Chinese Medical Journal 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,  CAO Xu-chen

NIU Yun (Breast Cancer Pathological Department and Research Laboratory, Breast Cancer Research Key laboratory of National Education Ministry, Tianjin Cancer Institute, Tianjin Medical University, Tianjin 300060, China)

FU Xi-lin (Breast Cancer Pathological Department and Research Laboratory, Breast Cancer Research Key laboratory of National Education Ministry, Tianjin Cancer Institute, Tianjin Medical University, Tianjin 300060, China)

YU Yong (Breast Cancer Pathological Department and Research Laboratory, Breast Cancer Research Key laboratory of National Education Ministry, Tianjin Cancer Institute, Tianjin Medical University, Tianjin 300060, China)

Peizhong Peter Wang (Division of Community Health, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada)

CAO Xu-chen (Breast Cancer Surgical Department, Breast Cancer Research Key laboratory of National Education Ministry, Tianjin Cancer Institute, Tianjin Medical University, Tianjin 300060, China)

Correspondence to: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. E-mail:yunniu2000@yahoo.com.cn)
Keywords
breast neoplasm; frozen section; differential diagnosis
Abstract

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 classified.
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.

The 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 technique. Although 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.

METHODS

Subjects
A series of consecutive 13961 frozen section specimens obtained intra-operatively were examined by Breast Pathological 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.

Study methods
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 established by two 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.

RESULTS

Number of cases and proportion
The number of cases for frozen section examination 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%, respectively.

Age distribution
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 Table.
 

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Table. Malignant and benign lesions diagnosed by frozen section and paraffin section

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 chemotherapy, well 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.

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 the moderate florid papillomatosis with the central necrosis of ecomedo intraductal carcinoma, and florid adenosis, sclerosing adenosis, intraductal papilloma with pseudo invasion (Fig. 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, well-differentiated 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 some cases.

Four cases of radical scar in our series showed inconsistency between gross examination (Fig. G) and frozen section diagnosis (Fig. H).


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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).

DISSCUSION

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 resulted from elastic fibro-hyperplasia.

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 intra-operatively, it can not represent the overall profile of the tumor, especially phyllodes tumor and adenofibroma with abundant cells, atypical hyperplasia and canceration, ductal carcinoma in situ and microinvasive carcinoma.37,38

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 certain shortcomings.

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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