Use and Abuse of Frozen Sections in Diagnosis of Follicular Thyroid Lesions
Virginia A. LiVolsi
University of Pennsylvania
The intraoperative pathology consultation is an essential tool in surgical management of diseases in
many organs. Frozen section can serve as the first diagnostic procedure to differentiate between benign
and malignant tumors and helps in further planning of the surgery.
The reasons for frozen
section request given by surgeons include: diagnosis of the lesion, identification of tissue type (e.g.
parathyroid), assessment of margins, determination of operability (i.e., liver metastases present will
abort a Whipple procedure), assessment of adequacy of lesional material for definitive workup (i.e.
suspected malignant lymphoma, and provision of tissue for special studies (i.e. molecular analysis for
sarcoma). In the modern era with advances in radiology and increasing experience with fine needle
aspiration cytology, the diagnosis of many lesion is already known preoperatively, so that the most
common reason for frozen section request even a decade ago (i.e., diagnosis) is becoming less frequent.
In certain organ systems, the role of intraoperative frozen section has always been and continues to
be problematic. One of these areas is in thyroid diseases and especially nodules; herein, the role of
intra-operative consultation is controversial; this is especially true for encapsulated follicular
patterned lesions which comprise the major reason for thyroid surgery in current practice.
Before the wide use of fine needle aspiration biopsy of thyroid nodules, the frequency of thyroid
surgery was much greater than in current surgical practice.
The value of frozen section in those
cases was not disputed, since the differential diagnosis of papillary carcinoma versus nodular goiter
could be relatively easily rendered and appropriate surgery accomplished.
Thus in the days when
preoperative diagnosis was not easily made, intraoperative frozen section made sense.
In the more modern era, in the thyroid the selection of patients requiring surgery is usually made on
the basis of FNA diagnoses of either neoplasm, suspicious for neoplasm or malignant.
with a definite FNA diagnosis of malignancy are subjected to total or near total thyroidectomy, whereas,
lobectomy is performed in cases diagnosed as follicular neoplasm; upon completion of the histopathologic
examination a completion thyroidectomy can be performed if the nodule removed is diagnosed as
A similar surgical treatment is also followed in cases diagnosed as suspicious for
malignant or indeterminate for neoplasm.
However, this two-step surgery consisting of lobectomy
followed by completion thyroidectomy does subject the patient to two surgical procedures and the
Several authors have shown that intra-operative consultation is necessary for the definite surgical
management of thyroid nodules.
As mentioned above the primary use of frozen section in surgical
pathology is to establish a diagnosis; however, in some instances frozen section may fail the task of
establishing a definitive diagnosis; this leads to deferral of diagnosis to final histopathologic
The definite surgical procedure is delayed until a final pathology diagnosis is rendered on permanent
sections. (It is obvious that should an abnormal lymph node be identified and on frozen section a
diagnosis of metastatic carcinoma consistent with thyroid primary is rendered, no additional diagnostic
intraoperative assessment is needed}.
Both the surgical and pathology literature contain institutional experiences regarding the use of
intra-operative assessment of thyroid lesions.
The experiences and conclusions drawn from
these publications can be equally divided into two groups; ones that found that this procedure to be of
limited utility and others who concluded that frozen section is useful (of more or of equal diagnostic
value compared to fine-needle aspiration).
The arguments against the use of frozen sections in thyroid nodules include: 1) FNA can diagnose
papillary carcinoma in more than 90% of cases; therefore, it is not cost effective to perform frozen
section in cases diagnosed as definite for malignancy on FNA; 2) frozen section can induce artifactual
nuclear clearing, which can be mistaken for papillary thyroid carcinoma leading to false positive
intraoperative diagnosis; 3) frozen section is of limited value in the diagnosis of follicular or Hürthle
cell carcinoma, because the diagnosis of malignant follicular and Hürthle cell lesion is dependent upon
demonstration of true capsular and/or vascular invasion which requires a thorough and detailed
examination of the lesion's capsule.
Therefore, due to limited sampling at the time of the
frozen section a majority of lesions diagnosed on FNA as follicular / Hürthle cell neoplasm or
indeterminate for neoplasm will be deferred to final histopathologic examination.
Among the investigators who have suggested that frozen sections can be beneficial in thyroid lesions
particularly in follicular/Hürthle cell lesions, the most commonly quoted report is from Mayo Clinic. 
These authors studied a cohort of 1023 patients undergoing surgery for a diagnosis of follicular and
Hürthle cell thyroid neoplasm; 78% of cases were diagnosed as malignant on frozen section, thus leading
to a definite surgical management and avoiding the delay of a two step surgical procedure (lobectomy
followed by completion thyroidectomy). However, in our view this study describes the experience from a
unique pathology laboratory, where the majority of surgical specimens are diagnosed on the basis of
multiple frozen sections. Hence if we consider the working environment of usual surgical pathology
laboratory in both community practices and academic centers, it will not be cost effective and
practically impossible to perform multiple frozen sections to distinguish between benign and malignant
follicular and Hürthle cell tumors.
One of the major arguments to prove the limited utility of frozen section in thyroid nodules is the
fact that for practical reasons, extensive sectioning of the capsule in follicular patterned thyroid
nodules cannot be done.
In a recent study from Johns Hopkins University, frozen section was
only able to render a diagnosis of malignancy in 1 of 29 cases diagnosed as follicular neoplasm on
FNA.  In a similar study from our institution 50% of the diagnoses on frozen sections performed on
various thyroid lesions were deferred to permanent histologic sections; of these 22% were diagnosed as
malignant on final histology requiring additional surgery.  Chen et al studied 125 patients with
follicular thyroid lesions and from these 87% were deferred to permanent sections after intra-operative
assessment. In addition, 5% of cases were misdiagnosed as malignant leading to unnecessary total
thyroidectomy.  The Hopkins group also assessed the cost of the procedure and found every useful
frozen section cost over $12000.
In addition, due to the limited sampling performed at the time of the frozen section, some malignant
follicular lesions may be under-diagnosed as benign.  This is issue is well addressed in the study by
Kingston et al; of 198 follicular neoplasms21% were misinterpreted as benign on frozen section
examination.  A similar study by Crowe et al showed that 6% of the malignant lesions in their series
were not correctly identified on frozen section. 
A majority of thyroid nodules that are excised have undergone pre-operative FNA, the most sensitive
diagnostic technique available for the management of thyroid lesions.
However, it is important to
be aware of the fact that FNA induced trauma can lead to a variety of histologic alterations within
thyroid nodules.  These have been described in various publications and include hemorrhage,
infarction, nuclear atypia and capsular and vascular pseudo-invasion.
The latter can be mistaken
for foci of true tumor invasion on frozen section; similarly the nuclear atypia can also be mistaken for
In our experience, the post FNA foci of pseudo-invasion are usually linear
and are surrounded by areas of hemorrhage and granulation tissue.  However, such distinction between
true and false post-FNA foci of capsular and or vascular invasion is only possible in detailed
examination of well-fixed permanent histologic sections.
Mchenry et al studied a cohort of 78 patients with thyroid nodules and compared the FNA and frozen
section diagnosis along with the cost benefit analysis of frozen section examination. These authors
found that diagnosis was deferred in 38 patients (50%), and one to six frozen sections were performed in
each patients leading to alteration in surgical management in only 2 patients (3%).
A study of 812
patients by Morisini et al comparing the FNA, frozen section and final diagnosis found that frozen
section was less sensitive for the diagnosis of papillary cancer and more specific for the diagnosis of
follicular carcinoma.  In this study there were 21 false negative diagnoses and no false positive
diagnosis on frozen section. However, this study fails to provide any details about the number of frozen
sections performed and examined and the times required for the analyses.
In view of the above-mentioned studies, we believe that in everyday practice of pathology, frozen
section examination is of limited value in the diagnoses of follicular and Hürthle cell tumors and does
not lead to any additional information as compared to preoperative FNA. In addition, it is not practical
to do multiple frozen sections on a thyroid nodule to possibly reach a definite diagnosis. If one
evaluates the risk of a follicular or Hurthle cell neoplasm being malignant, one recognizes that only
about 20% will be diagnosed as carcinoma after complete histopathologic examination,
so that in
the majority of patients, lobectomy will be adequate therapy.
Is there any role for intra-operative assessment in the surgical management of thyroid nodules?
Despite the above-mentioned review outlining the arguments in favor and against the use of frozen
section in the surgical management of thyroid nodules, it has been shown by both retrospective and
prospective analyses that intra-operative evaluation of thyroid nodules can be useful in cases diagnosed
as suspicious for papillary thyroid carcinoma on FNA.
Rodriguez et al investigated
the value of frozen section in cases diagnosed as benign, suggestive of neoplasm, or malignant on FNA.
They found that frozen section examination was particularly helpful in cases with a "suggestive" cytology
diagnosis, whereas, there was no significant change in diagnosis in cases with benign or malignant
diagnoses.  Basolo et al reported the use of intra-operative cytology as an adjunct to frozen section
analysis of thyroid.  In this publication the intra-operative cytology
(IOC) preparation were stained
with Ultrafast-Papanicolaou method. The nuclear morphology was comparable to that seen in FNA smears.
According to this study there was a 98% correlation between IOC and final histologic diagnosis as
compared to 71% correlation between frozen section alone and final histologic diagnosis. Tworek et al
studied the impact of IOC and frozen section, and found that IOC was highly sensitive and specific in the
diagnosis of papillary thyroid carcinoma.  In our experience, Ultrafast-Papanicolaou stained scrape
preparations serve as a useful adjunct to the frozen section ; use of this techniquehas led to completion
thyroidectomy in some cases , which had been diagnosed as suspicious for papillary thyroid carcinoma on
Interestingly, in our experience and that of others, most of these cases represent
follicular variant of papillary thyroid carcinoma on final histopathologic examination.
majority of these are encapsulated follicular patterned lesions without any obvious capsular and/or
vascular invasion. Thus these cases can be easily mistaken as follicular adenoma on frozen section
alone, since the nuclear features of papillary thyroid carcinoma are frequently not observed in frozen
I have for the most part included studies which agree with my view of the general lack of diagnostic
utility for thyroid nodules in the era of FNA. However, it would be remiss and unfair not to include
studies in the literature that espouse an opposite point of view. In addition to the study cited above
from the Mayo Clinic, several of these report on large numbers of cases and their results deserve to be
considered. Within the past five years, a number of reports about FNA and frozen section of thyroid
nodules have been published from around the world: these indicate that the yields are equivalent or that
frozen section is not cost effective in the era of FNA
; some studies indicate that selective use
of frozen section often with intraoperative imprint cytology in lesions considered "suspicious" on FNA
may be useful
. Only a rare report favors frozen section diagnosis in the thyroid
In view of the ample evidence presented in the literature regarding the use of intraoperative
consultation for the thyroid nodule, one can draw the following major conclusions:
One special case deserves to be mentioned and I have been seeing more of these lesions in the past 2-3
years: this is the situation of either an ultrasound detected subcentimeter nodule  with equivocal
or no FNA and the incidental (usually subcapsular) white subcentimeter nodule found grossly in the
intraoperative period. Frozen section on these small lesions is to be condemned in my opinion, for two
- Intraoperative consultation is not indicated in cases diagnosed as definite for malignancy on FNA due to high sensitivity and specificity (indeed, I have often told residents that if surgeons do not believe a definitive cytologic diagnosis of papillary cancer, they should either not have FNA performed or get themselves another cytopathologist; doing both FNA with a definite diagnosis and also a frozen section is wasteful of resources in the medical care environment)
- The records of good cytopathologists indicate that the false positive rate for papillary carcinoma approaches 0%
- in the majority of cases frozen section is of limited or no value in the diagnosis of follicular or Hürthle cell carcinoma, because the histologic characterization of these lesions requires detail analysis of the tumor capsule for demonstrating capsular and/or vascular invasion-an analysis which is not practical in the daily practice of pathology
- intraoperative consultation (frozen section combined with IOC) is most effective in cases, which are diagnosed as suspicious for papillary thyroid carcinoma on FNA
Sanctioning a total thyroidectomy for
such a lesion on a frozen section seems inappropriate and overtreatment in any event.
- the freezing artifact often so interferes with the cytomorphology of the permanent sections that a definitive diagnosis may never be made with certainty; and
- even if the lesion is a carcinoma, it is a papillary microcarcinoma and of no significance anyway.
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