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Eur J Cardiothorac Surg 1998;13:190-195
© 1998 Elsevier Science NL

Frozen section diagnosis and surgical biopsy of lymph nodes,

tumors and pseudotumors of the mediastinum

Department of Pathology, Marie Lannelongue Surgical Center, 133 Avenue de la Résistance, 92350 Le Plessis-Robinson, France

Received 25 August 1997; accepted 16 December 1997.

Corresponding author. Tel.: +33 01 40942807; fax: +33 01 40942805.

	Abstract

Top Abstract Introduction Materials and methods Results Discussion References

 
Objective: Our experience with the use of frozen section (FS) was reviewed in order to assess its interest and limits, during minimally aggressive mediastinal surgery for staging of lung carcinomas and biopsy of primary lesions. Methods: The retrospective study was based on a series of 420 consecutive mediastinal biopsies with FS performed through cervicotomy (n=12), mediastinoscopy (n=345), mediastinotomy (n=43), manubriotomy (n=13) or videothoracoscopy (n=7), in 417 patients, aged 8–86 years (mean: 52.5±15.6). The FS diagnoses were compared with the final diagnoses and consequences of the FS analyses were analyzed. Results: Biopsies with FS had a 99.4% (351/353) efficiency rate for a precise definitive diagnosis (excluding normal lymph nodes). However, two patients required a second operation: one for typing a lymphoma and the other to correct a FS misdiagnosis of small cell carcinoma on a crushed normal lymph node. The sensitivity for detection of carcinoma lymph node metastases was 99% (200/202). The two false negative FS diagnoses, including one post-chemotherapy, were related to micrometastases. There were 46 correct FS diagnoses of non-metastatic lymph node which were followed by an immediate thoracotomy during the same anesthesia, for benign lung lesions (n=9) or for carcinomas (n=37), including 30 lung carcinomas that were immediately resected and proved to have no mediastinal involvement (n=24), or only a limited involvement in a non-biopsied site (n=6). In the 51 cases of primary mediastinal tumors excluding carcinomas, FS indicated a resectable lesion with a sensitivity of 87.5% (7/8) and a specificity of 97.7% (43/44). Five lesions were immediately resected: one Castleman’s disease, one intrathoracic goiter, two of six thymomas and a Hodgkin’s disease, which was diagnosed as thymoma on FS. An invasive thymoma was resected during a second operation after a FS diagnosis of carcinoma. FS had a sensitivity of 100% in the 62 cases of sarcoidosis and a sensitivity of 90% in the 20 cases of infectious lesions. One of the 18 cases of tuberculosis and an infectious pseudo-tumor of the anterior mediastinum had no microbiologic study because of FS diagnoses of tumor necrosis and lymphoma. Conclusions: FS efficiently secures the adequacy of the samples and guides the surgeon’s decision making for the resection of lung carcinomas, but is less effective for a precise diagnosis of some primary mediastinal lesions, which may have close histologic appearances.

Key Words: Frozen section • Mediastinoscopy • Mediastinotomy • Lung neoplasm-staging • Lymphoma • Thymoma • Sarcoidosis • Tuberculosis

	Introduction

Top Abstract Introduction Materials and methods Results Discussion References

 
A precise histologic diagnosis is often required for mediastinal lesions since they are varied, may be clinically confused, and are each associated with a specific therapeutic approach. These lesions can often be biopsied with minimally aggressive surgery [1]. During this surgery, frozen section (FS) is routinely used to ensure that biopsied samples are diagnostic and sufficient, to permit a thoracotomy for possible resection of lung carcinomas according to mediastinal involvement, to permit the resection of mediastinal lesions, possibly with an aggressive surgery according to histological type, or to indicate a possibly infectious lesion and the need for bacteriologic studies. However, FS is a difficult task in the general practice of pathology [2] [3]. It is time-consuming and has no absolute accuracy. In order to discuss the interest and limits of FS during mediastinal surgical biopsy, we present our experience.

	Materials and methods

Top Abstract Introduction Materials and methods Results Discussion References

 
Between July 1993 and June 1996 (3 years), 420 consecutive mediastinal biopsies, with a low-aggressive surgery and with FS, were performed at our institution on 417 patients, aged 8–86 year (mean: 52.5±15.6). Three patients had two operations each. The main patients’ characteristics and surgical procedures are listed in Table 1. No FS was aimed at assessing the margins of a mediastinal resection and FS examinations of resected lesions, or of mediastinal samples during a thoracotomy or a sternotomy, were excluded. Cervicotomy without mediastinoscopy was only considered when the mediastinal lesion was directly biopsied (excluding cervical lymph nodes biopsies). Tissue samples were sent by pneumatic dispatch from the operating theatre to the laboratory. They were then macroscopically examined. In order to limit the freezing alteration of the tissue for further study on paraffin sections, when possible, only a macroscopically representative part of the fragments was used for FS. This section of the fragments, set in an embedding medium (Cryomatrix, Shandon Life Sciences International, Runcorn, UK), was frozen with the help of a freezer spray (Shandon). Sections (10 µm thick) were performed with a cryostat at -22°C, placed on a glass slide, fixed in 95° ethanol with 1% of acetic acid 1N, and stained with toluidine blue. Slides were cover-slipped with water or an aqueous mounting medium (Immu-mount, Shandon). These slides were either thrown away or kept until final diagnosis. One to five FS per case (mean: 1.30±0.69) were performed on successive samples. These last were required to secure a final specific diagnosis in 44 cases (especially because of fibrosis or necrosis) or to definitively confirm the negative diagnoses (normal, hyperplastic or non-metastatic lymph nodes). After FS, the material was thawed, fixed and studied through routine histologic techniques, including special stains and immunohistochemistry when required. The final diagnoses were established on paraffin sections from the material submitted for FS and possibly from subsequently excised tissues during the same surgical procedure (excluding the material afterwards resected through thoracotomy). Cases were classified according to these final diagnoses.

The sensitivities and the specificities of FS (not of the surgical procedures) for the detection of carcinomatous lymph node metastases and for recognition, among primary mediastinal tumors, of those that must be resected if possible (thymomas and benign tumors), were assessed as follows: sensitivity=true positive/(true positive+false negative) and specificity=true negative/(true negative+false positive). The sensitivities for the diagnosis of sarcoidosis and for detection of infectious lesions were estimated likewise.

	Results

Top Abstract Introduction Materials and methods Results Discussion References

 
The relevant FS misdiagnoses and FS insufficiencies are listed in Table 2 with the principal benefits of correct FS diagnoses.

Normal, hyperplastic or fibrotic lymph nodes: 67 cases
The FS was immediately followed by a thoracotomy in 46 cases (Table 2). Six of the 26 lung carcinomas, which had an immediate complete resection, proved to have mediastinal metastases in non-biopsied sites: subaortic (n=2), subcarinal (n=3) or paratracheal on lymphadenectomy specimen (n=1). Two of these six patients had had a preoperative chemotherapy. A thoracotomy was also immediately performed for six benign lung lesions. Four of them (abscess, tuberculosis, aspergilloma and bronchogenic cyst) were treated by lobectomy and the two others (pneumonia) were simply biopsied. In one patient, during a mediastinoscopy, a FS diagnosis of small cell carcinoma corresponded to a final diagnosis of normal lymph node with crushing artifacts; a mediastinal lymph node metastasis of a pulmonary SqCC was diagnosed during a second operation (videothoracoscopy).

Sarcoidosis: 62 cases
The correct diagnosis was suspected on FS of the first sample sent by the surgeon in all cases (sensitivity of 100%) and samples were almost always kept for bacteriological studies. The FS also permitted the immediate resection of two lung carcinomas (one primary and one metastatic) with no mediastinal involvement.

Active tuberculous lesions of the mediastinum: 18 cases
In 17 cases, the FS diagnosis of tuberculosis was explicit (n=12) or suspected because of necrosis (n=2) or granulomas (n=3) and samples were used for bacteriological studies. The patient with a lung carcinoma had an immediate resection following the FS and had no mediastinal involvement by the tumor. In another patient with a lung opacity, a resection of a lobe that was destroyed by tuberculosis was also immediately performed. In one case associated with a lung opacity, a FS diagnosis of tumor necrosis was rendered leading to an absence of culture.

Lymphoma: 46 cases
In 45 cases, the correct diagnosis was suspected on FS (in association with the hypotheses of inflammation or small cell carcinoma, each in two cases). The correct FS diagnosis permitted an iliac crest biopsy during the anesthesia in 26 cases and in most cases frozen tissue was kept for immunohistochemy and molecular biology. A FS diagnosis of lymph node involvement by a chronic lymphoid leukemia also permitted the immediate resection of a lung carcinoma without mediastinal metastasis. In one patient with anaplastic large cell lymphoma, samples taken through mediastinoscopy were sufficient for the diagnosis of lymphoma but a precise subtyping required additional samples through mediastinotomy during a second operation. One FS diagnosis of thymoma lead to the resection of a 5-cm tumor, invading a fragment of pericardium, that proved to be a Hodgkin’s disease.

Thymoma: 5 cases
The correct diagnosis was suspected on FS in four cases. Three were clinically non-resectable but in one case, the FS permitted an immediate and complete resection through a sternotomy. In one patient with a paratracheal relapse of a previously resected thymoma (epithelial type), a FS diagnosis of carcinoma lead to a delayed resection.

Miscellaneous diagnoses: 12 cases
A correct FS diagnosis permitted an immediate resection of an ectopic goiter, a case of Castleman’s disease, a thymic cyst (that proved to be associated with a small thymoma) and of an hyperplastic thymus. In seven cases, FS was only used to ensure sufficient material for a final diagnosis: two sarcomas, one yolk sac tumor, one metastatic melanoma (suspicion of lymphoma on FS), one mediastinal involvement by a mesothelioma (suspicion of carcinoma on FS), one fibrous mediastinitis (with 4 FS diagnoses of fibrosis) and one mycobacterial infection in a HIV positive patient. A false FS diagnosis of lymphoma lead to an absence of bacteriologic study in the case of an infectious pseudotumor of the anterior mediastinum secondary to a chest cutaneous staphyloccal infection.

Synthetic results
Sufficient material for a precise definitive diagnosis (excluding normal or fibrotic lymph nodes) was obtained in 351 of 353 cases (99.4%). In the 51 cases of primary mediastinal tumors, excluding carcinomas and the two sarcomas (43 lymphomas excluding locations of chronic lymphoid leukemia, six thymomas including the one with thymic cyst, one goiter and one Castleman’s disease) FS indicated a lesion theoretically to be resected with a sensitivity of 87.5% (7/8) and a specificity of 97.7% (43/44). In the 20 cases of infectious lesions, including 18 cases of tuberculosis, FS pointed out or confirmed the need for bacteriologic study in 18 (sensitivity: 90.0%).

	Discussion

Top Abstract Introduction Materials and methods Results Discussion References

 
The histologic diagnosis of a mediastinal lesion can sometimes be carried out with confidence on clinical, biological and radiological bases. For instance, an anterior mediastinal tumor can be considered a malignant non-seminomatous germ cell tumor when associated with elevated seric markers. In other cases, transbronchial or percutaneous needle biopsy may be used [4]. However, these techniques do not always yield sufficient material for an accurate diagnosis [5]. The biopsy of an associated cervical or supraclavicular lymphadenopathy may also avoid a mediastinal exploration, especially in cases of sarcoidosis, tuberculosis, lymphoma or metastasis. In other cases, cervicotomy (retrosternal biopsy), cervical mediastinoscopy, anterior mediastinotomy or video-assisted thoracoscopy are safe, very efficient and low aggressive methods for surgical biopsy of the mediastinum [1]. Manubriotomy, though more invasive, was included in this study, since the role of FS was the same during this procedure. Sternotomy or thoracotomy is rarely required for simple mediastinal biopsies but is rather used when a surgical resection is straightaway proposed for small or well circumscribed lesions.

Pulmonary non-small cell carcinomas with important mediastinal lymph node involvement are generally not treated by surgical resection. The mediastinal metastases must be histologically proven in order to neither wrongly refuse a surgical treatment nor to unnecessarily treat patients by chemotherapy [6]. Indeed, as in our series, a mediastinal lymph node enlargement in a patient with a pulmonary cancer does not always correspond to a metastasis. With a negative mediastinoscopy, a lung carcinoma can be considered as having, at worst, a limited mediastinal involvement that does not prevent the patient benefiting from resection [7]. When such a negative mediastinoscopy is confirmed by FS, an immediate thoracotomy can be performed. This approach avoids successive anesthesias, reduces operative risk and shortens hospital stay [8] [9]. In contrast, confirmation of the mediastinal involvement on FS spares useless additional surgical explorations and biopsies and, incidentally, may permit the placement of a central catheter for chemotherapy, taking advantage of the anesthesia. Histological diagnosis of non-small cell carcinoma is usually easy on FS, even on very small samples. The risk of false negative FS diagnosis is limited to cases of micrometastases and the sensitivity was 99% in our series (including small cell carcinomas) and 94.6% in an other series [8]. Even intraoperative imprint cytology can be used in this circumstance [9].

Pulmonary small cell carcinoma often has no endobronchial component easily biopsied, is often associated with lymph node metastases and may even appear as a predominantly mediastinal tumor. Thus the diagnosis is often made by mediastinal biopsy. FS from small samples may be difficult to interpret. On FS the tumor cells may resemble lymphocytes and the lesion may be confused with a lymphoma. Taking advantage of the anesthesia, one may then perform an unnecessary bone marrow biopsy. The resemblance can even lead to confusion with small crushed fragments of normal or hyperplastic lymph node. In doubtful cases, the sample must be considered insufficient and additional tissue must be requested from the surgeon. A confusion with a poorly differentiated non-small cell carcinoma has no consequences in the case of mediastinal extension of a pulmonary carcinoma which is not planned to be resected. The FS diagnosis may simply be: undifferentiated carcinoma, awaiting paraffin sections for more specification.

Our experience confirms that the precise diagnosis of lymphomas of the mediastinum can be made on samples taken with low-aggressive techniques (mediastinoscopy or anterior mediastinotomy) [10]. The non-Hodgkin’s lymphomas are mainly either diffuse large B-cell lymphomas or T-lymphoblastic lymphomas [11], which are easily recognised by immunochemistry. Other types are less common and generally associated with peripheral lymphadenopathy. Large cell and lymphoblastic mediastinal lymphomas present as non-resectable large and rapidly growing masses and FS is mainly required to ensure that the biopsied material is sufficient [11]. The FS diagnosis may also permit a biopsy of the iliac crest under anesthesia. The diagnosis of mediastinal Hodgkin’s disease is one of the most difficult to ascertain on small biopsies. The lesion contains variable amount of fibrosis. This fibrosis, which is usually nodular, may simulate the fibrous septae which lobulate a thymoma. These fibrous septae are generally more sharply delineated and often have a more angular shape than the nodular fibrosis of Hodgkin’s disease. However, these differences may be difficult to appreciate on FS of small biopsies. Furthermore, thymomas and mediastinal Hodgkin’s disease both have a relatively slow growth rate, may be associated with no symptoms or with non-specific symptoms and thus may be clinically confused. Therefore, the diagnosis of thymoma must be made with caution on FS since a false diagnosis may lead to a useless and possibly aggressive resection of an infiltrative lesion of Hodgkin’s disease. The fibrosis in Hodgkin’s disease may also be very important, especially at the periphery of the tumor. Thus, in order to avoid the possibility of a wrong diagnosis, such as fibrous mediastinitis, samples must be sufficiently large and contain cellular material.

A thymoma is often resected without pre-operative or intraoperative histological diagnosis when a myasthenia gravis indicates the diagnosis, or when the tumor presents as a well circumscribed nodule of the thymus [12]. In other cases, a biopsy with FS may be required before resection of an invasive tumor. The possible confusion with Hodgkin’s disease is discussed above. A confusion with large cell or lymphoblastic mediastinal lymphomas has the same consequences but is less likely to occur because of different clinical aspects. Histologically, the best way to distinguish a thymoma from a lymphoma on FS is to examine the periphery of the tumor. Tumor cells of a lymphoma invade adipose or muscular tissue in a diffuse manner dissociating muscular and fat cells, whereas thymomas are partially bordered by fibrosis. A mediastinal seminoma, another lymphocyte-rich tumor, is also likely to be confused with a thymoma. In contrast with a thymoma, this rare tumor may also be treated efficiently even without being removed. On FS, a spindle cell thymoma can be confused with a mesenchymal tumor (localized fibrous tumor, schwannoma, etc). Fortunately, the diagnosis can be corrected on paraffin sections from the resected tumor with no consequences. Finally, some epithelial thymomas resemble carcinomas and the distinction may be impossible on FS of small samples.

Sarcoidosis was a very frequent diagnosis in our series. The diagnosis is easily suggested on FS, since the diagnostic granulomas diffusely involves the parenchyma of the paratracheal lymph nodes and even of the smallest ones. A small fragment must be kept for bacteriological studies. Additional tissue is only required when a tumor is suspected and when sarcoidosis seems an incidental diagnosis. Our series indicates that mediastinoscopy is a very effective diagnostic tool permitting the confirmation of clinically and biologically suspected sarcoidosis.

The possibility of mediastinal infectious lesions must always be considered. Such lesions may simulate a mediastinal Hodgkin’s disease: they may have a tumor-like appearance, are associated with an inflammatory syndrome and histologically present inflammatory cells. A necrotic lesion, especially in a mediastinal lymph node in a patient with a pulmonary or other cancer, even after chemotherapy, is not always a necrotic metastasis. Not exceptionally, it corresponds to a tuberculosis. Tuberculosis may also mimic a sarcoidosis. In all doubtful cases, samples must be taken for bacteriological studies.

Mediastinal biopsies with low aggressive surgery are short procedures. An increase in the operative time may theoretically lead to increased operative morbidity in compromised patients and would have to be considered in the cost–benefit assessment of FS. In our experience, the time increase due to FS does not appear significant: a limit of 10 min must not be exceeded and this can be achieved with a brief time for the sample transport, a good organisation and a good motivation of both surgical teams and pathologists. Eventually, a precise diagnosis on FS from surgical mediastinal biopsy is rarely required. The main utility of FS is to check that the biopsied samples are sufficient for a final diagnosis. The FS analysis must help to point the need of a microbiologic study or the need to store frozen tissue for special studies especially in cases of lymphomas. FS is also very important for guiding the surgeon for a possible resection of lung carcinomas according to mediastinal involvement. In conclusion, when the above-mentioned pitfalls and difficulties are well known, the surgical biopsy of mediastinal lesions with minimally aggressive techniques and with the help of FS is a very effective diagnostic tool.

	Acknowledgments

 
The authors are grateful to the surgical teams of our hospital (Drs P. Dartevelle and P. Levasseur), and Dr Paolo Macchiarini for reviewing the manuscript. We also thank Mrs Marie-Laure Legenty for secretarial assistance.

	References

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