Journal of Cytology
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ORIGINAL ARTICLE  
Year : 2013  |  Volume : 30  |  Issue : 2  |  Page : 125-129
Cytomorphologic significance of marginal vacuoles in diffuse thyroid enlargements


1 Department of Pathology, Saraswathi Institute of Medical Sciences, Hapur, Ghaziabad, India
2 Department of Pathology, S.N. Medical College, Agra, Uttar Pradesh, India

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Date of Web Publication29-May-2013
 

   Abstract 

Background: Fine needle aspiration cytology (FNAC) of the thyroid is an established first-line test for thyroid lesions. Marginal vacuoles (MVs) have been associated with hyperactivity of the thyroid, but some studies have pointed towards their nonspecific status.
Aims: To assess the presence of MVs in diffuse thyroid enlargements and evaluate the strength of correlation between MVs, levels of thyroid hormone and cytological diagnosis.
Materials and Methods: Ninety-seven cases of diffuse thyromegaly were studied. Cytomorphological features were examined with special attention to MVs. MVs were graded as scant, moderate and abundant. Hormonal status of the patients was recorded. The presence and grading of MVs was correlated with cytological diagnosis and hormonal status. The strength of association was studied by applying the Chi-square test and test of proportion; a P ? 0.05 was considered significant.
≤ 0.05 was considered significant.
Results: Abundant MVs were not associated with hypothyroidism in this study; 79% of these cases were hyperthyroid. The correlation between moderate/insignificant MVs and functional status of the thyroid gland was inconclusive. Further, abundant MVs in thyroid FNACs were seen in cases of primary hyperplasia and Hashimoto's thyroiditis. There was a significant correlation between the presence of abundant/moderate MVs and primary hyperplasia and their absence in colloid goiter (P = 0.01 and 0.004, respectively).
Conclusions: A significant association was found between abundant MVs and a hyperthyroid state. Moderate/absent MVs in diffuse goiters were not found to correlate with thyroid function. Thus, all diffuse goiters with prominent MVs require hormonal evaluation to rule out hyperfunction of the thyroid.

Keywords: Marginal vacuoles; thyroid fine needle aspiration cytology; thyroid hormones.

How to cite this article:
Gupta A, Singhal M, Kalhan S, Gupta A, Singhal O, Kaur V. Cytomorphologic significance of marginal vacuoles in diffuse thyroid enlargements. J Cytol 2013;30:125-9

How to cite this URL:
Gupta A, Singhal M, Kalhan S, Gupta A, Singhal O, Kaur V. Cytomorphologic significance of marginal vacuoles in diffuse thyroid enlargements. J Cytol [serial online] 2013 [cited 2019 Oct 18];30:125-9. Available from: http://www.jcytol.org/text.asp?2013/30/2/125/112657



   Introduction Top


Fine needle aspiration cytology (FNAC) of the thyroid gland is firmly established as a first-line diagnostic test for the evaluation of goiter and as the single most effective test for preoperative diagnosis of lesions of the thyroid gland. [1],[2] Recent studies have also confirmed that FNAC is more sensitive as well as specific in segregating neoplastic and non-neoplastic thyroid pathology. [2],[3] Identification of predominant cell pattern, cell morphology and background details in FNAC smears play an important role in diagnosing various thyroid lesions with accuracy. [3]

Marginal vacuoles (MVs) have been described as irregular cytoplasmic vacuoles measuring 1-7 μm in diameter, deeply eosinophilic in the periphery with a largely unstained central area on May-Grünwald-Giemsa (MGG) stained smears. They tend to gather peripherally in a group of follicular epithelium and hence are called marginal vacuoles. The term fire flare has also been used because of the resemblance of MVs to a rising or spreading fire. MVs stain poorly or not at all with periodic acid-Schiff (PAS). They are not positive for acid phosphatases. In wet fixed smears stained with hematoxylin and eosin, MVs are not as distinct as in dry fixed MGG-stained smears.

The true nature of MVs is not known, although ultrastructural studies have indicated that these are dilated cisternae of endoplasmic reticulum generated by hyperactivity and vacuolar content as dilated phagolysosomes. [4] Soderstrom et al. [5] in 1972 were the first to discuss marginal vacuoles in the cytoplasm of follicular cells in smears from toxic goiters. They reported that MVs along with a nuclear ring pattern in follicular fragments are fairly specific signs of hyperfunction of the thyroid. Subsequent studies, however, revealed that MVs although suggestive of thyrotoxicosis were nonspecific as they are also encountered in nontoxic goiter, Hashimoto's thyroiditis and follicular carcinoma. [6] Das et al., [7] in 2006, were the most recent to comment on MVs; according to them, MVs represent diffusing out of thyroid hormones from the basal aspect of follicular cells on their way to interfollicular capillaries.

This study was conducted with the aim of looking for the presence of MVs and strength of correlation (if any) with thyroid hormone levels and cytological diagnoses in diffuse thyroid enlargements.


   Materials and Methods Top


This study was conducted on 97 cases presenting with diffuse thyromegaly. The hormonal status of the patients was also recorded. FNAC was done using standard procedure on an outpatient basis. Air-dried smears were prepared and stained with MGG stain. Adequacy of the samples was assessed by using the Hamburger criteria, that is, six clusters of cells in at least two slides prepared from separate aspirates. [8] MVs were studied and graded as per the following criteria:

  1. No/scanty MVs: Distinct MVs exceeding 2 μm in diameter demonstrated in <10% of cells.
  2. Moderate MVs: MVs seen in 10-50% of the cells examined.
  3. Abundant MVs: Presence of MVs in >50% of the cells examined.
Though both abundant and moderate MVs were treated as separate entities in our study, the presence of at least a moderate degree of MVs was considered as significant for the sake of easy comparison with earlier published studies.

The hormonal status of all the patients having diffuse enlargements was taken into account and depending on the values of the thyroid function test, the patients were categorized as euthyroid, hyperthyroid and hypothyroid.

Based on cytomorphological features, we segregated three broad groups, namely, primary hyperplasia, Hashimoto's thyroiditis and colloid goiter.

The presence and degree of grading of MVs was then correlated individually both with the cytological diagnosis and thyroid hormonal status of the patient.

Statistical evaluation was done using SPSS version 15.0 (LEAD Technologies, Inc., Charlotte, North Carolina, USA). The Chi-square test and test of proportion were applied to study the strength of association amongst MVs with cytological diagnoses and hormonal status. A P ≤ 0.05 was considered as significant and a P ≤ 0.01 as highly significant.


   Results Top


The study evaluated 97 cases of goiters. Cytomorphological features were studied with special attention to the presence and grading of MVs. The latter was correlated with cytological diagnoses and thyroid function.

There were 84 (86.6%) females and 13 (13.4%) males in this study. Male-to-female ratio was 1:6.4. There was female preponderance in all the categories.

The mean age was 29.5 ± 13.5 years, with the maximum number of cases belonging to the third and fourth decades.

There was no statistically significant correlation between age/sex and the occurrence of MVs.

It was observed that among 97 diffuse goiters, Hashimoto's thyroiditis accounted for 52 of 97 cases (53.6%), followed by colloid goiter in 26 cases (26.8%). Primary hyperplasia accounted for 19 cases (19.6%) [Table 1]. On categorizing the cases according to their hormonal status, euthyroid cases accounted for 51 of 97 cases (52.6%). Those having hyperthyroidism accounted for 32 cases (33%) and the rest, that is, 14 cases (14.4%) were hypothyroid [Table 2].

On studying the association of cytological diagnosis with the presence of MVs and applying Pearson's Chi-square test and test of proportion, it was observed that primary hyperplasia had a significant correlation with the presence of MVs (P = 0.004) and colloid goiter with the absence of MVs (P = 0.01). However, Hashimoto's thyroiditis did not show a statistically significant correlation [Table 1].
Table 1: Correlation of marginal vacuoles with cytological diagnosis

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Table 2: Correlation of marginal vacuoles with hormonal status

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On studying the association of hormonal status with the presence of MVs, it was found that there was an overall significant correlation in all three hormonal groups with MVs (P = 0.001). On intragroup comparison, it was found that euthyroid and hyperthyroid patients had a significant correlation with a P value of 0.009 and 0.001, respectively. The correlation in the hypothyroid group was statistically insignificant with a P value of 0.14 [Table 2].

In cases of primary hyperplasia (n = 19), where 16 (84.2%) patients were hyperthyroid biochemically, abundant MVs could be detected in the majority (52.6%) of the smears and significant MVs (abundant + moderate) in 89.4% of the smears [Figure 1].
Figure 1: Primary hyperplasia: Thyroid follicular epithelium showing abundant MVs (MGG, ×400)

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As far as Hashimoto's thyroiditis was concerned (n = 52), 46% patients were euthyroid and the rest were either hypo or hyperthyroid in equal proportion. Abundant MVs were observed in 17%, moderate MVs in 36.5% and no MVs in 46% of the cases [Figure 2]. No significant correlation was observed between the presence of MVs and Hashimoto's thyroiditis.
Figure 2: Hashimoto's thyroiditis: Intraepithelial lymphocytes and Hurthle cells with abundant MVs (MGG, ×400)

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Majority of the patients with colloid goiter (n = 26) were euthyroid (92.3%). None of the patients was hypothyroid. Of all the patients, >90% had no MVs in their aspiration cytology smears. Three cases which showed moderate MVs were those in which besides abundant colloid, follicular epithelium was also present. A significant correlation was observed between the absence of MVs and colloid goiter.


   Discussion Top


A detailed study of 97 cases of diffuse thyroid enlargements was undertaken. Cytomorphological features were studied with special attention to the presence and grading of MVs and their correlation with thyroid function and cytological diagnosis. The presence of prominent MVs along with a nuclear ring pattern in follicular wall fragments are fairly specific signs of thyroid hyperfunction but their frequency can also be high in Hashimoto's thyroiditis, cellular adenomatoid nodules and follicular neoplasms. [5],[6] It has been suggested that MVs represent the diffusing out of thyroid hormones from the basal aspect of follicular cells. [7]

In our study, it was observed that abundant MVs were present in 10 of 19 cases (52.6%) of primary hyperplasia. Seventeen of 19 cases (89.4%) showed the presence of at least a moderate degree of MVs in their smears. In the earlier published study conducted by Soderstrom and Nilsson [5] and Jayaram et al., [9] abundant MVs were present in 40-60% cases of primary hyperplasia and could be significantly detected in more than 80% of the cases. Results of our study are in fair agreement with both of them.

Regarding the association between the presence of MVs and hormonal status in Hashimoto's thyroiditis, 28 out of 52 cases (53.8%) showed the presence of significant MVs (abundant + moderate) in our study. On correlating this feature with thyroid function, it was found that eight of 28 (29%) cases were hyperthyroid. Other workers have not correlated the presence of MVs in Hashimoto's thyroiditis with thyroid function.

None of our cases of colloid goiter showed abundant MVs. Moderate MVs were present in three of 26 cases (11%). This frequency is much less than that observed by Nilsson [5] who noted MVs in 32.6% of the cases of nontoxic goiter. The results of our study are in fair agreement with those of Das et al. [6] who observed MVs in 5.2% cases of colloid goiter.

Considering the correlation between abundant MVs (n = 19) in diffuse goiters and levels of thyroid hormone, some interesting observations emerged: None of these cases were hypothyroid; 21% of diffuse goiters with abundant MVs were euthyroid. Thus, the mere presence of abundant MVs does not necessarily imply hyperfunction of the thyroid. Hyperthyroid cases constituted 79% of this group; thus, all diffuse goiters with prominent MVs require hormone levels to evaluate hyperfunction of the thyroid. Though primary hyperplasia was the single largest contributor to this group, autoimmune thyroiditis was a close second. Together, these two entities accounted for all the cases in this group. This feature therefore indicates considerable cytologic overlap between the two conditions. On a detailed search of the literature, studies correlating the graded presence of MVs with thyroid function were not found. Correlation of MVs as a whole has, however, been done by Soderstrom and Nilsson, [5] Das et al. [6] and Jayaram et al. [9]

On correlating moderate MVs (n = 29) in diffuse goiters and thyroid hormone levels, it was noted that a significant proportion of these (5 of 29 cases; 17.2%) were hypothyroid. All hypothyroid cases had Hashimoto's thyroiditis. Hyperthyroid cases constituted seven of 29 (24.1%) cases of this group and primary hyperplasia accounted for six of these seven cases. Thus, no conclusion could be drawn on the basis of moderate MVs regarding functional status of the thyroid gland.

Regarding the correlation between the presence of no/scanty MVs (n = 49) in diffuse goiters and levels of the thyroid hormone, it was observed that the majority of such cases belonged to the category of colloid goiter and Hashimoto's thyroiditis, accounting for 46.9% and 38.8% cases, respectively. Hypothyroid cases accounted for nine of 49 (18.4%) of the cases. All the hypothyroid cases were of Hashimoto's thyroiditis and this is anticipated, as the gland is destroyed by an autoimmune process during the course of the disease. Euthyroid cases represented more than half of those with no/scanty MVs (61.2%). The majority of these patients had colloid goiter. We also encountered two cases of primary hyperplasia with no/scant MVs with biochemical evidence of hyperthyroidism. This implies that even hyperthyroid cases may lack MVs.


   Conclusions Top


The presence of abundant MVs in diffuse goiters was not associated with a hypothyroid state in this study. A significant association was found between abundant MVs and a hyperthyroid state. Moderate/absent MVs in diffuse goiters were not found to correlate with thyroid function. Thus, all diffuse goiters with prominent MVs require hormonal evaluation to rule out hyperfunction of the thyroid. It is also inferred that in the presence of abundant MVs in thyroid FNA smears, primary hyperplasia should be ruled out.

 
   References Top

1.Orell SR, Sterrett GF, Whitaker D. Fine needle aspiration cytology. 4 th ed. New York: Elsevier Churchill Livingstone; 2005.  Back to cited text no. 1
    
2.Ko HM, Jhu IK, Yang SH, Lee JH, Nam JH, Juhng SW, et al. Clinicopathologic analysis of fine needle aspiration cytology of thyroid: A review of 1,613 cases and correlation with histopathologic diagnoses. Acta Cytol 2003;47:727-32.  Back to cited text no. 2
    
3.Bommanahali BP, Bhat RV, Rupanarayan R. A cell pattern approach to interpretation of fine needle aspiration cytology of thyroid lesions: A cyto-histomorphological study. J Cytol 2010;27:127-32.  Back to cited text no. 3
    
4.Galera-Davidson H. Diagnostic problem in thyroid FNA. Diagn Cytopathol 1997;17:422-8.  Back to cited text no. 4
    
5.Soderstrom N, Nilsson G. Cytologic diagnosis of thyrotoxicosis. Acta Med Scand 1972;205:263-5.  Back to cited text no. 5
    
6.Das DK, Jain S, Tripathi RP, Parkash S, Khan IU, Rajwanshi A, et al. Marginal vacuoles in thyroid aspirates. Acta Cytol 1998;42:1121-8.  Back to cited text no. 6
    
7.Das DK. Marginal vacuoles (fire-flare appearance) in fine needle aspiration smears of thyroid lesions: Does it represent diffusing out of thyroid hormones at the base of follicular cells? Diagn Cytopathol 2006;34:277-83.  Back to cited text no. 7
    
8.Hamburger JI, Husain M. Semiquantitative criteria for fine-needle biopsy diagnosis: Reduced false-negative diagnoses. Diagn Cytopathol 1998;4:14-7.  Back to cited text no. 8
    
9.Jayaram G, Singh B, Marwaha RK. Grave's disease. Appearance in cytologic smears from fine needle aspirates of the thyroid gland. Acta Cytol 1989;33:36-40.  Back to cited text no. 9
    

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Correspondence Address:
Anshu Gupta
D-200, S.P.S. Residency, Vaibhav Khand, Indirapuram, Ghaziabad, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9371.112657

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