Intra-operative frozen section diagnosis of breast lesions: a retrospective analysis of 13,243 Chinese patients.
ABSTRACT Although cytological methods for breast oncology have been used in recent decades, intra-operative frozen section has been playing a vital role in making therapeutic decisions. We analyzed a large series of frozen section diagnoses for Chinese cases of breast lesion within the last 15 years. The experience was expected to increase the diagnostic accuracy of cases with breast lesions.
The data from consecutive 13243 cases of breast lesions diagnosed with intra-operative frozen sections between 1988 to 2002 were compared with paraffin sections in a case by case manner. The causes of false negative and positive diagnoses as well as delayed diagnoses were analyzed.
One hundred and seventeen cases (0.9%) were falsely diagnosed, with one false positive case and 116 false negative cases. The diagnosis of 47 cases (0.4%) was delayed. The proportion of several lesions had the features of the patients' ages. Six types (false invasion, peri-papilloma, adenoma of nipple duct, florid adenosis, sclerosing adenosis, and granulose cell tumor) of lesions may lead to false positive, and four types (morphological changes responding chemotherapy, well differentiated papillary carcinoma, invasive lobular carcinoma, and tubular carcinoma) to a false negative. Gross and microscopic findings may be inconsistent in two types of lesions (radial scar and florid adenosis) microscopic and clinical findings in three types (ganulomatous mastitis mammary, duct ectasia, and fat necrosis), and three types (abundant fat or sclerous tissues; borderline lesions and changes of post-chemotherapy) were likely wrongly classified.
Intra-operative frozen section can accurately identify breast lesions in many instances, leading to fewer errors on account of more diagnostic experience and understanding of diagnostic limitations.
- SourceAvailable from: Luís Ricardo Martinhão Souto[Show abstract] [Hide abstract]
ABSTRACT: To evaluate the accuracy of frozen section tests at different anatomical sites performed in an academic department of pathology. We conducted a retrospective study from a computerized database of all frozen section tests. These diagnoses were compared to definite paraffin, used as controls. The tests were divided into three groups: inconclusive, consistent and inconsistent, the latter being subdivided into false positives and false negatives. The main indications for examinations and anatomical sites involved with diagnostic disagreements were also analyzed. Four hundred and thirty-three specimens were frozen tested, and the main indication was diagnostic (75.75%). In 404 tests (93.30%) diagnoses of biopsies in paraffin and frozen section were consistent. In 20 cases (4.62%) the results of frozen section biopsy were inconclusive and in 9 (2.08%) they were false negative. There were no false positive results. The most commonly assessed organ was the thyroid (25.64%). In the overall analysis, the body region most related with inconclusive diagnoses was the thyroid (seven cases) and in relation to specific sites it was the lungs/pleura/mediastinum (13.33%). Skin was the organ that showed more discordant diagnoses between frozen biopsies and paraffin. The global accuracy of frozen section was 93.30%; for specific anatomical sites, diagnostic accuracy ranged from 86.67% to 100%.Revista do Colégio Brasileiro de Cirurgiões 06/2011; 38(3):149-54.
Chin Med J 2007; 120 (8): 630-635
Intra-operative frozen section diagnosis of breast lesions: a
retrospective analysis of 13 243 Chinese patients
NIU Yun, FU Xi-lin, YU Yong, Peizhong Peter Wang and CAO Xu-chen
Keywords: breast neoplasm; frozen section; differential diagnosis
Background Although cytological methods for breast oncology have been used in recent decades, intra-operative
frozen section has been playing a vital role in making therapeutic decisions. We analyzed a large series of frozen section
diagnoses for Chinese cases of breast lesion within the last 15 years. The experience was expected to increase the
diagnostic accuracy of cases with breast lesions.
Methods The data from consecutive 13243 cases of breast lesions diagnosed with intra-operative frozen sections
between 1988 to 2002 were compared with paraffin sections in a case by case manner. The causes of false negative and
positive diagnoses as well as delayed diagnoses were analyzed.
Results One hundred and seventeen cases (0.9%) were falsely diagnosed, with one false positive case and 116 false
negative cases. The diagnosis of 47 cases (0.4%) was delayed. The proportion of several lesions had the features of the
patients’ ages. Six types (false invasion, peri-papilloma, adenoma of nipple duct, florid adenosis, sclerosing adenosis,
and granulose cell tumor) of lesions may lead to false positive, and four types (morphological changes responding
chemotherapy, well differentiated papillary carcinoma, invasive lobular carcinoma, and tubular carcinoma) to a false
negative. Gross and microscopic findings may be inconsistent in two types of lesions (radial scar and florid adenosis)
microscopic and clinical findings in three types (ganulomatous mastitis mammary, duct ectasia, and fat necrosis), and
three types (abundant fat or sclerous tissues; borderline lesions and changes of post-chemotherapy) were likely wrongly
Conclusions Intra-operative frozen section can accurately identify breast lesions in many instances, leading to fewer
errors on account of more diagnostic experience and understanding of diagnostic limitations.
Chin Med J 2007;120(8):630-635
he frozen section technique for intra-operative
pathologic diagnosis has been used for more than 100
years.1 High quality sections could be obtained with the
emergence of the cryostat
cytological methods have been developed in recent
decades and more core needle biopsies are needed
recently before the operation, frozen sections are still
widely used in some countries including China.2-4 The
incidence and absolute value of breast cancer have been
rising in China.5,6
As for breast oncology, intra-operative frozen section
diagnosis has been playing a vital role in making
appropriate therapeutic decisions.7,8 Pathologists still
confront a serious challenge when surgeons expect them
to arrive at a reliable answer on the properties of the
extracted samples. As well, the patients hope to avoid a
second operation or wrong removal of their mamma.
The accuracy rate of diagnoses and the causes of the
misdiagnoses have been previously described.9-11 On
average correct rates of diagnoses are between 92.6% and
98.0% (the cases from dozens at least to more than two
thousands at most). However, the misdiagnosis may
lead to injuries to patients, especially a false positive
diagnosis. Just as Avery12 commented – “frozen section
error－rare but disastrous.”
In the majority of cases, the morphology of the breast
lesions is typical, and a diagnosis is easily made. In some
cases, however, it is very difficult to diagnose accurately
because of false appearances.13,14 Frozen section
diagnoses were performed for 13243 cases of breast
lesions obtained over a 15-year period in this series. The
data and clinicopathologic experience were reviewed.
A series of consecutive 13961 frozen section specimens
obtained intra-operatively were examined by Breast Patho-
Breast Cancer Pathological Department and Research Laboratory
(Niu Y, Fu XL and Yu Y), Epidemical and Bio-statistic Department
(Peizhong Peter Wang), Breast Cancer Surgical Department (Cao
XC), Breast Cancer Research Key laboratory of National
Education Ministry, Tianjin Cancer Institute, Tianjin Medical
University, Tianjin 300060, China
Division of Community Health, Faculty of Medicine, Memorial
University of Newfoundland, St. John’s, NL, Canada (Peizhong
Correspondence to: Dr. NIU Yun, Breast Cancer Pathological
Department and Research Laboratory, Breast Cancer Research Key
Laboratory of National Education Ministry, Tianjin Cancer Institute,
Tianjin Medical University, Huan Hu Xi Road, Ti Yuan Bei, He Xi
District, Tianjin 300060, China (Tel: 86-22-27303428. Fax:
86-22-23359337. Email: email@example.com, yunniu2000
Chinese Medical Journal 2007; 120 (8): 630-635
logical Department and Research Laboratory of Tianjin
Cancer Institute, Tianjin Medical University from
January 1, 1988 to December 31, 2002. Among them,
the breast lesions accounted for 13243 of cases.
There were 13165 females and 78 males in the 13243
cases. Their ages ranged from 12 to 75 years old (median,
50 years). Clinical diagnosis could not be made in 1269
cases; benign tumor was diagnosed before operation in
3282 cases, and malignant tumor in 8692 cases.
Informed consent was obtained from the patients before
this investigation, which was approved by the ethics
committee of the institute.
Fresh breast specimen was taken during operation and
examined immediately by pathologists. From the
representative region ot the lesion, one to two pieces of
the specimen were taken for frozen section examination.
The cryostat sections were prepared by technicians using
Rapid Sectioning Cryostats (Rapid Sectioning Cryostats,
MINOTOME, USA, 1988-1992 and Bright CHINI-CUT-
4000, England,1993-2002). The sections varied from 4
µm to 6 µm in thickness, and stained quickly with
hematoxylin and eosin (HE). A strict quality standard was
used to ensure the quality of the prepared section. The
pathological diagnosis was
pathologists through microscopic observation.15 The
interval was 20 to 30 minutes from preparation of the
specimen to issuing a report.
Frozen section diagnosis of every case was registered
chronologically and put into the clinical document of the
patient immediately. The diagnostic result was unchanged
once input into the document. A data bank was set up in
January 2002 (named Breast Lesion Frozen Diagnosis,
BLFD), which had such functions as searching, ordering,
exporting and statistical analysis, and preparation of 17
items, for example, document number, age, frozen section
diagnosis. The records of the 13243 cases were then
stored in the data bank with the data consistent with these
mentioned in the document. For each lesion, the data-
bank was queried separately for analysis in this study.
As acknowledged, routine paraffin section diagnosis is
the “gold standard” and the results of frozen section
cannot be regarded as the final diagnosis of the patient.
The results of frozen section were compared with those of
routine paraffin section diagnosis postoperatively and
the definite diagnosis rate for benign or malignant nature
of frozen section was assessed in this study.15 The causes
of false positive and negative diagnoses as well as
delayed diagnoses were analyzed.
Number of cases and proportion
The number of cases for frozen section examination
established by two
increased from 230 to 1761 cases year by year in this
hospital. A total of 13196 of 13243 cases (99.6%) were
diagnosed timely by the intra-operative frozen section
diagnosis. Benign lesions accounted for 4754 cases
(36.0%, 4754/13196) and malignant lesions for 8442
cases (64.0%, 8442/13196). And 47 cases (0.4%, 47/13243)
were delayed for paraffin section in order to be examined.
The first three lesions diagnosed by frozen section were
invasive ductal carcinoma (55.4%), benign tumor (18.4%)
and benign hyperplastic lesion (10.9%). The proportions
was 3.1% for carcinoma in situ and was 1.6% for invasive
ductal carcinoma with a predominant intraductal
component. The proportions for invasive lobular
carcinoma and sarcoma were 0.3% and 1.1%,
Fibroadenoma was seen frequently between 20-29 years,
fibroadenoma with abundant cells at age of 30-39 years,
and borderline and malignant phyllodes tumors 40-49
years. Papilloma or invasive ductal carcinoma was seen at
age of 50-59 years and then presented a declining
tendency. However, papillary carcinoma was seen
increasingly over 49 years old.
Accuracy rate of frozen section diagnosis
The accuracy rate of frozen section diagnosis for benign
or malignant tumors in our series was 99.1%
(13079/13196) compared to final paraffin section
diagnosis. There were 1 false positive case, 116 false
negative cases, and 47 cases delayed in diagnoses. The
false positive rate was 0.0% (1/13196) and the false
negative rate was 0.9% (116/ 13196).
Frozen section diagnosis vs paraffin section diagnosis
The results of frozen section diagnosis of malignant
lesions, as well as comparison with final paraffin section
diagnosis including consistency in benign and malignant
nature and pathological classification are shown in Table.
The results of frozen section diagnoses of benign lesions
and comparisons with paraffin section diagnosis
including status of false negative lesions are also listed in
Diagnostic errors or diagnostic delay
False positive conditions might attribute to false invasion,
papillomatosis, adenoma of the nipple duct, florid
adenosis, sclerosis adenosising and granulose cell tumor.
While, false negative diagnosis might be due to
morphological changes after
differentiated papillary carcinoma, invasive lobular
carcinoma and tubular carcinoma. Inconsistent conditions
between microscopic and gross examinations were
radial scar, florid adenosis and so on and those between
microscopic and clinical findings were granulomatous
mastitis mammary, ductal ectasia and fat necrosis.
Diagnostic delay was closely relates to abundant fat or
sclerotic tissue in samples, borderline lesions and
morphologic changes after chemotherapy.
Chin Med J 2007; 120 (8): 630-635
Table. Malignant and benign lesions diagnosed by frozen section and paraffin section
(%) rate (%)#
8442 100.00 99.99
Frozen section diagnosis Case No.*
Consistent False positive
The main conditions of inconsistency
Apocrine carcinoma, micropapillary
carcinoma, invasive lobular carcinoma,
medullary carcinoma（101 cases）
Invasive ductal carcinoma with a
7307 86.56 99.99
1 (adenoma of
Carcinoma in situ
406 4.81 100.00 0 73.65
Other types ▲
carcinoma with a PIC
323 3.83 100.00 0 100.00
217 2.57 100.00 0 78.80 Ductal carcinoma in situ（46）
147 1.74 100.00 0 99.32 Phyllodes tumors (1)
42 0.50 100.00 0 80.95 invasive ductal carcinoma (8)
4754 100.00 97.56 116 - -
Bordline and malignant phyllodes
tumors was low-diagnosed
Papillary carcinoma was low-diagnosed
papillary or hyperplasia
Invasive carcinoma was mixed
△Consistent rate means consistent rate of the pathologic
Benign tumors* *
2426 51.03 97.04 71 -
1432 30.12 97.33 38 -
Other benign lesions
896 18.85 99.22 7 -
*Case No: case number; # Consistent rate means consistent rate of the benign and malignant lesions;
mucinous carcinoma, medullary carcinoma, micropapillary carcinoma, papillary carcinoma, tubular carcinoma, etc;
**Benign tumor includes fibroadenoma, papilloma, hamartoma, lipoma, adenoma of the nipple, granulosa cell tumor and so on; ##Hyperplasitic lesions include lobular
hyperplasia, cysthyperplasia, fibrous tissue hyperplasia, papillomatosis, radial scar, and so on;
mastitis, mammary duct ectasia and so on.
☆ Carcinoma in situ includes ductal carcinoma in situ, lobular carcinoma in situ, Paget’s disease of the nipple, canceration, etc; ▲Other types include
★ PIC: predominant intraductal component;
△△Other benign lesions include inflammation, fat necrosis, granulomatous
Fig. The morphologic features and the differentiations of some lesions in frozen section. A: The lactiferous ductal hyperplasia in
adenoma of the nipple formed various size of glandular-nest with diffuse and spore-like growth along ductal branches to surrounding
stroma. The complex glandular-duct-like and irregular structure mimic false invasive image in frozen section (HE, original
magnification×40); B: The nonspecial invasive ductal carcinoma in frozen section (HE, original magnification×40); C: The cells of
granulose cell tumor showed loose nest like or fascicular pattern and collagenous stroma distributing and surrounding these cells, the
eosinophilic cytoplasmic granules of tumor cells are not conspicuous in the frozen section (HE, original magnification×40); D: The
non-specific nvasive carcinoma in the frozen section (HE, original magnification×100); E: A confluent growth of adenosis glands and
acinous in the florid adenosis don’t form distinct lobular structure. The florid epithelial and myoepithelial hyperplasia effaced glandular
and mimic invasive carcinoma in frozen section (HE, original magnification×40); F: The nonspecial invasive ductal carcinoma in the
frozen section (HE, original magnification×40). G: The gross appearance of radial scar is similar to that of small invasive carcinoma;
H: The radial scar in frozen section (HE, original magnification×40). Under a microscope, the radial scar belongs to a benign
sclerosing lesion and results from elastotic change. Scale bars=100 µm (A-F, H) or 2.5 mm (G).
Morphologic features and differentiations
In our series an adenoma of the nipple (Fig. A) was
recognized as to invasive ductal carcinoma (Fig. B). The
other benign diseases which were hard differentiated from
the malignancy in our work included granulose cell tumor
(Fig. C) with the invasive carcinoma (Fig. D), the
eosinophilic secretions in
papillomatosis with the central necrosis of ecomedo
intraductal carcinoma, and florid adenosis, sclerosing
adenosis, intraductal papilloma with pseudo invasion (Fig.
the moderate florid
Chinese Medical Journal 2007; 120 (8): 630-635
E) with the invasive ductal carcinoma (Fig. F).
Some malignancies leading to frequent false negative
diagnoses included the pathologic changes of post-
therapy, chronic inflammation,
papillary carcinoma and papilloma, diffused pattern of
invasive lobular carcinoma and chronic inflammation,
tubular carcinoma and adenosis.
Invasive micropapillary carcinoma and non-specific
invasive ductal carcinoma, breast lymphoma and
invasive lobular carcinoma were difficult to classify in
Four cases of radical scar in our series showed
inconsistency between gross examination (Fig. G) and
frozen section diagnosis (Fig. H).
After the establishment of criteria for the evaluation of
frozen section diagnosis of the breast,16-18 Cserni19
described frozen section in the operation as a “trap” after
reviewing 2110 cases of frozen section diagnosis in 13
years. His series contained 22 cases of false negative and
1 of false positive. Cserni explained these errors were due
to (1) misinterpretation; (2) poor quality of frozen
sections; (3) sampling errors during sectioning; (4)
ignorance of macroscopic features; (5) lesions difficult to
interpret; (6) ductal carcinoma in situ as the only lesion in
the specimen; and (7) sections not deep enough. Some
authors12,20 have proposed that frozen section shouldn’t
be used as the only method because of its limitations, and
it may be adopted when other methods failed. In some
countries such as China, however, frozen section is still
the major rapid diagnostic method at present. Hence, it is
necessary to deepen the understanding of various
challenges which may be confronted with by pathologists
during frozen section examinations.
First, the conditions which may lead to false positive
diagnosis should be discussed. The false positive case in
our series, adenoma of the nipple21,22 was misdiagnosed
as invasive ductal carcinoma. Under a microscope, there
were hyperplastic lactiferous ducts of the nipple, forming
various papillary and glandular nests with diffuse or
spore-like growth along ductal branches to the
surrounding stroma. The complex glandular-duct-like,
irregular structure and false invasive image in sclerotic
stroma led to misdiagnosis. Azzopardi et al23 indicated
that when sclerosis and pseudoinfiltrative patterns were
prominent, an invasive carcinoma was closely simulated.
The background stroma shows loose myxoid features,
large collagenous bands or elastosis. The main
differentiating method from our experience depends on
the lesion only involving the nipple but without Paget
disease or myoepithelial cells.
Three cases of granular cell tumor of the breast were not
mistakenly diagnosed.24,25 Interestingly the lesion often
possessed indistinctive cell borders and collagenous
stroma. Tumor cells were arranged in a loose nest-like
pattern or in a fascicular pattern, and collagenous stroma
surrounded these cells. The tumor cells were large in size,
and even its eosinophilic cytoplasmic granules were not
conspicuous in a frozen section. Additionally, florid
adenosis, sclerosing adenosis or intraductal papilloma
with pseudoinvasion sometimes were similar to invasive
ductal carcinoma.26-28 The main points of differential
diagnosis according to our experience include (1) an
all-round observation with a microscope at a low power;
(2)the absence of epithelial atypia; (3) the presence of
myoepithelial layer; (4) a dense collagen stroma with
the polar of the tubular.
Second, the circumstances that frequently lead to false
negative diagnosis should be discussed. One of the
important circumstances is chemotherapeutic effect.29
Some patients in our series had undergone pre-operative
chemotherapy (neoadjuvant chemotherapy) for 1-3 weeks.
The histomorphologic regression in paraffin section was
reported as the major response.30,31 However, there were
difficulties in determining the pathologic changes after
therapy in frozen section diagnosis. Especially when
cellular deterioration and necrosis prevailed or when the
number of malignant cells decreased, and when the tumor
tissue was replaced by neocapillaries, histocytes,
lymphocytes and fibrosis, the manifestations of the
disease might be misdiagnosed as chronic inflammation.
The well-differentiated papillary carcinoma, diffused
pattern of invasive lobular carcinoma32 and tubular
carcinoma33 were frequently misdiagnosed as benign
lesions. Of course, the morphology of these lesions was
similar to that of some benign lesions. Moreover, the
pathologists have knowledge from most of published
reports that the benign lesions were sometimes confused
with mentioned carcinoma. So they would rather choose a
low-diagnosis for these lesions than a high-diagnosis.
Third, it is hard to classify tumors in some cases. In
invasive micropapillary carcinoma no clear space in the
intervening stroma was observed of the frozen section, in
which dehydration was not performed.34 In another case,
lymphoma with a nest-like architecture in the frozen
section was recongised as an invasive carcinoma.35
Pathologists could be misled by some findings as the first
impression in gross examination. The instances were seen
in 4 cases with radial scar in our series.36 A sclerosing
area without distinctive boundaries in the specimen was
seen, and its cutting sections was concave, grey or
grey-yellow with coarse radical cords. Under a
microscope, the change
It should be emphasized that there are limitations of
frozen section diagnosis. Because only a small piece of
tissue is selected for a frozen section diagnosis
resulted from elastic
Chin Med J 2007; 120 (8): 630-635
intra-operatively, it can not represent the overall profile of
the tumor, especially phyllodes tumor and adenofibroma
with abundant cells, atypical hyperplasia and canceration,
Sometimes inconsistencies are presented when clinical
symptoms and microscopic findings are compared, for
example, in granulomatous mastitis.39-41 However, some
clinicians overestimated their own experience and radical
operations were performed incorrectly for two patients
before frozen section diagnosis was made. In other
lesions, such as fat necrosis and mammary duct ectasia,
clinical symptoms might also be misinterpreted as breast
carcinoma. There was a difference in opinions (or
disagreements of the views) between the surgeon and
pathologist at that moment. Thus communication is
extremely important before surgery to reach an agreement.
Our data also suggest that the age of the patient is
essential to intra-operative diagnosis.
In short, intra-operative frozen section diagnosis of breast
lesion is very important. It is still a dominant and
effective examination at present, even though there are
Acknowledgements: We gratefully acknowledge Prof. P. H. Sinn
of Pathologic Institute, Heidelberg University of Germany and Prof.
Fan LD of Tianjin People’s Hospital for fruitful discussion on the
pathology in the study. We sincerely thank Ms. Sherry Hunt of
Memorial University of Newfoundland of Canada and Mr. Wang
ZH of Tianjin Cancer Institute of China for correcting the English
language of the article. We are also grateful to the pathologists (Fan
Y and Lang RG) who contributed to our work.
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(Received April 28, 2006)
Edited by QIAN Shou-chu and HAO Xiu-yuan