Differences between Follicular Variant and Conventional Papillary Thyroid Carcinoma According to Fine-needle Aspiration Cytology

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1 Journal of Basic & Clinical Medicine Differences between Follicular Variant and Conventional Papillary Thyroid Carcinoma According to Fine-needle Aspiration Cytology Takashi Koshikawa 1, Nao Fujita 2, Nanae Ueda 2, Yuko Ota 2, Ei-ichi Sasaki 3, Yoshiko Murakami 3, Yasushi Yatabe 3, Yasuhisa Hasegawa 4 1 Department of Pathology, Shubun University Faculty of Nursing, Ichinomiya; and 2 Department of Clinical Laboratories, 3 Pathology and Molecular Diagnostics, and 4 Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan Abstract Introduction Journal of Basic & Clinical Medicine 2018; 7(1):1-7 Objectives: This paper was aimed to study the differences between follicular variant papillary thyroid carcinoma (FVPTC) and conventional papillary thyroid carcinoma (PTC) according to fineneedle aspiration cytology and to propose how to distinguish them cytologically. Methods: We re-evaluated cytological smears of FVPTCs and conventional PTCs that were histologically confirmed after a surgical procedure. Results: Nuclear characteristics, including intranuclear cytoplasmic inclusions, nuclear grooves, and powdery chromatin, are important signs of papillary carcinoma, but they are not useful for differentiation of FVPTC from conventional PTC. Aside from nuclear findings, papillary cell clusters, monolayered cell sheets, ropy colloids, and multinucleate giant cells are characteristic features of conventional PTC. On the other hand, microfollicular cell clusters are a characteristic feature of both invasive and noninvasive FVPTC. In case that nuclear findings are likely to be papillary carcinoma, the data on cell clusters and on the smear background need to be considered. If the following parameters are scored - papillary cell clusters, predominance of monolayered cell sheets, predominance of microfollicular cell clusters, ropy colloids, and multinucleate giant cells - then FVPTC can be distinguished from conventional PTC. Cytological characteristics of noninvasive FVPTC, recently renamed NIFTP (noninvasive follicular thyroid neoplasm with papillary-like nuclear features), are nearly identical to those of invasive FVPTC, except for nuclear inclusions. Although nuclear inclusions are more frequently seen in invasive FVPTC, it is difficult to distinguish noninvasive FVPTC from invasive FVPTC by fine-needle aspiration cytology. Conclusions: For discrimination of FVPTC from conventional PTC, papillary cell clusters, predominance of monolayered cell sheets, predominance of microfollicular cell clusters, ropy colloids, and multinucleate giant cells are effective characteristics. If these parameters are scored, then FVPTC as well as NIFTP can be clearly distinguished from conventional PTC. Key Words: Thyroid, papillary carcinoma, follicular variant, fine needle aspiration, cytology Received: January 23, 2018; Accepted: February 7, 2018 *Correspondence author: Dr. Takashi Koshikawa, Department of Pathology, Shubun University Faculty of Nursing. 6 Nikko-cho, Ichinomiya, Aichi , Japan koshikawa.t@shubun.ac.jp Follicular variant papillary thyroid carcinoma (FVPTC) is a subtype of thyroid papillary carcinoma (PTC) (1). Recently, noninvasive FVPTC has been renamed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and defined as a low-risk thyroid tumor because of its better clinical course relative to conventional PTC (2-4). Therefore, it is important to distinguish NIFTP and invasive FVPTC from conventional PTC by fine-needle aspiration cytology (FNAC). In this study, we evaluated the differences of cytological characteristics among NIFTP, invasive FVPTC and conventional PTC, and discussed how to differentiate among them by FNAC. Materials and Methods To investigate the cytological features of FVPTC including NIFTP and conventional PTC, we reviewed cytological smears of PTCs that were histologically confirmed after a surgical procedure. From 1999 to 2012, 2131 thyroid FNAC examinations were conducted in the Head and Neck Surgery Department, Aichi Cancer Center Hospital. Among them, 323 PTC cases were identified by surgical treatment. The PTC cases consisted of 316 conventional PTCs and 7 FVPTCs. Two of the 7 FVPTCs were noninvasive, now called NIFTP (2/323; 0.6%), and 5 were invasive (5/323; 1.5%). The patients with conventional PTC included 251 females and 65 males. Their ages ranged from 20 to 84 years (mean: 54.9). Patients with invasive FVPTC included 4 females and 1 male. Their ages ranged from 41 to 63 years (mean: 55.0). NIFTP patients consisted of 2 females, 37 and 71 years old (mean: 54.0 years), respectively. The results of routine cytological analysis for NIFTP, FVPTC, and conventional PTC according Thyroid Bethesda System (TBS) are shown in Table 1 (5). As to the conventional PTC, 214 of 316 cases (68%) were classified as malignant. As for the 5 FVPTC cases, however, only 1 of them (20%) was diagnosed as malignant, and most cases were classified into indistinct diagnostic categories. The 2 NIFTP cases were diagnosed as follicular neoplasms. The cytological specimens of most recent consecutive 60 cases of conventional PTC classified as malignant during routine examination were subjected to re-evaluation. The cytological specimens of the 5 FVPTC and 2 NIFTP cases were also analyzed. Both Diff-Quik and Papanicolaou smears of each case were examined under a microscope. The following 12 cytological characteristics were evaluated: nuclear inclusions, nuclear grooves, powdery chromatin, true papillary cell clusters, monolayered cell sheets, predominance of monolayered cell sheets in the smears, S&S PUBLICATIONS - 1 -

2 Table 1. Results of routine cytological diagnosis of NIFTP, FVPTC, and conventional PTC Cytological Diagnosis NIFTP FVPTC Conventional PTC Malignant SFM (Suspicious for Malignancy) FN/SFN (Follicular Neoplasm or Suspicious for Follicular Neoplasm) AUS/FLUS (Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance) Benign Unsatisfactory Total microfollicular cell clusters, predominance of microfollicular cell clusters in the smears, ropy colloids, dense globules of colloids, multinucleate giant cells, and Psammoma bodies. Results Cytological findings of conventional PTC Nuclear findings: One of the most typical cytological parameters of PTC is the nuclear shape. Nuclear inclusions, i.e., intranuclear cytoplasmic inclusions (Figure 1), are well known to be a diagnostic criterion (6-11). True nuclear inclusions contain cytoplasmic content and are surrounded by a chromatin border outside. Pseudonuclear inclusions without cytoplasmic content inside cannot be used for diagnosis. Nuclear grooves (Figure 2) and fine powdery chromatin (Figures 1 and 2) are also important characteristics of PTC. Nuclear grooves are not a useful parameter if its number is small. On the basis of our experience, we defined nuclear grooves as 2 grooves per nucleus. Cell clusters: Although nuclear findings are useful, some characteristics other than nuclear parameters are also important for a definitive diagnosis of PTC (6-11). Papillary cell clusters and papillary structure are the most essential signs of PTC. Papillary cell clusters with a fibrovascular core (Figure 3) are true papillary cell clusters. Pseudopapillary cell clusters, which lack a fibrovascular core, are also seen, but they are often difficult to distinguish from syncytial aggregates of microfollicular cell clusters. Papillary fibrovascular stroma is another distinctive characteristic and often forms a fingerlike radial structure (Figure 4). Papillary cell clusters are useful, but the most frequent cell clusters in PTC smears are monolayered sheets of tumor cells (Figure 5). Microfollicular cell clusters are seen in some PTC smears, but they are not characteristic signs of conventional PTC. Background characteristics: Background features, such as ropy colloids, multinucleate giant cells, and Psammoma bodies are additional important signs of papillary carcinoma (6-11). Ropy colloids are long-stretched colloids (Figure 6), also called chewing gum colloids. Multinucleate giant cells (Figure 7) are histiocytic giant cells. They are sometimes confused with multinucleate foamy macrophages. Nonetheless, these cell types can be distinguished because the cytoplasm of multinucleate giant cells is smooth and homogeneous, not foamy as in foamy macrophages. Psammoma bodies are concentric calcified bodies and are highly suggestive of PTC, but they are not seen frequently. Cytological characteristics of FVPTC and NIFTP FNAC smears of FVPTC are mainly composed of microfollicular cell clusters (Figure 8) with or without dense globules of colloids (6-11). They are very similar to a follicular neoplasm in the low-power view but show nuclear characteristics similar to those of papillary carcinoma in the high-power view (Figure 9). Microfollicular cell clusters often form syncytial aggregates (Figure 10). They look like papillary cell clusters without a fibrovascular core and sometimes are difficult to distinguish. Nuclear signs of FVPTC are subtle in contrast to those of conventional PTC (11), and nuclear inclusions are reported to be uncommon in FVPTC (12). Cytological characteristics of NIFTP, formerly noninvasive FVPTC, are nearly the same as those of invasive FVPTC. No distinguishing characteristics of noninvasive FVPTC are known at present (13-14). In principle, a noninvasive tumor is cytologically indistinguishable from an invasive one: The discrimination between NIFTP and invasive FVPTC by FNAC may be very difficult. A comparison of key characteristics of NIFTP, FVPTC, and conventional PTC Cytological findings of re-examined NIFTP, FVPTC, and conventional PTC are shown in Table 2. Regarding nuclear findings, nuclear grooves and powdery chromatin were similar among these 3 groups, but nuclear inclusions were less frequent in FVPTCs than in conventional PTCs, and not seen in NIFTPs. Thus, nuclear parameters except for nuclear inclusions are characteristic features of all 3 groups: NIFTP, FVPTC, and conventional PTC. In contrast, nuclear inclusions occur differently among these 3 groups: they are most frequent in conventional PTCs (100%), less frequent in FVPTCs (60%), and least frequent in NIFTPs (0%). Regarding cell clusters, true papillary cell clusters were seen in nearly a half of conventional PTC cases, but not in NIFTPs and FVPTCs. Monolayered cell sheets were noticed in all conventional PTCs but were rare in NIFTPs and FVPTCs. Moreover, the predominance of monolayered cell sheets was detected in 78% of conventional PTC cases. On the other hand, microfollicular cell clusters were more frequent in NIFTPs and FVPTCs than in conventional PTCs, and microfollicular cell clusters dominated in all cases of NIFTP and FVPTC but did not in conventional PTCs. Therefore, papillary cell clusters and monolayered cell sheets are characteristic features of conventional PTC, whereas microfollicular cell clusters are characteristic features of NIFTP and FVPTC. As for the background findings, ropy colloids and multinucleate giant cells were more frequently seen in conventional PTCs. Neither of these feature was detected in FVPTC cases. Dense globules of colloids and Psammoma bodies showed no obvious differences among the 3 groups. Accordingly, ropy colloids and multinucleate giant cells are characteristic features of conventional PTC, not of NIFTP or FVPTC

3 Fig. 1. Nuclear inclusions and powdery chromatin of papillary carcinoma (Papanicolaou stain, x100). Fig. 4. Papillary clusters with fingerlike radial stroma of papillary carcinoma (Diff-Quik stain, x10). Fig. 2. Nuclear grooves and powdery chromatin of papillary carcinoma (Papanicolaou stain, x100). Fig. 5. Monolayered clusters of papillary carcinoma (Papanicolaou stain, x20). Fig. 3. A true papillary cluster of papillary carcinoma (Diff-Quik stain, x20). Fig. 6. Ropy or chewing gum-like colloids of papillary carcinoma (Diff-Quik stain, x20)

4 Table 2. Cytological characteristics of NIFTP, FVPTC, and conventional PTC Cytological Characteristics NIFTP FVPTC Conventional PTC Nuclear inclusions 0% (0/2) 60% (3/5) 100% (60/60) Nuclear grooves 100% (2/2) 100% (5/5) 100% (60/60) Powdery chromatin 100% (2/2) 80% (4/5) 98% (59/60) Papillary cell clusters 0% (0/2) 0% (0/5) 53% (32/60) Monolayered cell sheets 0% (0/2) 14% (1/5) 100% (60/60) Predominance of monolayered cell sheets 0% (0/2) 0% (0/5) 78% (47/60) Microfollicular cell clusters 100% (2/2) 100% (5/5) 42% (25/60) Predominance of microfollicular cell clusters 100% (2/2) 100% (5/5) 0% (0/60) Ropy colloids 0% (0/2) 0% (0/5) 35% (21/60) Dense globules of colloids 50% (1/2) 40% (2/5) 40% (24/60) Multinucleate giant cells 0% (0/2) 0% (0/5) 57% (34/60) Psammoma bodies 0% (0/2) 0% (0/5) 3% (2/60) Fig. 7. A multinucleate giant cell of papillary carcinoma (Diff- Quik stain, x20). Fig. 9. Nuclear features of follicular variant papillary carcinoma (Papanicolaou stain, x100). Fig. 8. Microfollicular cell clusters of follicular variant papillary carcinoma (Papanicolaou stain, x20). Fig. 10. A syncytial aggregate of microfollicular cells and a dense globule of colloids (lower right) of follicular variant papillary carcinoma (Diff-Quik stain, x10)

5 Table 3. Scoring of nuclear characteristics of NIFTP, FVPTC, and conventional PTC Nuclear Findings Score Nuclear inclusions 1 Nuclear grooves 1 Powdery chromatin 1 Table 4. Results of nuclear scoring for NIFTP, FVPTC, and conventional PTC Conventional Total Score NIFTP FVPTC PTC 3 40% (2/5) 98% (59/60) 2 100% (2/2) 60% (3/5) 2% (1/60) 1 0 Table 5. Scoring of cytological characteristics other than nuclear features for NIFTP, FVPTC, and conventional PTC Cytological Parameters Score Papillary cell clusters 1 Predominance of monolayered cell sheets 1 Predominance of microfollicular cell clusters -1 Ropy colloids 1 Multinucleate giant cells 1 Table 6. Results of scoring of cytological findings other than nuclear features for NIFTP, FVPTC, and conventional PTC Total Score NIFTP FVPTC Conventional PTC 4 8% (5/60) 3 35% (21/60) 2 32% (19/60) 1 22% (13/60) 0 3% (2/60) % (2/2) 100% (5/5) How to distinguish NIFTP, FVPTC, and conventional PTC NIFTP and FVPTC showed different frequencies of nuclear inclusions but were very similar for other features. The two cannot be distinguished by cytological findings except for nuclear inclusions. The frequency of nuclear inclusions is the highest in conventional PTCs, somewhat lower in invasive FVPTC cases, and lowest in NIFTPs. This means that the nuclear atypia is most obvious in conventional PTC and less obvious in NIFTP and in invasive FVPTC. To discriminate them clearly, scoring of nuclear findings was conducted. Each nuclear characteristic and score are listed in Table 3. Each score represents 1 point, and total scores ranged from 3 to 0. The results on total scores are shown in Table 4. Although nearly all cases of conventional PTC had a score of 3, this score (3) was seen in 2 of 5 cases (40%) of invasive FVPTC and in no cases (0%) of NIFTP. Thus, the total score of 3 for the nucleus may be considered nearly compatible with malignancy. The following findings other than nuclear features - papillary cell clusters, predominance of monolayered cell sheets in the smears, predominance of microfollicular cell clusters in the smears, ropy colloids, and multinucleate giant cells - are useful for distinguishing NIFTP and invasive FVPTC from conventional PTC. Papillary cell clusters, the predominance of monolayered cell sheets, ropy colloids, and multinucleate giant cells are characteristic features of conventional PTC, whereas predominance of microfollicular cell clusters is a characteristic feature of NIFTP and invasive FVPTC. To discriminate them clearly, scoring of the parameters other than nuclear features was conducted. Each parameter and score are presented in Table 5. Each score except for the predominance of microfollicular cell clusters corresponded to 1 point because these findings are characteristic features of conventional PTC. On the contrary, predominance of microfollicular cell clusters was set to -1 because this finding is a characteristic feature of FVPTC, not of conventional PTC. Thus, total scores ranged from 4 to -1. The results on total scores are presented in Table 6. The total score was -1 in 2 NIFTP cases and in 5 FVPTC cases. On the other hand, the total score of conventional PTCs ranged from 0 to 4, i.e., there was no negative score in cases of conventional PTC. The difference in the total score is obvious between conventional PTC and FVPTC including NIFTP. By this scoring method, NIFTP and FVPTC can be clearly distinguished from conventional PTC. Discussion The prevalence of FVPTC in PTC cases varies considerably among reports. There is a tendency toward higher prevalence in Western countries and lower prevalence in Asian countries. Western reports have a wide range: from 10% to 30% (9,11), and Asian reports show an average prevalence of 4.0% (range: 2.2% to 9.8%) (14). The largest study in Japan on FVPTC and NIFTP was conducted in Kuma Hospital (14) and showed prevalence of 2.8% for FVPTC and 0.8% for NIFTP. Our data, i.e., the prevalence of 1.5% for FVPTC and 0.6% for NIFTP, are somewhat lower than those reported in Asian countries. The nuclear features in FVPTC and NIFTP are not as obvious as in conventional PTC (11-12) and hence are not always sufficient for identification of malignancy by cytology. Therefore, FVPTC and NIFTP are often not classified as malignant (16-19), and many of them are classified into the following TBS categories: AUS/FLUS (atypia of undetermined significance or follicular lesion of undetermined significance), FN/SFN (follicular neoplasm or suspected follicular neoplasm), or SFM (suspicious for malignancy). Our data showed the same results. Some reports state that there are no reliable cytological features that distinguish NIFTP from invasive FVPTC (20-21). Our results contradict this viewpoint. According to our data, nuclear inclusions are seen in more than a half of invasive FVPTC cases, but never in NIFTP. Furthermore, regarding the nuclear score, invasive FVPTC had a higher score than NIFTP did. These results suggest that nuclear atypia of NIFTP is milder than that of invasive FVPTC. Ibrahim and Wu (16) reported that invasive FVPTC is diagnosed by FNAC as suspicious for PTC or as PTC in nearly 75% of all cases, but only 1 case (4%) of NIFTP was diagnosed as suspicious for PTC. That study supports our observations. Nonetheless, there are some opinions opposed to this conclusion; thus, this subject is still debatable. In this regard, further studies on the nuclear findings, especially nuclear inclusions, in NIFTPs and invasive FVPTCs are necessary. At present, it is generally considered difficult to distinguish NIFTP from invasive FVPTC by FNAC. Some authors have reported that ultrasonography is effective at differentiating NIFTP and invasive FVPTC (14,22). Therefore, for preoperative diagnosis of NIFTP, - 5 -

6 not only FNAC results but also ultrasonography findings should be considered. After the recent renaming of noninvasive FVPTC to NIFTP, the noninvasive FVPTC is no longer the malignant tumor. Therefore, this change makes it necessary to distinguish NIFTP and invasive FVPTC from conventional PTC. In general, it is very difficult or impossible to determine whether a tumor is noninvasive or invasive by cytology. For example, follicular thyroid adenoma and carcinoma are called follicular neoplasm because they cannot be differentiated cytologically. Similarly, there are no effective parameters to distinguish NIFTP from invasive FVPTC at present. Consequently, it is better to not classify FVPTC as malignant like conventional PTC to avoid false positive diagnosis because cases that look like invasive FVPTC according to FNAC may include some NIFTPs. In this article, cytological differences among NIFTP, invasive FVPTC, and conventional PTC were studied, and a method for differentiating NIFTP and invasive FVPTC from conventional PTC is proposed. In general, nuclear findings are considered important for PTC diagnosis. Judging by our results, however, the cell clusters and smear background are more useful for discrimination of NIFTP and invasive FVPTC from conventional PTC. Papillary cell clusters, the predominance of monolayered cell sheets, ropy colloids, and multinucleate giant cells are suggestive of conventional PTC, whereas the predominance of microfollicular cell clusters is suggestive of NIFTP or invasive FVPTC. By comprehensive analysis of these parameters, cytologists can infer which diagnosis is more likely. To make the discrimination easier, here we proposed a simple scoring method for these 5 characteristics. By this scoring method, NIFTP and invasive FVPTC can be clearly distinguished from conventional PTC. When NIFTP or invasive FVPTC are suggested by this approach, a false diagnosis can be avoided by not classifying the tumor as malignant. Although there is a limitation of this study, namely, the small number of cases of NIFTP and invasive FVPTC, we found several cytological characteristics (other than nuclear features) that are useful for distinguishing conventional PTC from FVPTC or NIFTP. Besides, intranuclear inclusions show somewhat different prevalence rates among these tumors. Further research is needed to confirm our findings. Conclusions Cytological characteristics of NIFTP, invasive FVPTC, and conventional PTC were studied, and a method of differential diagnosis was proposed. For discrimination, papillary cell clusters, predominance of monolayered cell sheets, predominance of microfollicular cell clusters, ropy colloids, and multinucleate giant cells are effective characteristics. 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