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Intraoperative Frozen Section Diagnosis in Urological Oncology
European Urology
European Urology 47 (2005) 129–136
Review
Intraoperative Frozen Section Diagnosis in Urological Oncology$ F. Algabaa,b,*, Y. Arcea, A. Lo´pez-Beltra´nc, R. Montironid, G. Mikuze, A.V. Bonof a
Section of Pathology, Fundacio´ Puigvert, 08025 Barcelona, Spain Department of Morphology, Faculty of Medicine, Autonomous University, Barcelona, Spain c Department of Pathology, Reina Sofia University Hospital and Cordoba University Medical School, Faculty of Medicine, Cordoba, Spain d Institute of Pathology Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region, Ancona, Italy e Institute of Pathology, Leopold Franzens University, Innsbruck, Austria f Ospedale di Circolo e Fondazione Macchi, Varese, Italy b
Accepted 18 August 2004 Available online 9 September 2004
Abstract The intraoperative frozen sections are indicated if the pathological findings change the surgical procedure. In urological oncology is not recommended, as a general attitude, in the tumor diagnosis/staging during the surgery. The assessment of the surgical margins is recommended in partial surgical resections but the literature discourages its systematic use in the radical surgical resections. The assessment of the lymph nodes is specially indicated in the penile cancer with intermediate or high risk and non-palpable nodes, and is debated its utility in non-palpable lymph nodes of cystectomies and prostatectomies. # 2004 Elsevier B.V. All rights reserved. Keywords: Frozen sections; Intraoperative diagnosis; Urological oncology
1. Introduction The performance of a pathologic study during surgery determines fast diagnostic decision making that is consequential upon the operation itself. Therefore, the pathologists should be solidly trained in their specialty and should also be acquainted with the surgical procedure, i.e. which technique is being used, what the surgeon wishes at the time of biopsy. The types of intraoperative frozen sections (IFS) are quite varied. Sometimes just a small fragment of the lesion is available, and in this case the fragment is studied in its entirety. In other occasions the whole of the specimen is received and in this case it is the pathologist who chooses the most representative area $
This publication is made under the auspices of the European Society of Uropathology (a full section office member of the European Association of Urology, EAU) and the Uropathology Working Group (European Society Pathology, ESP). * Corresponding author. Tel. +34 93 4169700; Fax: +34 93 4169730. E-mail address: [email protected] (F. Algaba).
in order to answer the surgeon’s question. In general surgical pathology, 9.5% of errors are due to poor sampling [1], a clear-cut communication between the surgery and the pathology departments may minimize this kind of error. The intrinsic characteristics of the technique (tissue freezing) is the cause that some pathologies, in which cell details should be subtler, are more harmed that other, as is the case with lymphomas [1]. On the other hand, with fewer sections of the specimen the ability to go in depth into the selected tissue is also diminished—approximately one-fourth of the underdiagnoses have such origin [1]. In spite of all of the above, the misdiagnosis index by IFS that is significant for the patient is very low and also dependent upon the expectations placed on such diagnosis because it is more precarious than postoperative diagnosis. For this reason the surgeon should be aware of the most precise indications and also of its limitations. The object of this review is to reflect the status of the issue in urologic oncology.
0302-2838/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2004.08.010
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2. Handling of intraoperative frozen section specimens All specimens sent for IFS should be fresh and contain no fixative. If the specimen is small (1– 2 cm) and to avoid dehydrate during transportation, it is advisable to cover it with a gauze moistened with physiological saline; it is contraindicated to place the specimen floating in saline because the freezing process would be hindered due to the great hydric imbibition of the tissues. The urologist should indicate any specific requirements by means of signs on the specimen; however, close communication between urologists and pathologists should be the rule at all times. The frozen sections are stained by fast methods, and the remaining tissue is processed exactly like any other sample. In some cases the intraoperative cytology (imprints, scrapings or aspirates) can be useful with a good correlation with the standard frozen section [2].
3. Intraoperative frozen section in kidney tumors 3.1. Diagnosis of a renal mass Even though 16.9% of the renal masses excised are not carcinomas, only 13% of them are pathologies of dubious surgical treatment (complex cysts or pseudotumoral inflammatory pathologies). The rest are benign tumors, and exceptionally sarcomas or metastases whose removal is often justified [3]. The cost-effectiveness of determining the nature of an uncertain renal mass during surgery is controversial, since as high as 20%–37% of false negatives have been reported [4], with quite variable false positive figures oscillating from practically nil [5] to 34% [4]. The causes of the false negatives can be multiple: a specimen not distinctive due to being too superficial and not having reached the tumor itself; the absence of a feasible neoplasia (necrosis or fibrosis); the cystic nature of the mass [6], and the problems encountered when trying to preserve the typical cytoarchitecture of most of the carcinomas as frozen section (Fig. 1). The origin of false positives may be due to the overvaluation of crushed tubules mimicking tumor [7], as well as the intrinsic limitations of the freezing method, that do not enable to precisely identify the size of the nucleus. It does not seem, therefore, suitable to consider IFS a good method. Only in those cases in which the urologist needs to distinguish an urothelial carcinoma with renal parenchyma invasion from a renal cell
Fig. 1. Frozen section from a renal cell carcinoma. The crushed cells difficult the correct evaluation.
carcinoma with urinary tract extension, macroscopic and microscopic examination of the complete nephrectomy specimen (and not just a small sample of the tumor) will enable the pathologist to identify the origin of the neoformation rapidly. 3.2. Assessment of the surgical margins in nephron-sparing surgery IFS is much more useful for determining the status of the surgical margins in nephron-sparing surgery. Even though the usual cause of local recurrence following partial renal surgery is subclinical multifocality (which in turn is associated with the cellular subtype) [8], we should not disregard the risk contributed by an affected surgical margin, that may be related to the correlation existing between recurrences and the size and the degree of differentiation of the tumor [9]. The pathologist may receive two different kinds of specimens: small fragments selected by the urologist from which he/she considers suspicious areas, or else the whole specimen of a partial nephrectomy. The second alternative is advisable to avoid the crushed tissues that the small samples might contain. The complete partial nephrectomy specimen should be externally inspected by the pathologist and its surgical margin should be inked [10] (Fig. 2), it should be sectioned at 5-mm intervals, and the relationship between the tumor and the inked area should be observed. If the surgical margin were clearly far from the tumor, it would not be necessary to perform a frozen section; if there were any doubt, the IFS should be carried out. The margin is considered positive if the tumor extends to the inked surface [10]. Invasion of the calyceal system of the pelvis without infiltration of the
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Fig. 3. High grade urothelial carcinoma.
Fig. 2. Complete frozen section of a nephron-sparing specimen. The arrows indicate the surgical margin inked.
wall margin of the urinary tract is not considered a positive margin [11]. 3.3. Organ-confined assessment IFS is justified in cases of nephron-sparing surgery with suspected invasion of the perirenal tissue or of the ganglia because it might condition the modification of the surgical indication [12], which does not happen when a radical nephrectomy is about to be made.
4. Intraoperative frozen section in urinary tract tumors IFS requirement in urinary tract tumors depends of the surgical approach. Two great groups may be considered generally partial and total resections. 4.1. Surgical margin assessment in partial resection specimens The criteria for indicating open partial cystectomy are quite strict. In these cases the urologist may send the pathologist samples of the margins in order to determine their status, or else the whole specimen. If the latter, it should be oriented in such a way that the pathologist is able to recognize the location of the margins. These should be suitably inked and the selection of the margins to be frozen should be made by means of a perpendicular section of the full thickness of the wall [13].
Regarding partial resection specimens from other urinary tract locations, the approach is similar to that of the bladder. The excision margins are not evaluated in the samples obtained by transurethral resection, but some of us (FA) have been summoned at the moment of endourological approach of the upper urinary tract tumors for intraoperative determination of the degree of differentiation. This indication may be debatable but it is based upon the idea of being able to perform endoscopic resections of the low-grade tumors (none of our grade 1 cases showed muscular invasion), whereas in high-grade tumors (75% of our cases are invaders) an open surgery is better indicated. In this type of IFS the section should have the best quality available, and only the indisputable cases should be considered high grade (Fig. 3). 4.2. Surgical margin assessment in radical specimens Three different margins may be defined in the total cystectomy specimens—both ureters, the urethral and the radial margins. 4.2.1. Ureteral margin assessment The ureteral margins are very rarely affected by the tumor. If the urologist suspects this may be the case, IFS is indicated. The situation is completely different if the macroscopic appearance is normal, as the intraepithelial lesions are uncommon and only the unequivocal cases of carcinoma in situ should be diagnosed (Fig. 4). Nevertheless, the infrequent finding of a carcinoma in situ at the ureteral margin (5.7% of the cystectomies) [14] has low postoperative mobility (3%–8%) [14,15], and this fact, together with the diagnostic difficulty (Fig. 4) it entails, discourages the performance of ureteral FSI [16].
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destroyed. Assessment of the Gleason grade in frozen sections is extremely unreliable.
Fig. 4. Ureteral frozen section with normal urothelium. The slight swelling of the cells is a consequence of the frozen.
4.2.2. Urethral margin assessment In most cases the status of the urethral mucosa is known through preoperative biopsies. Some authors find it advisable to determine the status of the urethral margin intraoperatively as the results appear to be the same [17,18]; however, most of the literature [19] does not recommend urethral margin IFS. 4.2.3. Radial margin The perivesical adipose tissue and the peritoneum may be considered radial margin. Its status should be determined in the final analysis [13], but IFS should be performed solely if its affectation entails any modification of surgery. 4.3. Lymph node assessment The IFS of regional lymph nodes is related to the Center’s position regarding lymph node metastases. If our point of reference is survival, we observe that there is no survival beyond 3 years in patients with macroscopic lymph node disease, whereas if the disease is microscopic the survival can be as much as 55% at 5 years [20]. It is thus warranted that the possibility of not performing cystectomy be considered only in cases with macroscopically suspicious nodes (in which case the IFS is indicated), whereas when the lymph nodes are normally-looking the IFS is not advisable.
5. Intraoperative frozen section in prostate cancer Frozen sections of cores biopsies should be refused categorically because the diagnoses are nor reliable and the material for paraffin histology is more o less
5.1. Intraoperative frozen section in transurethral resection specimens The almost systematic determination of serum PSA with subsequent needle biopsies, and the almost complete disappearance of orchiectomy as a therapy for prostate cancer have been the cause of the urologist almost never requesting intraoperative diagnosis in prostate chips. However, if the special circumstances of a specific patient needs for it, the urologist should select the chips to be sent as it is impossible to freeze all the fragments. The selection criteria are not quite precise, but a consistency greater than normal and a yellow color can direct us to a carcinoma with 100% specificity and 39% sensitivity [21]. Even so the limitations are great, especially concerning Gleason scores 1 and 2, and particularly if the patient has been previously treated with hormone deprivation and even with certain pharmacologic treatments for benign prostatic hyperplasia that may elicit morphological changes similar to the ones caused by hormone therapy [22]. Consequently, the performance of IFS in transurethral resection material is strongly advised against. 5.2. Assessment of surgical margins in radical prostatectomy specimens Due to improved selection of the patients eligible to a radical prostatectomy, the participation of the pathologist is not usually required in the course of surgery; however, the increasingly younger age of the patients diagnosed with prostatic cancer has indeed increased the number of cases in which preservation of the neurovascular bundles is attempted, and these are the cases where IFS of the margins may be necessary. The place with higher risk of positive margin changes depends on the surgical approach chosen. The apex has been observed to bear the highest risk margin in the retropubic approach, the bladder neck in the perineal approach, and the posterolateral site in the laparoscopic approach [23]. Over the base of these findings, special care should be taken with the neurovascular bundles when performing laparoscopic prostatectomies; however, when a nerve-sparing radical prostatectomy is considered, it should be remembered that the main extraprostatic extension path goes precisely through the neurovascular bundles [24], and consequently in the cases with some risk of nonorgan-confined disease in which a nerve-sparing prostatectomy is being considered, it is advisable to perform IFS of the neurovascular bundles with a positive predictive value of 73% and a negative predictive value
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of 94% [25]. This is why the practice of IFS in these patients has enabled the performance of nerve-sparing prostatectomies without increasing the percentage of positive margins [26]. The handling of IFS material depends on the type of specimen the pathologist receives. If neurovascular bundle tissue is sent to him, he/she only needs to freeze it. If what is sent is the complete prostatectomy specimen, some authors advise that the urologist marks the suspicious area with Indian ink as the whole margin of the specimen cannot be studied [25]. 5.3. Lymph node assessment The prediction nomograms constructed by combining the figures of the serum PSA, of the Gleason biopsy score and of the clinical T category [27] are highly sensitive for determining which patients have low, intermediate or high risk of lymph node metastasis. The contribution of the nodes IFS is scarce and discloses nothing new regarding patients with low and intermediate risk of metastasis. IFS can only be warranted in high-risk patients in whom the urologist is considering the possibility of performing radical prostatectomy, in order to avoid unnecessary morbidity [28]. In these cases, if the urologist identifies an big and/or hard lymph nodes most send them to the pathologist; the adipose tissue of the lymph node area is sent only if there is no detectable nodule. It is advisable that the pathologist is aware of the Gleason biopsy score in order to maximize the selection of the portion of tissue to be frozen; it is recommended to try to freeze all nodules found in the dissection of cases with a Gleason score 8 or higher [29], whereas if the Gleason score is lower, the examination of 2–3 nodes can disclose over 50% of the micrometastases [30]. Even so, the practice of IFS in radical prostatectomies is not recommended as a routine method, since the preoperative identification of clinical parameters is more efficient [31]. 5.4. Intraoperative frozen sections in organ donors Kidneys and other organs were transplanted long before PSA screening was introduced. That means many patients were transplanted in spite of having a clinical silent prostate cancer and probably some donors have also had a silent cancer. Therefore one would have expected an increase of prostate cancer in men who underwent transplantation. Actually the epidemiological studies shows an increase in many cancers but not in prostate cancer, to now only one case of transplanted (donor derived) prostate cancer has been reported in a heart recipient [32]. However in cases of organ donors with elevated serum PSA (must be decided the PSA figure is considered abnormal in
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the transplantation group) multiple biopsies not only of the prostate but specially of the prostate capsule and the periprostatic tissue of the peripheral zone and neurovascular bundles should be performed. Such biopsies could be processed shortly (4 hours) of by IFS of wedge biopsies.
6. Intraoperative frozen sections in testicular tumors The current methods of diagnosis of testicular tumor masses define their nature in a high proportion, and so it is quite rare that the pathologist is summoned intraoperatively to define them. But the evolution of the current medical attitude, which considers occasional testis-sparing surgery, as well as special circumstances of lonely testes or bilateral tumor masses or suspected non-germinal cell tumors may lead the urologist to request IFS [33]. 6.1. Accuracy of intraoperative frozen sections of testicular tumors Most times the pathologist is requested to distinguish a benign neoplasia from a malignant tumors. This means that he/she should distinguish not only nonneoplastic processes (granulomatous, vascular, etc.) from a neoformation, but should also be able to recognize epidermal cysts and mature prepubertal teratomas from non-teratoma germinal cell tumors. The IFS can also be useful for the diagnosis of small sex-cord stromal tumors, which can be treated by local excision. It is obvious that diagnostic problems may exist between seminomas and granulomatous processes and even Leydig cell tumors, as well as between teratomas and squamous metaplasma in hydrocele [33], but as a general rule there is an excellent correlation between the IFS diagnosis and the final diagnosis [34–36], even for recognizing testicular infiltrations with hematological neoplasias (Fig. 5). In some cases the intraoperative touch-imprint cytology can be useful [37]. Even so, it is advisable to always take samples of the peritumoral normal testicular parenchyma in order to make a paraffin (not IFS) study and detect potential intratubular germ cell neoplasia [38], which would determine a subsequent total orchiectomy.
7. Intraoperative frozen section in penile cancer The IFS is discouraged for the diagnosis of penile tumor, because a lot of lesions have a well
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Fig. 5. Testicular involvement for a lymphoproliferative proliferation.
differentiated squamous cell growth that can mimic non-neoplastic lesions [39,40] and vice versa some hyperplasic lesions can have a pseudoepitheliomatous appearance [41]. 7.1. Assessment of surgical margins in penile cancer specimens Differently from other urological locations, virtually all of the resections due to penile cancer are sent to the pathologist for margin assessment. The margins to be studied are determined by the spreading pathways [42], and so it is the urethral margin the one that should always be frozen (sometimes it is sent by the urologist as it is possible that is does not coincide exactly with the other margins, depending on the type of the reconstructive surgery), tissue from the corpus spongiosum and the corpora cavernosa (with special care of the penile fascia) and from the penile skin. in the primary tumors from the foreskin the entire circumference and thickness of the mucosal margin of resection should be study in the IFS [41]. In total penectomies only the urethra and surrounding tissues most be send for IFS, infrequently the penile skin must be evaluated because the tumor is near to this margin [41]. 7.2. Lymph node assessment In the low risk patients with non-palpable nodes the IFS is not recommended. In the intermediated risk patients without palpable nodes the sentinel lymph node is recommended specially using gamma probe [43]. In patients at high risk of nodal involvement the
Fig. 6. Non-neoplastic lymph nodes in one microscopic slide.
IFS is strongly recommended [44] (Fig. 6) because a bilateral modified lynphadenectomy if positive nodes are present in the frozen sections is recommendable [45]. In palpable lymph nodes patients the IFS is useful to distinguish metastatic to inflammatory nodes because less that the 50% of these patients are metastatic. 8. Conclusions The IFS in urological oncology has a limited role. The accuracy and usefulness is in close relation with the urologists-pathologists communication and precise urological indication in every patient. The IFS are not recommended, as a general attitude, in the tumor diagnosis/staging during the surgery. The margins assessment is strongly recommended in partial resections as nephron-sparing nephrectomies, partial cystectomies, in nerve-sparing prostatectomies, and penile carcinoma specimens. The lymph nodes assessment is useful in penile carcinomas with non-palpable nodes, especially in the intermediate and high risk groups. The other IFS indications are urologist dependent, but we must remember that the intraoperative pathological study is only indicated if the findings have implications in the surgical decisions.
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Review
Intraoperative Frozen Section Diagnosis in Urological Oncology$ F. Algabaa,b,*, Y. Arcea, A. Lo´pez-Beltra´nc, R. Montironid, G. Mikuze, A.V. Bonof a
Section of Pathology, Fundacio´ Puigvert, 08025 Barcelona, Spain Department of Morphology, Faculty of Medicine, Autonomous University, Barcelona, Spain c Department of Pathology, Reina Sofia University Hospital and Cordoba University Medical School, Faculty of Medicine, Cordoba, Spain d Institute of Pathology Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region, Ancona, Italy e Institute of Pathology, Leopold Franzens University, Innsbruck, Austria f Ospedale di Circolo e Fondazione Macchi, Varese, Italy b
Accepted 18 August 2004 Available online 9 September 2004
Abstract The intraoperative frozen sections are indicated if the pathological findings change the surgical procedure. In urological oncology is not recommended, as a general attitude, in the tumor diagnosis/staging during the surgery. The assessment of the surgical margins is recommended in partial surgical resections but the literature discourages its systematic use in the radical surgical resections. The assessment of the lymph nodes is specially indicated in the penile cancer with intermediate or high risk and non-palpable nodes, and is debated its utility in non-palpable lymph nodes of cystectomies and prostatectomies. # 2004 Elsevier B.V. All rights reserved. Keywords: Frozen sections; Intraoperative diagnosis; Urological oncology
1. Introduction The performance of a pathologic study during surgery determines fast diagnostic decision making that is consequential upon the operation itself. Therefore, the pathologists should be solidly trained in their specialty and should also be acquainted with the surgical procedure, i.e. which technique is being used, what the surgeon wishes at the time of biopsy. The types of intraoperative frozen sections (IFS) are quite varied. Sometimes just a small fragment of the lesion is available, and in this case the fragment is studied in its entirety. In other occasions the whole of the specimen is received and in this case it is the pathologist who chooses the most representative area $
This publication is made under the auspices of the European Society of Uropathology (a full section office member of the European Association of Urology, EAU) and the Uropathology Working Group (European Society Pathology, ESP). * Corresponding author. Tel. +34 93 4169700; Fax: +34 93 4169730. E-mail address: [email protected] (F. Algaba).
in order to answer the surgeon’s question. In general surgical pathology, 9.5% of errors are due to poor sampling [1], a clear-cut communication between the surgery and the pathology departments may minimize this kind of error. The intrinsic characteristics of the technique (tissue freezing) is the cause that some pathologies, in which cell details should be subtler, are more harmed that other, as is the case with lymphomas [1]. On the other hand, with fewer sections of the specimen the ability to go in depth into the selected tissue is also diminished—approximately one-fourth of the underdiagnoses have such origin [1]. In spite of all of the above, the misdiagnosis index by IFS that is significant for the patient is very low and also dependent upon the expectations placed on such diagnosis because it is more precarious than postoperative diagnosis. For this reason the surgeon should be aware of the most precise indications and also of its limitations. The object of this review is to reflect the status of the issue in urologic oncology.
0302-2838/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2004.08.010
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2. Handling of intraoperative frozen section specimens All specimens sent for IFS should be fresh and contain no fixative. If the specimen is small (1– 2 cm) and to avoid dehydrate during transportation, it is advisable to cover it with a gauze moistened with physiological saline; it is contraindicated to place the specimen floating in saline because the freezing process would be hindered due to the great hydric imbibition of the tissues. The urologist should indicate any specific requirements by means of signs on the specimen; however, close communication between urologists and pathologists should be the rule at all times. The frozen sections are stained by fast methods, and the remaining tissue is processed exactly like any other sample. In some cases the intraoperative cytology (imprints, scrapings or aspirates) can be useful with a good correlation with the standard frozen section [2].
3. Intraoperative frozen section in kidney tumors 3.1. Diagnosis of a renal mass Even though 16.9% of the renal masses excised are not carcinomas, only 13% of them are pathologies of dubious surgical treatment (complex cysts or pseudotumoral inflammatory pathologies). The rest are benign tumors, and exceptionally sarcomas or metastases whose removal is often justified [3]. The cost-effectiveness of determining the nature of an uncertain renal mass during surgery is controversial, since as high as 20%–37% of false negatives have been reported [4], with quite variable false positive figures oscillating from practically nil [5] to 34% [4]. The causes of the false negatives can be multiple: a specimen not distinctive due to being too superficial and not having reached the tumor itself; the absence of a feasible neoplasia (necrosis or fibrosis); the cystic nature of the mass [6], and the problems encountered when trying to preserve the typical cytoarchitecture of most of the carcinomas as frozen section (Fig. 1). The origin of false positives may be due to the overvaluation of crushed tubules mimicking tumor [7], as well as the intrinsic limitations of the freezing method, that do not enable to precisely identify the size of the nucleus. It does not seem, therefore, suitable to consider IFS a good method. Only in those cases in which the urologist needs to distinguish an urothelial carcinoma with renal parenchyma invasion from a renal cell
Fig. 1. Frozen section from a renal cell carcinoma. The crushed cells difficult the correct evaluation.
carcinoma with urinary tract extension, macroscopic and microscopic examination of the complete nephrectomy specimen (and not just a small sample of the tumor) will enable the pathologist to identify the origin of the neoformation rapidly. 3.2. Assessment of the surgical margins in nephron-sparing surgery IFS is much more useful for determining the status of the surgical margins in nephron-sparing surgery. Even though the usual cause of local recurrence following partial renal surgery is subclinical multifocality (which in turn is associated with the cellular subtype) [8], we should not disregard the risk contributed by an affected surgical margin, that may be related to the correlation existing between recurrences and the size and the degree of differentiation of the tumor [9]. The pathologist may receive two different kinds of specimens: small fragments selected by the urologist from which he/she considers suspicious areas, or else the whole specimen of a partial nephrectomy. The second alternative is advisable to avoid the crushed tissues that the small samples might contain. The complete partial nephrectomy specimen should be externally inspected by the pathologist and its surgical margin should be inked [10] (Fig. 2), it should be sectioned at 5-mm intervals, and the relationship between the tumor and the inked area should be observed. If the surgical margin were clearly far from the tumor, it would not be necessary to perform a frozen section; if there were any doubt, the IFS should be carried out. The margin is considered positive if the tumor extends to the inked surface [10]. Invasion of the calyceal system of the pelvis without infiltration of the
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Fig. 3. High grade urothelial carcinoma.
Fig. 2. Complete frozen section of a nephron-sparing specimen. The arrows indicate the surgical margin inked.
wall margin of the urinary tract is not considered a positive margin [11]. 3.3. Organ-confined assessment IFS is justified in cases of nephron-sparing surgery with suspected invasion of the perirenal tissue or of the ganglia because it might condition the modification of the surgical indication [12], which does not happen when a radical nephrectomy is about to be made.
4. Intraoperative frozen section in urinary tract tumors IFS requirement in urinary tract tumors depends of the surgical approach. Two great groups may be considered generally partial and total resections. 4.1. Surgical margin assessment in partial resection specimens The criteria for indicating open partial cystectomy are quite strict. In these cases the urologist may send the pathologist samples of the margins in order to determine their status, or else the whole specimen. If the latter, it should be oriented in such a way that the pathologist is able to recognize the location of the margins. These should be suitably inked and the selection of the margins to be frozen should be made by means of a perpendicular section of the full thickness of the wall [13].
Regarding partial resection specimens from other urinary tract locations, the approach is similar to that of the bladder. The excision margins are not evaluated in the samples obtained by transurethral resection, but some of us (FA) have been summoned at the moment of endourological approach of the upper urinary tract tumors for intraoperative determination of the degree of differentiation. This indication may be debatable but it is based upon the idea of being able to perform endoscopic resections of the low-grade tumors (none of our grade 1 cases showed muscular invasion), whereas in high-grade tumors (75% of our cases are invaders) an open surgery is better indicated. In this type of IFS the section should have the best quality available, and only the indisputable cases should be considered high grade (Fig. 3). 4.2. Surgical margin assessment in radical specimens Three different margins may be defined in the total cystectomy specimens—both ureters, the urethral and the radial margins. 4.2.1. Ureteral margin assessment The ureteral margins are very rarely affected by the tumor. If the urologist suspects this may be the case, IFS is indicated. The situation is completely different if the macroscopic appearance is normal, as the intraepithelial lesions are uncommon and only the unequivocal cases of carcinoma in situ should be diagnosed (Fig. 4). Nevertheless, the infrequent finding of a carcinoma in situ at the ureteral margin (5.7% of the cystectomies) [14] has low postoperative mobility (3%–8%) [14,15], and this fact, together with the diagnostic difficulty (Fig. 4) it entails, discourages the performance of ureteral FSI [16].
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destroyed. Assessment of the Gleason grade in frozen sections is extremely unreliable.
Fig. 4. Ureteral frozen section with normal urothelium. The slight swelling of the cells is a consequence of the frozen.
4.2.2. Urethral margin assessment In most cases the status of the urethral mucosa is known through preoperative biopsies. Some authors find it advisable to determine the status of the urethral margin intraoperatively as the results appear to be the same [17,18]; however, most of the literature [19] does not recommend urethral margin IFS. 4.2.3. Radial margin The perivesical adipose tissue and the peritoneum may be considered radial margin. Its status should be determined in the final analysis [13], but IFS should be performed solely if its affectation entails any modification of surgery. 4.3. Lymph node assessment The IFS of regional lymph nodes is related to the Center’s position regarding lymph node metastases. If our point of reference is survival, we observe that there is no survival beyond 3 years in patients with macroscopic lymph node disease, whereas if the disease is microscopic the survival can be as much as 55% at 5 years [20]. It is thus warranted that the possibility of not performing cystectomy be considered only in cases with macroscopically suspicious nodes (in which case the IFS is indicated), whereas when the lymph nodes are normally-looking the IFS is not advisable.
5. Intraoperative frozen section in prostate cancer Frozen sections of cores biopsies should be refused categorically because the diagnoses are nor reliable and the material for paraffin histology is more o less
5.1. Intraoperative frozen section in transurethral resection specimens The almost systematic determination of serum PSA with subsequent needle biopsies, and the almost complete disappearance of orchiectomy as a therapy for prostate cancer have been the cause of the urologist almost never requesting intraoperative diagnosis in prostate chips. However, if the special circumstances of a specific patient needs for it, the urologist should select the chips to be sent as it is impossible to freeze all the fragments. The selection criteria are not quite precise, but a consistency greater than normal and a yellow color can direct us to a carcinoma with 100% specificity and 39% sensitivity [21]. Even so the limitations are great, especially concerning Gleason scores 1 and 2, and particularly if the patient has been previously treated with hormone deprivation and even with certain pharmacologic treatments for benign prostatic hyperplasia that may elicit morphological changes similar to the ones caused by hormone therapy [22]. Consequently, the performance of IFS in transurethral resection material is strongly advised against. 5.2. Assessment of surgical margins in radical prostatectomy specimens Due to improved selection of the patients eligible to a radical prostatectomy, the participation of the pathologist is not usually required in the course of surgery; however, the increasingly younger age of the patients diagnosed with prostatic cancer has indeed increased the number of cases in which preservation of the neurovascular bundles is attempted, and these are the cases where IFS of the margins may be necessary. The place with higher risk of positive margin changes depends on the surgical approach chosen. The apex has been observed to bear the highest risk margin in the retropubic approach, the bladder neck in the perineal approach, and the posterolateral site in the laparoscopic approach [23]. Over the base of these findings, special care should be taken with the neurovascular bundles when performing laparoscopic prostatectomies; however, when a nerve-sparing radical prostatectomy is considered, it should be remembered that the main extraprostatic extension path goes precisely through the neurovascular bundles [24], and consequently in the cases with some risk of nonorgan-confined disease in which a nerve-sparing prostatectomy is being considered, it is advisable to perform IFS of the neurovascular bundles with a positive predictive value of 73% and a negative predictive value
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of 94% [25]. This is why the practice of IFS in these patients has enabled the performance of nerve-sparing prostatectomies without increasing the percentage of positive margins [26]. The handling of IFS material depends on the type of specimen the pathologist receives. If neurovascular bundle tissue is sent to him, he/she only needs to freeze it. If what is sent is the complete prostatectomy specimen, some authors advise that the urologist marks the suspicious area with Indian ink as the whole margin of the specimen cannot be studied [25]. 5.3. Lymph node assessment The prediction nomograms constructed by combining the figures of the serum PSA, of the Gleason biopsy score and of the clinical T category [27] are highly sensitive for determining which patients have low, intermediate or high risk of lymph node metastasis. The contribution of the nodes IFS is scarce and discloses nothing new regarding patients with low and intermediate risk of metastasis. IFS can only be warranted in high-risk patients in whom the urologist is considering the possibility of performing radical prostatectomy, in order to avoid unnecessary morbidity [28]. In these cases, if the urologist identifies an big and/or hard lymph nodes most send them to the pathologist; the adipose tissue of the lymph node area is sent only if there is no detectable nodule. It is advisable that the pathologist is aware of the Gleason biopsy score in order to maximize the selection of the portion of tissue to be frozen; it is recommended to try to freeze all nodules found in the dissection of cases with a Gleason score 8 or higher [29], whereas if the Gleason score is lower, the examination of 2–3 nodes can disclose over 50% of the micrometastases [30]. Even so, the practice of IFS in radical prostatectomies is not recommended as a routine method, since the preoperative identification of clinical parameters is more efficient [31]. 5.4. Intraoperative frozen sections in organ donors Kidneys and other organs were transplanted long before PSA screening was introduced. That means many patients were transplanted in spite of having a clinical silent prostate cancer and probably some donors have also had a silent cancer. Therefore one would have expected an increase of prostate cancer in men who underwent transplantation. Actually the epidemiological studies shows an increase in many cancers but not in prostate cancer, to now only one case of transplanted (donor derived) prostate cancer has been reported in a heart recipient [32]. However in cases of organ donors with elevated serum PSA (must be decided the PSA figure is considered abnormal in
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the transplantation group) multiple biopsies not only of the prostate but specially of the prostate capsule and the periprostatic tissue of the peripheral zone and neurovascular bundles should be performed. Such biopsies could be processed shortly (4 hours) of by IFS of wedge biopsies.
6. Intraoperative frozen sections in testicular tumors The current methods of diagnosis of testicular tumor masses define their nature in a high proportion, and so it is quite rare that the pathologist is summoned intraoperatively to define them. But the evolution of the current medical attitude, which considers occasional testis-sparing surgery, as well as special circumstances of lonely testes or bilateral tumor masses or suspected non-germinal cell tumors may lead the urologist to request IFS [33]. 6.1. Accuracy of intraoperative frozen sections of testicular tumors Most times the pathologist is requested to distinguish a benign neoplasia from a malignant tumors. This means that he/she should distinguish not only nonneoplastic processes (granulomatous, vascular, etc.) from a neoformation, but should also be able to recognize epidermal cysts and mature prepubertal teratomas from non-teratoma germinal cell tumors. The IFS can also be useful for the diagnosis of small sex-cord stromal tumors, which can be treated by local excision. It is obvious that diagnostic problems may exist between seminomas and granulomatous processes and even Leydig cell tumors, as well as between teratomas and squamous metaplasma in hydrocele [33], but as a general rule there is an excellent correlation between the IFS diagnosis and the final diagnosis [34–36], even for recognizing testicular infiltrations with hematological neoplasias (Fig. 5). In some cases the intraoperative touch-imprint cytology can be useful [37]. Even so, it is advisable to always take samples of the peritumoral normal testicular parenchyma in order to make a paraffin (not IFS) study and detect potential intratubular germ cell neoplasia [38], which would determine a subsequent total orchiectomy.
7. Intraoperative frozen section in penile cancer The IFS is discouraged for the diagnosis of penile tumor, because a lot of lesions have a well
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Fig. 5. Testicular involvement for a lymphoproliferative proliferation.
differentiated squamous cell growth that can mimic non-neoplastic lesions [39,40] and vice versa some hyperplasic lesions can have a pseudoepitheliomatous appearance [41]. 7.1. Assessment of surgical margins in penile cancer specimens Differently from other urological locations, virtually all of the resections due to penile cancer are sent to the pathologist for margin assessment. The margins to be studied are determined by the spreading pathways [42], and so it is the urethral margin the one that should always be frozen (sometimes it is sent by the urologist as it is possible that is does not coincide exactly with the other margins, depending on the type of the reconstructive surgery), tissue from the corpus spongiosum and the corpora cavernosa (with special care of the penile fascia) and from the penile skin. in the primary tumors from the foreskin the entire circumference and thickness of the mucosal margin of resection should be study in the IFS [41]. In total penectomies only the urethra and surrounding tissues most be send for IFS, infrequently the penile skin must be evaluated because the tumor is near to this margin [41]. 7.2. Lymph node assessment In the low risk patients with non-palpable nodes the IFS is not recommended. In the intermediated risk patients without palpable nodes the sentinel lymph node is recommended specially using gamma probe [43]. In patients at high risk of nodal involvement the
Fig. 6. Non-neoplastic lymph nodes in one microscopic slide.
IFS is strongly recommended [44] (Fig. 6) because a bilateral modified lynphadenectomy if positive nodes are present in the frozen sections is recommendable [45]. In palpable lymph nodes patients the IFS is useful to distinguish metastatic to inflammatory nodes because less that the 50% of these patients are metastatic. 8. Conclusions The IFS in urological oncology has a limited role. The accuracy and usefulness is in close relation with the urologists-pathologists communication and precise urological indication in every patient. The IFS are not recommended, as a general attitude, in the tumor diagnosis/staging during the surgery. The margins assessment is strongly recommended in partial resections as nephron-sparing nephrectomies, partial cystectomies, in nerve-sparing prostatectomies, and penile carcinoma specimens. The lymph nodes assessment is useful in penile carcinomas with non-palpable nodes, especially in the intermediate and high risk groups. The other IFS indications are urologist dependent, but we must remember that the intraoperative pathological study is only indicated if the findings have implications in the surgical decisions.
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