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Ann Thorac Surg 2004;78:1755-1759
© 2004 The Society of Thoracic Surgeons

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Original article: general thoracic

Frozen Section Diagnoses of Small Pulmonary Nodules: Accuracy and Clinical Implications

^a Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA
^b Department of Thoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA

Accepted for publication May 3, 2004.

^* Address reprint requests to Dr Marchevsky, Department of Pathology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
marchevsky{at}cshs.org

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: Pulmonary nodules are frequently first diagnosed by frozen section, immediately followed by lobectomy or other procedures. The frozen section diagnosis of pulmonary nodules can be difficult, as inflammatory and fibrotic lesions can be confused for malignancy, creating intraoperative dilemmas for pathologists and thoracic surgeons.

METHODS: We reviewed our experience at Cedars-Sinai Medical Center with the frozen section diagnoses of 183 consecutive pulmonary nodules smaller than 1.5 cm in diameter and calculated the sensitivity, specificity, and predictive values of this diagnostic procedure.

RESULTS: One hundred and seventy four nodules were correctly classified by frozen section as neoplastic or nonneoplastic, six lesions were diagnosed equivocally, and two neoplasms were missed owing to sampling errors. The equivocal frozen section diagnoses included two bronchioloalveolar carcinomas (BAC) interpreted as "atypical hyperplasia, favor BAC," two BAC diagnosed as "alveolar hyperplasia," and two carcinoid tumors labeled as "atypical carcinoma" and "spindle cell lesion, carcinoid versus sclerosing hemangioma," respectively. The sensitivities for a diagnosis of neoplasia were 86.9% and 94.1% for nodules smaller than 1.1 cm in diameter and measuring 1.1 to 1.5 cm, respectively. The diagnostic accuracy of frozen sections was significantly better in nodules larger than 1.0 cm in diameter (p = 0.05). There were no false-positive diagnoses of malignancy, resulting in 100% specificity.

CONCLUSIONS: Intraoperative consultation with frozen section is a sensitive and specific procedure for the diagnosis of malignancy from small pulmonary nodules. The distinction between BAC and atypical adenomatous hyperplasia, and of small peripheral carcinoid tumors from other lesions, can be difficult by frozen section. Thoracic surgeons need to become aware of these problems and develop appropriate therapeutic strategies.

	Introduction

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The preoperative diagnosis of small intrapulmonary nodules can be difficult by transbronchial or transthoracic biopsies or other invasive procedures because of sampling problems [1–4]. Thoracoscopy and intraoperative consultation with frozen section are frequently used in practice to establish the initial diagnosis of lung cancer in these patients [5–7]. Lobectomy, pneumonectomy, or other modes of resection immediately follow an intraoperative diagnosis of malignancy in patients with lung nodules.

Frozen sections of lung nodules can be difficult to interpret, as reactive proliferative epithelial changes in inflamed lung tissue can closely simulate a malignancy. The surgical pathologist is presented with a dilemma: either render an intraoperative diagnosis of malignancy based on atypical changes that could be artificially enhanced by the technical artifacts of the frozen section procedure, or defer the diagnosis until permanent histologic sections can be examined [8–11]. A diagnosis such as "atypia, defer to permanent sections" in a lung nodule at the time of frozen section can be helpful to a surgical pathologist, as it avoids possible diagnostic mistakes and potential medico-legal exposure. However, this equivocal frozen section interpretation delays the correct diagnosis of a pulmonary nodule and subjects the patient to the increased morbidity associated with a second anesthesia to resect the lesion after the diagnosis is established by examination of permanent histologic sections. Ideally, frozen section diagnostic deferrals should be kept to a minimum, as long as diagnostic accuracy is not compromised.

The recent development of newer imaging modalities such as spiral computerized tomography (CT) scans allows for the identification of malignant lung nodules in high-risk individuals that can be as small as 5 mm in diameter [12–14]. For example, Pastorino and associates [12] conducted a recent study of 1035 high-risk individuals aged 50 years or older who were followed with yearly spiral CT and the selective use of positron emission tomography. At year 2 of the study, they identified 440 lung nodules larger than 5 mm in 29% of the patients [12].

Peripheral lung lesions as small as 5 mm in diameter are very difficult to diagnose with transbronchial or transthoracic biopsies. Many of these patients undergo wedge biopsy and intraoperative diagnosis based on a frozen section. These cases frequently result in a practical dilemma for surgical pathologists, raising the question of whether a lung nodule smaller than 1 cm diameter should be "cut" for a frozen section. This task can be technically difficult to perform and can yield histologic slides that may be difficult to interpret.

We reviewed the experience at Cedars-Sinai Medical Center with the intraoperative diagnosis of small lung nodules during a recent 9-year period in an attempt to assess the accuracy of the procedure and suggest practical guidelines for pathologists and thoracic surgeons.

	Material and Methods

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The records of the Department of Pathology and Laboratory Medicine of Cedars-Sinai Medical Center were reviewed for the period 1993 to 2001 to retrieve lung surgical pathology cases where a frozen section was performed for the diagnosis of pulmonary nodules measuring up to 3 cm in greatest diameter, the size cut-off used by the American Joint Commission of Cancer for the assignment of pT1 category to lung neoplasms [12–14]. Seven hundred and thirty seven cases with pulmonary nodules measuring up to 3 cm were identified during the 9-year period, including 509 primary lung neoplasms, 88 pulmonary metastases, and 140 with nonneoplastic conditions.

Arbitrarily, we studied the pulmonary nodules representing the smaller half of this cohort, using a 1.5-cm diameter as a maximum cut-off for case selection, as larger nodules are, in our experience, easier to accurately diagnose by intraoperative consultation and frozen section. Two hundred thirty-three of the pT1 nodules were 1.5 cm or less. Patients with metastatic tumors were not included in the study. Only one of the patients in the study had received a neoadjuvant therapy that can affect interpretations on frozen sections and permanent sections.

Intraoperative consultations with frozen section were performed in 183 of these 233 patients. To determine whether the diagnostic accuracy of the frozen section diagnoses was inversely related to the nodule size, the 183 cases were subdivided into two subgroups: nodules smaller than 1.1 cm in diameter and those measuring 1.1 to 1.5 cm. The pathology reports of all cases and the frozen section and permanent histologic slides of cases with equivocal or incorrect diagnoses were reviewed. The frequencies of various diagnoses and the sensitivity, specificity, and positive and negative predictive values of a frozen section diagnosis of malignancy in a small pulmonary nodule were calculated.

One-way analysis of variance was performed to determine, within each of the two subgroups of nodules, whether there was a significance difference in the size of the lesions, by diagnosis (Statgraphics 5 Plus, Manugistics Rockville MD). The proportions of correct and incorrect frozen section diagnoses in the two subgroups were compared with the Fisher exact test.

	Results

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Seventy-four pathology specimens were from male patients and 109 from female patients. The age of the patients ranged from 21 to 91 year old. Tables 1 and 2 list the frequencies of the various neoplastic and nonneoplastic diagnoses encountered in the 183 patients. Seventy-nine nodules were nonneoplastic as a result of granulomas, hamartoma, and other conditions listed in Table 2. No false diagnosis of malignancy was rendered in any of the cases.

Six of the 40 neoplastic nodules smaller than 1.1 cm in diameter were given equivocal frozen section diagnoses. They included two bronchioloalveolar carcinomas (BAC) interpreted as "atypical hyperplasia, favor BAC," two BAC diagnosed as "alveolar hyperplasia," and two carcinoid tumors labeled as "atypical carcinoma" and "spindle cell lesion, carcinoid versus sclerosing hemangioma," respectively. The two patients with a frozen section diagnosis of "atypical hyperplasia, favor BAC" underwent lobectomies during the same operations. The diagnosis of BAC was confirmed in both instances by an examination of the permanent histologic sections. The two patients with a frozen section diagnosis of "alveolar hyperplasia" were treated with wedge resections (Figs 1A and B). These lesions measured 0.9 and 1.0 cm respectively, and as the wedge resection margins were free of tumor, the patients did not undergo a second operation. The patient with a carcinoid tumor diagnosed by frozen section as "atypical carcinoma" underwent a lobectomy during the initial operation. The other patient with a carcinoid tumor diagnosed equivocally by frozen section was treated with wedge resection, which exhibited negative surgical margins.

View larger version (106K): [in this window] [in a new window]   Fig 1. (A) Frozen section of a 0.9-cm diameter peripheral bronchioloalveolar carcinoma (BAC), nonmucinous type. Note the presence of extensive fibrosis and focal alveolar spaces lined by atypical cells with enlarged nuclei exhibiting anisocytosis, some hyperchromasia and nuclear overlap (arrows). The frozen section was interpreted equivocally as "atypical changes, favor BAC." The patient was successfully treated with lobectomy during the same operation. Although this is a frozen section of good technical quality, it is more difficult to appreciate fine cytologic details in this material than in "permanent" histologic sections. The atypical changes seen in this frozen section are difficult to distinguish from those of reactive pneumocytes. The diagnostic problem should be discussed with the thoracic surgeon to provide a subjective assessment of the likelihood of malignancy. Thoracic surgeons need to understand that there is a small possibility of a false-positive diagnosis of malignancy, depending on the level of experience of the pathologist (hematoxylin & eosin, x100). (B) Higher magnification of the lesion described in (A) showing in more detail the presence of atypical cells with enlarged nuclei exhibiting anisocytosis, some hyperchromasia and nuclear overlap (hematoxylin & eosin, x400).

The proportions of correct and incorrect frozen section diagnoses were significant by size subgroup (two-sided probability p = 0.05). Table 3 shows, by lesion size, the sensitivity, specificity, and positive and negative predictive values of the frozen section diagnoses of malignancy in small pulmonary nodules. The 6 patients with equivocal diagnoses and the 2 patients with "benign" diagnoses were considered as false-negative diagnoses in these calculations, although 4 of these patients had been treated correctly with lobectomy during the initial surgical procedures.

	Comment

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Intraoperative consultations with a frozen section had limitations in distinguishing bronchioloalveolar carcinoma (BAC) from atypical adenomatous hyperplasia (AAH) and reactive pneumocyte hyperplasia, at establishing a diagnosis of specific cell type in patients with nonsmall cell carcinomas, and at distinguishing small peripheral carcinoid tumors of the lung from other conditions [15]. AAH is a focal lesion, often 0.5 cm or less in diameter, in which the involved alveoli and respiratory bronchioles are lined by monotonous, slightly atypical cuboidal-to-low-columnar epithelial cells with dense nuclear chromatin, prominent nucleolus, and scant cytoplasm [16]. Six of the 104 neoplastic lesions were diagnosed equivocally by frozen section and two neoplasms were under-diagnosed owing to sampling error. As a result of these errors, 1 patient had to undergo a second VATS procedure with general anesthesia for resection of her BAC; and 3 patients (2 with small BACs and 1 with carcinoid tumor) underwent wedge resections.

In our opinion, pathologists should strive to render a deferred diagnosis of "atypia" as sparingly as possible when dealing with small pulmonary nodules, as these patients are likely to need a second operation with general anesthesia for definitive treatment of their malignancies if the lesions are not initially correctly diagnosed. Pathologists should also warn their thoracic surgeons that the histopathologic distinction between AAH and BAC in small pulmonary nodules can be difficult and may result in a few false-positive or false-negative frozen section diagnoses. Furthermore, the frozen section procedure may exhaust all available tissues, precluding a definitive diagnosis of a malignant or benign condition that is based on permanent sections. Personal judgment has to be used in the handling of individual patients, and frozen sections should be performed only in situations when the pathologist can be certain that enough materials will remain available for a definitive diagnosis.

Adequate communication between the thoracic surgeon and the pathologist is also important during intraoperative consultations. For example, if the pathologist indicates great concern about the possibility of malignancy in a frozen section with "atypia, defer to permanent sections," the patient is likely to undergo a lobectomy and lymph node dissection. In contrast, if the pathologist indicates that the "atypia" is likely to be reactive, the thoracic surgeon may decide to wait for a definitive diagnosis. Awareness of the clinical consequences of various terminologies will allow for the development of a more consistent diagnostic language by pathologists and better therapeutic and informed consent strategies for the management of patients with small pulmonary nodules.

Lesions smaller than 5 mm should probably not be used for frozen section, unless the pathologist is assured that additional diagnostic materials are available for a biopsy, as the materials could be difficult to cut and interpret and there is a probability that the procedure will render inadequate tissue remnants for definitive diagnosis. Indeed, the issue of performing a frozen section on tumors smaller than 1 cm in diameter has been debated in the breast cancer literature, and it has been recommended that frozen sections should not be performed on breast lesions smaller than 1 cm in diameter [17–23]. This recommendation is intended to avoid false-positive diagnoses of malignancy in these patients and to preclude the possibility that the tissues from the small breast nodule could be all sectioned during the performance of the frozen section. The latter situation can result in the unfortunate situation where there are no residual diagnostic materials for a definitive diagnosis based on "permanent" sections. This practice is now followed in our department and other large medical centers for most breast cancer patients.

The need for accurate frozen section diagnoses for pulmonary nodules is, however, in sharp contrast to the need for frozen section diagnoses for breast masses. Several decades ago, it was common to do a breast biopsy under general anesthesia and proceed with a mastectomy if the frozen section diagnosed cancer. Today, breast biopsies are usually done with local anesthesia, and a decision regarding further surgery is made at a postoperative discussion with the results of permanent section. In contrast, a wedge resection of a lung mass requires a general anesthesia, so an accurate frozen section diagnosis is needed to avoid a second general anesthesia.

Thoracic surgeons need to understand that pathologists are unlikely to render a diagnosis of well-differentiated adenocarcinoma in nodules measuring 5 mm or less in diameter, as this size cut-off is used as a diagnostic criterion to distinguish BAC from AAH [15, 16]. Atypical lesions larger than 1 cm in diameter are likely to be malignant, while atypical lesions measuring 5 to 10 mm are in a "gray zone" where the distinction between BAC and AAH is established on the basis of subtle atypical features that can be present in both conditions but are more prominent in small BACs. They include anisocytosis, prominent nucleoli and nuclear pseudoinclusions, and increased nucleo–cytoplasmic ratios [15, 16]. In addition, the cells of BAC tend to become slightly stratified, with several layers present in focal areas. The detection of these subtle histopathologic features can be difficult in frozen sections, where the quality of visualized materials can be less distinct than in permanent histopathologic sections.

Thoracic surgeons also need to understand other practical limitations of the frozen section diagnoses of small pulmonary nodules. For example, a study of 90,538 frozen section cases from multiple organ sites performed at 461 institutions conducted by the College of American Pathologists yielded concordances rates of 98.58% and discordance rates of 1.42% between frozen section and definitive diagnoses [10, 11]. Most of the frozen section discordances occurred because of the misinterpretation of the original frozen section (31.8%), the presence of diagnostic tissue in permanent sections of the frozen block while the frozen section was negative (30.0%), and the presence of diagnostic tissue in portions of the specimen not sampled by the frozen section (31.4%). Of the discordant diagnoses, 67.8% had false-negative diagnoses for neoplasm and the remainder were false-positive results.

In conclusion, both thoracic surgeons and pathologists need to approach the intraoperative diagnosis of small pulmonary nodules with caution, particularly those smaller than 1 cm in diameter. Surgeons probably need to inform their patients that there may be difficulties in the intraoperative diagnosis of their lesions, which could result in a second operation should the pathologist be unable to classify a lesion with certainty during surgery. In addition, and although we did not encounter false-positive diagnoses of malignancy, it is well-known that frozen sections may result in a small number of cases with false-positive diagnoses, and this possibility should probably be disclaimed as one of the possible risks of the surgical procedure.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The authors thank James Mirocha for assistance with the statistical tests.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Mazzone P, Jain P, Arroliga AC, Matthay RA. Bronchoscopy and needle biopsy techniques for diagnosis and staging of lung cancer. Clin Chest Med. 2002;23:137–158[Medline]
2. Jones AM, Hanson IM, Armstrong GR, O'Driscoll BR. Value and accuracy of cytology in addition to histology in the diagnosis of lung cancer at flexible bronchoscopy. Respir Med. 2001;95:374–378[Medline]
3. Savage C, Morrison RJ, Zwischenberger JB. Bronchoscopic diagnosis and staging of lung cancer. Chest Surg Clin N Am. 2001;11:701–721[Medline]
4. Nakamura H, Kawasaki N, Hagiwara M, Ogata A, Kato H. Endoscopic evaluation of centrally located early squamous cell carcinoma of the lung. Cancer. 2001;91:1142–1147[Medline]
5. McKenna RJ Jr. Thoracoscopic evaluation and treatment of pulmonary disease. Surg Clin North Am. 2000;80:1543–1553[Medline]
6. Gharagozloo F, Tempesta B, Margolis M, Alexander EP. Video-assisted thoracic surgery lobectomy for stage I lung cancer. Ann Thorac Surg. 2003;76:1009–1014[Abstract/Free Full Text]
7. Warner EE, Mulshine JL. Surgical considerations with lung cancer screening. J Surg Oncol. 2003;84:1–6[Medline]
8. Nashef SA, Kakadellis JG, Hasleton PS, Whittaker JS, Gregory CM, Jones MT. Histological examination of peroperative frozen sections in suspected lung cancer. Thorax. 1993;48:388–389[Abstract/Free Full Text]
9. Gianoulis M, Chan N, Wright JL. Inflation of lung biopsies for frozen section. Mod Pathol. 1988;1:357–358[Medline]
10. Novis DA, Zarbo RJ. Interinstitutional comparison of frozen section turnaround time. A College of American Pathologists Q-Probes study of 32868 frozen sections in 700 hospitals. Arch Pathol Lab Med. 1997;121:559–567[Medline]
11. Gephardt GN, Zarbo RJ. Interinstitutional comparison of frozen section consultations. A college of American Pathologists Q-Probes study of 90,538 cases in 461 institutions. Arch Pathol Lab Med. 1996;120:804–809[Medline]
12. Pastorino U, Bellomi M, Landoni C, et al. Early lung-cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year results. Lancet. 2003;362:593–597[Medline]
13. Diederich S. Screening for early lung cancer with low-dose spiral computed tomography. Lancet. 2003;362:588–589[Medline]
14. Marten K, Grabbe E. The challenge of the solitary pulmonary nodule: diagnostic assessment with multislice spiral CT. Clin Imaging. 2003;27:156–161[Medline]
15. Mori M, Rao SK, Popper HH, Cagle PT, Fraire AE. Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung. Mod Pathol. 2001;14:72–84[Medline]
16. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur Respir J. 2001;18:1059–1068[Abstract/Free Full Text]
17. Wightman HR. Frozen sections and breast biopsies. Am J Clin Pathol. 1997;107:493[Medline]
18. Hoda SA. Frozen section for mammographically directed breast biopsies. Am J Surg Pathol. 1996;20:1532[Medline]
19. Frankel KA. Frozen section for mammographically directed breast biopsies. Am J Surg Pathol. 1996;20:1531–1532[Medline]
20. Fechner RE. Breast frozen sections. Am J Surg Pathol. 1996;20:1296[Medline]
21. Niemann TH, Lucas JG, Marsh WL Jr. To freeze or not to freeze. A comparison of methods for the handling of breast biopsies with no palpable abnormality. Am J Clin Pathol. 1996;106:225–228[Medline]
22. Bianchi S, Palli D, Ciatto S, et al. Accuracy and reliability of frozen section diagnosis in a series of 672 nonpalpable breast lesions. Am J Clin Pathol. 1995;103:199–205[Medline]
23. Fechner RE. Frozen section examination of breast biopsies. Practice parameter. Am J Clin Pathol. 1995;103:6–7[Medline]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Clark Fuller Ward Houck Robert J. McKenna, Jr Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marchevsky, A. M. Articles by McKenna, R. J. Search for Related Content PubMed PubMed Citation Articles by Marchevsky, A. M. Articles by McKenna, R. J., Jr Related Collections Lung - cancer