (0%)
Subclinical 21/36 2/4 2/6 1/3
hyperthyroidism
(58.3%) (50%) (33.3%) (33.3%)
Toxic nodule 4/36 0/4 3/6 2/3

(11.1%) (0%) (50%) (66.7%)

Total 36/36 4/4 6/6 3/3

(100%) (100%) (100%) (100%)

Table 4: cytological features of the autonomous nodule related with his function.

Therapy Euthyroidism Hypothyroidism Relapse Complication

Medical 89/125 0/125 8/125 3/125

(125) (71,2%) (0%) (6.4%) (2.4%)

Surgery 21/24 9/24 1/24 3/24

(24) (87.5%) (37.5%) (4.2%) (12.5%)

Radioiodine 14/19 17/19 2/19 0/19

(19) (73.7%) (89.5%) (10.5%) (0%)

PEI 9/12 0/19 0/19 1/12

(12) (75%) (0%) (0%) (8.3%)

Table 5: evaluation and issues of the treatment of the autonomous nodule.