Fine-needle aspiration of the macrofollicular and microfollicular subtypes of the follicular variant of papillary carcinoma of the thyroid


  • Clara E. Mesonero M.D.,

    1. Departments of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
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  • Julie E. Jugle C.T. (A.S.C.P.),

    1. Cytopathology Division, University of Rochester Medical Center, Rochester, New York
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  • David C. Wilbur M.D.,

    1. Department of Pathology, University of Rochester Medical Center, Rochester, New York
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  • Ritu Nayar M.D.

    Corresponding author
    1. Department of Pathology, Northwestern University Medical School and Northwestern Memorial Hospital, Chicago, Illinois
    • Department of Pathology, Northwestern Memorial Hospital, Suite 314-A, Passavant Pavilion, 303 E. Superior Street, Chicago, IL 60611
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  • Presented in part at the 45th annual meeting of the American Society of Cytopathology, in Boston, Massachusetts, November 4-5, 1997.



The follicular variant of papillary carcinoma of the thyroid (FVPCT) is being increasingly diagnosed on excised thyroid nodules. However, the fine-needle aspiration (FNA) and intraoperative diagnosis is often that of a follicular neoplasm, especially in papillary carcinomas with a pure or predominantly follicular pattern. The authors undertook this study in an attempt to refine the cytologic criteria for the diagnosis of FVPCT.


The authors reviewed 16 cases with cytologic diagnoses of FVPCT (9 cases), suspicious for FVPCT (6 cases), or cellular adenomatoid nodule (1 case) based on aspirates stained with Papanicolaou stain or a Giemsa-type stain (Diff-Quik). All cases had been confirmed histologically as pure or predominantly (>80%) FVPCT in 13 cases and as follicular adenoma in 3 cases. Cytologic features evaluated included cellularity, cell arrangement, nuclear features, cytoplasm, and colloid.


Twelve of 13 cases of FVPCT were correctly diagnosed cytologically. Features that proved useful in the diagnosis of FVPCT were the concomitant and conspicuous presence of ovoid or pear-shaped nuclei with hypochromasia and nuclear grooves. Soft features included nuclear overlap and eccentric, small nucleoli. Cytoplasmic features were not useful in making this diagnosis. Based on cell arrangement and colloid, it was possible to predict microfollicular and macrofollicular variants. The microfollicular subtype showed rosettes or microfollicles and scant, thick colloid in casts and blobs. The macrofollicular subtype had predominantly sheets or spherules with abundant, thick background colloid. Nuclear pseudoinclusions and psammoma bodies were absent and multinucleated giant cells rarely found. Pitfalls leading to a "false-positive" FVPCT diagnosis included oncocytic adenoma (in 2 cases) and atypical adenoma (in 1 case). A cytologic diagnosis of cellular adenomatoid nodule was made in one case of macrofollicular FVPCT.


The authors present improved cytologic criteria for the diagnosis of pure FVPCT on smears stained with Papanicolaou stain or Diff-Quik, and they elaborate on the clues and pitfalls associated with this diagnosis. The cytologic features of the macrofollicular and microfollicular subtypes of FVPCT are also described. Cancer (Cancer Cytopathol) 1998;84:235-244. © 1998 American Cancer Society.

The follicular variant of papillary carcinoma (FVPCT) is a well-differentiated thyroid papillary carcinoma with follicular architecture on histology and nuclear characteristics of classic papillary carcinoma, i.e., enlarged, clear nuclei of the ground glass type and nuclear grooves. The tumors may or may not be encapsulated. Lindsay described FVPCT in detail in 1960.1 Despite its early recognition, these tumors have been misclassified by pathologists as both benign (adenoma and adenomatoid nodule)2 and malignant (carcinoma) follicular lesions.3 As noted by Livolsi and Asa,3 many pathologists used the Armed Forces Institute of Pathology fascicle4 guidelines that recommended classifying a thyroid tumor as a follicular carcinoma if its pattern on histology was follicular in ≥50% of its total mass. It was not until 1977 that Chen and Rosai5 and subsequent investigators6-8 emphasized the importance of nuclear, rather than histologic, features in making a diagnosis of papillary carcinoma of the thyroid. As a result of improved criteria, FVPCT is being diagnosed with increasing frequency on both cytology (fine-needle aspirates and intraoperative cytology) and histology (excised nodules). Some authors have indicated that there may also be a true relative increase in the incidence of papillary carcinoma as a whole, possibly as a result of environmental factors.3

We, like some other pathologists,3, 9 believe that it is important to classify a well-differentiated malignant thyroid neoplasm as either papillary or follicular. Thyroid papillary carcinoma is a subtype of well-differentiated thyroid carcinoma that behaves differently from follicular carcinoma.9 Papillary carcinoma, regardless of its architectural pattern (be it classic papillary, follicular, or mixed), is generally associated with a good prognosis, the disease being localized to the neck with uni/multifocal involvement of the thyroid gland and local lymph node metastases. A more recently recognized and less common variant of papillary carcinoma with follicular architecture is the macrofollicular variant,2 an encapsulated variant/subtype that has an architectural pattern showing predominantly large follicles, and therefore simulating histologically a macrofollicular adenoma or an adenomatoid nodule.

Ultrasonography or scintiscan cannot reliably diagnose FVPCT preoperatively,10 because the specificity of these tests is very low for this diagnosis. It is important to recognize papillary carcinoma with microfollicular or macrofollicular architecture prior to surgery-not only as a neoplasm, but as a malignant neoplasm, because the treatment of choice (i.e., subtotal/total thyroidectomy for nodules > 1.5 cm in greatest dimension) differs from that for minimally invasive follicular carcinomas and benign follicular lesions.11

In recent years, several reports describing the morphologic features of FVPCT have been published in the cytology literature.12-17 These reports emphasize the nuclear features characteristic of FVPCT; however, some of them15, 16 question the ability to make this diagnosis cytologically. To the best of our knowledge, reports on the cytologic features of the macrofollicular variant of FVPCT are not available. Moreover, the majority of the available literature does not separate the cytologic features of pure or predominant FVPCT from mixed classic and follicular papillary carcinoma. This distinction is important in our opinion because it is the pure or predominantly follicular variant of papillary carcinoma that presents a diagnostic challenge cytologically and is often diagnosed as a follicular neoplasm.17

The aims of our study were as follows:

  • 1To evaluate our capability of recognizing FVPCT preoperatively on fine-needle aspiration smears;
  • 2To compare the preoperative diagnosis of FVPCT on fine-needle aspiration specimens with intraoperative consultations (frozen sections);
  • 3To identify diagnostic pitfalls associated with the cytologic diagnosis of FVPCT;
  • 4To define improved cytologic criteria based on aspirates stained with Papanicolaou stain or a Giemsa-type stain (Diff-Quik, Baxter, McGaw Park, IL) for the diagnosis of the microfollicular and macrofollicular subtypes of FVPCT.


The surgical pathology and cytopathology files at the University of Rochester Medical Center between July 1988 and August 1996 were reviewed for the diagnosis of thyroid papillary carcinoma, not otherwise specified, and thyroid papillary carcinoma, follicular variant. From the surgical pathology files, we selected only cases of papillary carcinoma that had a pure or predominantly follicular architecture (>80%) on hematoxylin and eosin-stained histologic slides and in which aspirates were available for review. From the cytology files, cases with a definite diagnosis of FVPCT were all included, as well as cases in which a diagnosis of FVPCT was suspected or could not be ruled out, provided they had histologic follow-up.

All cytology and histology slides were reviewed by two of the authors (C.E.M. and R.N.) and the diagnosis of FVPCT was confirmed. A total of 16 cases, 13 of which were histologically confirmed as FVPCT, were selected for this study. At the University of Rochester, all thyroid aspirates are reviewed by one of the authors (C.E.M.) with a special interest in thyroid pathology; therefore, consistent diagnostic criteria were applied to all cases.

The cytologic features evaluated in every case included cellularity, cell arrangement, nuclear features, cytoplasm and colloid, and other background features. Cellularity was graded as follows: low (1+), moderate (2+), or high (3+). Cell arrangements sought included those characteristic of follicular lesions (spherules, rosettes, and microfollicles) and papillary lesions (papillae and sheets) and those seen in either type of lesion (syncytia and tissue fragments). Nuclear features evaluated included shape, location and presence of nucleoli, distribution of chromatin, grooves, intranuclear inclusions, and nuclear overlap. Nuclear overlap was graded as mild (1+), moderate (2+), or marked (3+). Nuclear grooves were scored as occasionally present (1+), identified in at least 50% nuclei (2+), or identified in greater than 50% of nuclei (3+). Nuclear chromasia was evaluated as follows: mild clearing of nuclear chromatin (1+), moderate clearing of nuclear chromatin (2+), or marked clearing of nuclear chromatin (3+). The amount and nature of the cytoplasm and colloid were noted. The background features we specifically sought were multinucleated histiocytes and psammoma bodies. Intranuclear pseudoinclusions, multinucleated giant cells, and psammoma bodies were scored as follows: absent (0), rare (1+), or frequent (2+).

These features were studied on Papanicolau-stained slides and Diff-Quik-stained slides; both stains were available in the majority of the cases. The cases were also subclassified on review of the aspirates as microfollicular or macrofollicular variants, based on the architectural arrangement of the cells and the amount and type of colloid present, and were subsequently compared with the histologic findings.


Table 1 summarizes the main clinicopathologic findings and cytologic-histologic correlations. Table 2 lists the cytologic diagnosis and cytologic features observed in cases of histologically confirmed pure or predominant FVPCT, and Table 3 lists the features of cases that were "pitfalls" encountered in this study.

Table 1. Clinicopathologic Findings and Cytologic-Histologic Correlations
Case no.Cytologic diagnosisSurgical pathologySize (cm)LobeSurgical procedureLymph nodesAge (yrs)GenderFrozen sectionRadiation history
  1. FVPCT: follicular variant of papillary carcinoma of the thyroid; M: macrofollicular; m: microfollicular; D: deferred to permanent sections; FN: follicular neoplasm; PC: papillary carcinoma; CAN: cellular adenomatoid nodule.

1FVPCT-mFVPCT-m0.8Lt.Left lobectomy041FDNo
2FVPCT-mFVPCT-m2.1Lt.Left lobectomy037FNoneNo
3FN/FVPCT-mFVPCT-m1.5Rt.Total thyroidectomy027MNoneYes, 7 yrs ago
4Atyp/FVPCT-mFVPCT-m0.5Rt.Lobectomy and isthmus068FNoneNo
5FVPCT-m+PCFVPCT-m(80%) + PC(20%)2.0Bilat.Subtotal thyroidectomy1/537FFVPCTNo
6FVPCT-m+PCFVPCT-m (80%) + PC (20%)1.6Rt.Right lobectomy followed by left lobectomy019FFNNo
7FVPCT-M,mFVPCT-M,m5Rt.Total thyroidectomy029FPCNone
8FVPCT-M,mFVPCT-M,m1.0Rt.Subtotal thyroidectomy031FNoneNo
9FVPCT-M,mFVPCT-M,m2.2Bilat.Total thyroidectomy054MNoneNo
10FVPCT-MFVPCT-M,m2.1-2.5Bilat.Total thyroidectomy027FFNYes
11FVPCT-MFVPCT-M1.9Rt.Total thyroidectomy047FNoneNo
12Atyp./FVPCT-MFVPCT-M2.9Rt.Right lobectomy followed by left lobectomy015FDNo
13CANFVPCT-M0.6Rt.Right lobectomy039FNoneNo
14FN/FVPCT?Oncocytic adenoma8 cmLt.Subtotal thyroidectomy075FFNNo
15FN/FVPCT?Oncocytic adenomaUnstatedRt.Right lobectomy and isthmus033FFNNo
16FN, FVPCT?Atypical adenoma3.5Lt.Lobectomy047FFNNo
Table 2. Macrofollicular and Microfollicular Variants of Papillary Carcinoma of the Thyroid: Cytologic Features
Case no.Cytologic diagnosisCellularityArchitectureNuclear shapeNuclear overlapNuclear grooves/inclusionsHypochromasiaNucleolusColloidMnG/PB
  1. FVPCT: follicular variant of papillary carcinoma of the thyroid; MnG: multinucleated giant cell; M: macrofollicular; PB: psammoma bodies; m: microfollicular; ecc: eccentric; conspic: conspicuous.

1FVPCT-m3+Syncytial, rosette, microfollicleRound, ovoid2+3+/02+Small, ecc1+/film + inspissated0/0
2FVPCT-m2+Syncytial, rosette, microfollicleRound, ovoid2+2+/01+Small, ecc1+/blobs0/0
3FN/FVPCT-m3+Syncytial, rosette, microfollicleRound, ovoid2+2+/02+Small, ecc1+/blobs0/0
4Atyp./FVPCT-m2+Syncytial, rosetteRound, ovoid3+3+/01+Small, ecc1+/blobs0/0
5FVPCT-m+PC3+Syncytial sheet, papillary fragment, rosette, microfollicleRound, ovoid3+3+/1+1+Small, ecc3+/"chunks"1/0
6FVPCT-m+PC3+Syncytial, rosette, microfollicleRound, ovoid2+3+/1+1+Small, ecc1+/inspissated0/0
7FVPCT-M,m2+Sheet, syncytial, spherule, rosetteRound, ovoid2+1+/01+Small, ecc3+/"chunks"0/0
8FVPCT-M,m3+Syncytial, sheet, microfollicleRound, ovoid1+3+/01+Small, ecc1+/blobs1/0
9FVPCT-M,m2+Syncytial, sheet, spheruleRound, ovoid1+2+/01+Small, ecc2+/blobs0/0
10FVPCT-M3+Syncytial, spherule, rosette, microfollicleRound, ovoid2+1+/01+Small, ecc1+/inspissated0/0
11FVPCT-M3+Sheet, spherule, rosetteRound, ovoid3+3+/02+Conspic.1+/blobs0/0
12Atypical/FVPCT-M3+Sheet, rosette, rare microfollicleRound, ovoid1+2+/02+Central, ecc3+/film1/0
Table 3. Follicular Variant of Papillary Carcinoma of the Thyroid: Pitfalls
Case no.Cytologic diagnosisCellularityArchitectureNuclear shapeNuclear overlapNuclear grooves/ inclusionsHypochromasiaNucleolusColloidMnG/PB
  1. FVPCT: follicular variant of papillary carcinoma of the thyroid; CAN: cellular adenomatoid nodule; FN: follicular neoplasm; PB: psammoma bodies.

13CAN3+Sheet, spheruleRound, ovoid1+1+, 02+Conspic1+film0/0
14FN, FVPCT?3+Tissue fragment, syncytial, single cellsRound, ovoid2+1+, 03+Conspic, central1+blobs0/0
15FN, FVPCT?3+Tissue fragment, syncytial, rosette, microfollicleRound, ovoid3+3+, 01+Small, ecc1+ inspissated0/0
16FN, FVPCT?3+Tissue fragment, microfollicle, rosetteRound, ovoid3+3+, 00 (Hyperchromasia)Conspic, central1+inspissated and in blobs0/0

Thirteen patients with histologically diagnosed FVPCT ranged in age from 15 to 68 years, with a mean age of 36 years. All but two patients were females. The tumor nodules varied in size from 0.5 to 2.9 cm in greatest dimension and were confined to 1 lobe in 10 cases (2 on the left, 8 on the right). Regional lymph node metastases were noted in only one case. The clinical presentation of these patients was similar to that described for classic papillary carcinoma.18, 19

Twelve of these 13 cases had been correctly diagnosed as FVPCT on cytology. Among these 12 cases, 9 (Cases 2-8,10, and 11) were diagnosed unequivocally as FVPCT and 3 (Cases 1,9, and 12) were diagnosed as follicular neoplasm, with FVPCT not excluded or suspected. Histologically, 10 of 12 cases had a pure follicular growth pattern. In addition, 2 cases had a classic papillary carcinoma component (20% or less of the tumor mass).

The nuclear features that proved useful in the diagnosis of FVPCT included the concomitant and conspicuous presence of three criteria: ovoid and pear-shaped nuclei, nuclear hypochromasia, and nuclear grooves (Fig. 1 (43K)). Less consistently applicable features noted in our study were the presence of eccentric, small nucleoli and nuclear overlap (Fig. 2 (46K)). We found that the nuclear hypochromasia and nuclear grooves were much easier to detect on Papanicolaou-stained cytologic preparations than on Diff-Quik-stained slides. Nucleoli were hardly observed on Diff-Quik-stained preparations (Fig. 3 (42K)). The nuclei in all cases varied from round to ovoid or pear-shaped, with grooves more often identified in enlarged, ovoid, or pear-shaped nuclei. Round nuclei were small, within the nuclear size range of follicular neoplasms, but with distinct hypochromasia and eccentric, small nucleoli often located close to the nuclear membrane. The cytoplasm was better appreciated with Diff-Quik staining and tended to be scant, somewhat dense, and better defined than in follicular adenomas/carcinomas. However, it was not abundant or granular, as seen in Hürthle cells, and it did not prove to be a useful feature in differentiating between follicular neoplasms and FVPCT.

Figure 1.

The cells show ovoid and pear-shaped hypochromatic nuclei and nuclear grooves (Papanicolaou stain, original magnification x 1000).

Figure 2.

The cells show nuclear overlap, round-to-ovoid hypochromatic nuclei, eccentric small nucleoli, and nuclear grooves. Note that a groove is seen in the ovoid-to-pear-shaped nucleus (arrow) (Papanicolaou stain, original magnification x 400).

Figure 3.

The cells show enlarged round, ovoid, and pear-shaped nuclei. The hypochromasia, nuclear grooves, and nucleoli are difficult to appreciate (Diff-Quik, original magnification x 1000).

The 12 cases of FVPCT diagnosed on cytology were subclassified on review as microfollicular (4), macrofollicular (3), mixed macrofollicular and microfollicular (3), and mixed microfollicular and classic papillary (2). The features that were useful in subclassifying the subtypes of FVPCT included architectural arrangement and quantity and quality of colloid (Table 2). The microfollicular subtype of FVPCT showed syncytial tissue fragments, rosettes, cords, and microfollicles, with prominent nuclear overlap and scant, thick colloid inspissated in microfollicles, as casts, or round blobs (Figs. 4 (77K), 5 (73K)). The macrofollicular subtype, on the other hand, had cells arranged in sheets, in spherules, and occasionally in small, papillary tufts (Fig. 6 (67K)). In this subtype, colloid was abundant, thick, in "chunks," or in thin films seen in the background and also within spherules (Fig. 7 (56K)).

Figure 4.

A microfollicular subtype of FVPCT shows rosettes, cords, and microfollicles with inspissated colloid (arrow, insert) (Papanicolaou stain, original magnification x 200).

Figure 5.

A microfollicular subtype of FVPCT shows rosettes, cords, and casts of colloid (arrows) (DIff-Quik, original magnification x 200).

Figure 6.

A macrofollicular subtype of FVPCT shows tissue fragments, sheets, and small papillary tufts (arrow) (Papanicolaou stain, original magnification x 200).

Figure 7.

A macrofollicular subtype of FVPCT shows tissue fragments and spherules filled with colloid (arrows) (Papanicolaou stain, original magnification x 200).

Intranuclear pseudoinclusions, psammoma bodies, and multinucleated-type giant cells were absent in pure microfollicular variants. Rare nuclear pseudoinclusions were seen only in the two cases with a classic papillary carcinoma component, and rare multinucleated-type giant cells were present in tumors with a macrofollicular or classic papillary component. Psammoma bodies were not identified in any of the cases.

Intraoperative consultations (frozen sections) were performed in 9 of the 16 study cases. In two cases the diagnosis was deferred to the interpretation of permanent sections, and in five cases a diagnosis of follicular neoplasm was rendered. Only two of the nine cases evaluated intraoperatively were correctly diagnosed as FVPCT. In both cases, the diagnosis was based on the interpretation of smears prepared from the tumors cut surface rather than on the frozen tissue section.

One case (Case 13), histologically a macrofollicular subtype of FVPCT, had been issued a false-negative cytologic diagnosis of benign follicular proliferation (cellular adenomatoid nodule) (Tables 1 and 3).

Three cases diagnosed on cytology as "follicular neoplasms, suspicious for FVPCT" (Cases 14,15, and 16) were considered false-positives because histologically they corresponded to oncocytic/Hürthle cell neoplasms (2 cases) and atypical adenoma (1 case). These cases had been correctly interpreted as follicular neoplasms on frozen section.


Papillary carcinoma is the most common thyroid tumor among patients of all ages and comprises approximately 80% of all thyroid carcinomas in the United States.19 The tumor is histologically composed of a cell population of ovoid, enlarged, and overlapping follicular cells showing optically clear nuclei, nuclear grooves, and/or cytoplasmic intranuclear pseudoinclusions. The architecture can be papillary, follicular, solid, or mixed. Cases with mixed patterns showing a considerable papillary component do not pose diagnostic problems on histologic sections and are also reliably diagnosed on cytology. However, cases with pure follicular architecture raise the possibility of a follicular neoplasm if the pattern is microfollicular, and a FVPCT can also be misdiagnosed as an adenomatoid nodule if the pattern is predominantly macrofollicular. The key to making an accurate diagnosis of papillary carcinoma relies on examination of all histologic sections with careful attention to nuclear features. The diagnosis of pure FVPCT is more difficult to establish on cellular material aspirated from thyroid nodules. Lack of thorough sampling of the nodule and absence of some of the cytologic features of classic papillary carcinoma, such as psammoma bodies, intranuclear cytoplasmic inclusions, and multinucleated giant cells, add to the challenge of making a cytologic diagnosis of FVPCT. The cytologic diagnosis of FVPCT is, however, of importance because the fine-needle aspiration of thyroid nodules is used as a screening and diagnostic tool that has therapeutic implications. Thyroid nodules diagnosed as neoplasms are excised with either a simple lobectomy or a subtotal thyroidectomy, depending on the size and type of the neoplasm.11 Although a more aggressive surgical approach is taken in cases of papillary carcinoma at many institutions, it is somewhat controversial. Some studies indicate that conservative surgery is as effective as more extensive surgery.20, 21 Intraoperative consultations are often of limited value in distinguishing follicular adenoma/carcinoma from FVPCT,18 especially if touch preparations or smears from the cut surface of the nodule are not obtained. Frozen sections alone are often suboptimal for evaluating the nuclear features of an excised lesion, and cytologic preparations are helpful if the pathologist routinely signs out cytology or uses such preparations during intraoperative consultation.

Recognition of the cytologic features of FVPCT is important in making a precise diagnosis on fine-needle aspirations and intraoperatively prepared smears or touch preparations. Several reports have described the cytologic features of FVPCT.12-17 From these reports, we assume that many of the authors12, 13, 16 refer to diagnostic features of the microfollicular variant of FVPCT, because abundant background colloid and spherules are not described in most reports. Moreover, these authors do not state whether the FVPCT they studied were pure or mixed with the classic variant of papillary carcinoma on cytology or histology. We suspect that many of the cases described in these reports did have a significant component of classic papillary carcinoma, because the presence of intranuclear cytoplasmic inclusions, psammoma bodies, and multinucleated giant cells is described.12, 16 The reliability of a preoperative diagnosis of FVPCT is also questioned by some of these authors.15, 16

The cytologic features described as being found in FVPCT include tumor cellularity,13, 16, 17 nuclear grooves,13, 15 abundant colloid,15 microfollicles,12, 13, 15, 17 and syncytial clusters without acinar formation or monolayered sheets.16 Kini et al.14 describe FVPCT as having scant or absent colloid, frequent intranuclear inclusions, powdery chromatin, and "cytologic features of papillary carcinoma in the same or other slides." A more recent study by Gallagher et al.17 adds several important diagnostic features, such as the appearance of colloid, the presence of nuclear enlargement, arrowhead-type nuclei, and nuclear hyperchromasia. In this study, which was performed on 35 cases stained only by Diff-Quik stain, nuclear grooves were very scarce, intranuclear cytoplasmic inclusions were seen in approximately one-third of cases, and giant cells/psammoma bodies were rare. When these authors looked at their cytologic-histologic correlation, they found that the tumors with more than two-thirds follicular architecture were diagnosed on cytology as follicular neoplasms or cellular adenomatoid nodules suspicious for follicular neoplasms. Leung et al.15 correlated the cytologic and histologic features in 48 cases of papillary carcinoma that included 13 cases of FVPCT. They found no significant differences in nuclear and architectural features among various subtypes of papillary carcinoma of the thyroid; however, colloid was found much more commonly in FVPCT compared with classic tall cell and encapsulated papillary carcinoma. They describe intranuclear cytoplasmic inclusions in all cases, giant cells in 46%, and absence of psammoma bodies.

We believe that with improved cytologic criteria, the distinction between FVPCT and other follicular lesions in the thyroid can be made. Unlike Kini et al.,14 we did not distinguish follicular adenoma from follicular carcinoma on cytology, but instead grouped them together in the category "follicular neoplasms." Other pathologists17 feel that the distinction between follicular neoplasm and FVPCT is not clinically significant because in both cases the patient undergoes surgery. However, we feel it is important to recognize FVPCT preoperatively, because an intraoperative consultation diagnosis based on frozen section only may be noncontributory and/or misleading unless intraoperative cytology is used. An accurate diagnosis may preclude the necessity for completion thyroidectomy at a later date, at institutions where near-total thyroidectomy is performed for papillary carcinoma, especially in larger lesions.11 This problem is not uncommon; in fact, it occurred in two of our cases (Cases 1 and 6) in which the intraoperative consultation was nonconclusive (Case 1) or misleading (Case 6).

The criteria we identified as being the most useful in making a cytologic diagnosis of FVPCT were the concomitant and conspicuous presence of 1) small, round nuclei and enlarged, ovoid or pear-shaped nuclei; 2) nuclear grooves; and 3) fine, powdery chromatin pattern, imparting "hypochromasia" to all or the majority of nuclei.

In our experience, follicular adenomas/carcinomas usually have larger, round nuclei with a coarser chromatin pattern, thus appearing hyperchromatic on Papanicolaou stain (Figs. 8 (37K),9 (76K)). Nuclear grooves are rare, unless there is a Hürthle cell change.

Figure 8.

A follicular adenoma shows round, hyperchromatic nuclei (Papanicolaou stain, original magnification x 200).

Figure 9.

A follicular carcinoma shows nuclei larger than those of the adenoma in Figure 8 (37K) and exhibits coarsely clumped chromatin and more prominent, often centrally located nucleoli (Papanicolaou stain, original magnification x 400).

Other useful, although less consistently identified, features included nuclear overlap and small, eccentric nucleoli. These "softer" features, however, were always associated with the three major features noted above in all confirmed cases of FVPCT.

Architectural features of FVPCT identified in our study were those of benign or neoplastic follicular lesions. Sheets and spherules were seen largely in the macrofollicular subtype, while cords, rosettes, and microfollicles were seen predominantly in the microfollicular subtype. An admixture of architectural patterns was observed in aspirates from nodules that had mixed histologic architecture. Intranuclear cytoplasmic inclusions were seen only in lesions with a coexisting classic papillary component, and rare multinucleated giant cells were present in tumors with a macrofollicular and/or classic papillary growth pattern. Psammoma bodies were not observed in any of our cases on either cytology or histology.

Colloid was found to be scant, inspissated, and thick, often within microfollicles in the microfollicular subtype. It appeared as abundant background "film" or as thick chunks or "blobs," either in the background or within spherules in the macrofollicular subtype of FVPCT.

We recommend the use of Papanicolaou-stained preparations because they increase the specificity of the diagnosis of FVPCT, making appreciation of nuclear hypochromasia, nuclear grooves, and nucleoli easier than on Diff-Quik-stained slides. Both stains are, however, complementary, because the nuclear enlargement is more exaggerated on Diff-Quik-stained preparations and colloid is easier to appreciate. Nuclear overlap is appreciated with ease on both stains.

Our study included 1 case (Case 13) in which a benign diagnosis of a cellular adenomatoid nodule was made on cytology. This case was diagnosed as a macrofollicular variant of FVPCT on histology. However, on review, the histologic sections revealed only focal classic nuclear features of papillary carcinoma within the nodule. The aspirate did not show the nuclear features of papillary carcinoma. We attribute this false-negative diagnosis to a sampling problem during the aspiration. A diagnosis of "follicular neoplasm, suspicious for FVPCT" was made in 3 cases (Cases 14,15,16). Two of these (Cases 14 and 15) were diagnosed as "follicular neoplasm with oncocytic features, FVPCT not excluded," and proved to be oncocytic adenomas on excision. A review of the aspirates revealed cells arranged in patterns consistent with a microfollicular neoplasm. In 1 case (Case 14), there were numerous single cells, a feature not observed in follicular neoplasms or FVPCT. The nuclei were round to oval with marked variation in nuclear size and had marked hypochromasia, prominent central nucleoli, and rare grooves. This case should have been diagnosed as an oncocytic neoplasm, because the nuclear features fulfilled all the criteria for this diagnosis. The other case (Case 15) had nuclei with open chromatin, central and eccentric conspicuous nucleoli, and numerous nuclear grooves. This case did have some nuclear features that overlapped with those of papillary carcinoma. The distinguishing finding was that of abundant, granular cytoplasm, a feature not usually seen in FVPCT. However, it must be kept in mind that the rare oxyphilic variant of papillary carcinoma has been described in detail in a recent publication.22 Case 16 (atypical adenoma) was diagnosed as a "follicular neoplasm, cannot exclude FVPCT" on cytology. A review of the aspirate did not show all the nuclear features we have described for the diagnosis of FVPCT. The nuclei were hyperchromatic with conspicuous nucleoli that were more often central than eccentric. In retrospect, the focal presence of nuclear features of papillary carcinoma or the presence of only one feature (i.e., grooves) should not prompt a diagnosis of FVPCT.

Thus, the cytologic features observed in our study that proved to be most reliable in making a diagnosis of FVPCT were the conspicuous and concomitant presence of ovoid or pear-shaped nuclei with hypochromasia and nuclear grooves. Subclassification of the microfollicular and macrofollicular subtypes of FVPCT can be made on cytology based on the architectural arrangement of the follicular cells and the quantity and quality of colloid present. Although separation of FVPCT into these subtypes has no prognostic significance, pathologists should be aware of these entities due to the possibility of misdiagnosing the macrofollicular variant of FVPCT as a cellular adenomatoid nodule. This misdiagnosis can occur due to the presence of abundant background colloid, the presence of "benign spherules," and subtle nuclear features.2 As pointed out by Gallagher et al.,17 it is more important to avoid misdiagnosis of FVPCT as a benign lesion than to distinguish it from a follicular neoplasm. Although follicular neoplasms and pure FVPCT, especially the microfollicular subtype, have overlapping cytologic features, close attention to nuclear features can result in more accurate classification of follicular lesions of the thyroid gland. In our experience, as well as that of others,17 it is particularly the predominant and/or pure follicular subtype of papillary carcinoma that is difficult to diagnose on cytology. We believe that this difficulty exists partly because some of the more commonly recognized features of classic papillary carcinoma-such as intranuclear cytoplasmic inclusions, psammoma bodies, and multinucleated giant cells-are infrequent or absent in the predominantly or purely follicular variant. As in surgical pathology, it is close attention to nuclear features that aids the cytopathologist in making a diagnosis of papillary carcinoma of the thyroid.

The results of this study led us to the following conclusions:

  • 1A high sensitivity and specificity can be reached in the diagnosis of FVPCT by application of consistent cytologic criteria, especially nuclear features.
  • 2A preoperative diagnosis of FVPCT on aspirate cytology is superior to intraoperative frozen section in separating other follicular lesions from FVPCT. The intraoperative diagnostic ability to make this distinction can be augmented by the use of cytologic smears or touch preparations.
  • 3Cellular adenomatoid nodule, follicular (oncocytic) neoplasms, and atypical adenoma were the "pitfalls" encountered in the cytologic diagnosis of FVPCT in this study.
  • 4Both Papanicolaou and Diff-Quik-stained cytologic preparations are useful and complementary in making the diagnosis of FVPCT. Cell arrangement and quality and quantity of colloid help in predicting FVPCT subtypes.