—  SHORT COURSE #24  —

Frozen Section Diagnosis, Indications and Pitfalls

Section 3 - Breast, Kidney, Prostate and Urinary Bladder

Anthony Montag, M.D.
Aliya N. Husain, M.D.
Jerome B. Taxy, M.D.


Primary Breast Tumors and Frozen Section (Case 1)
A frozen section on a breast mass is done solely to definitively and immediately treat a malignant tumor. Historically, at least through the 1970's, all clinically identified breast masses were palpable lesions; the diagnosis was almost always based on an excisional biopsy and a frozen section. In this setting, the frozen section is the paradigm for clinically relevant decision-making in surgical pathology. The purpose of the frozen section was to save the patient a second anesthesia and operative procedure: if the lesion were malignant, an immediate mastectomy, typically a modified radical, was done. When this sequence was in vogue the tumors were relatively large and the excisions often generous. There was ample tumor to examine and, in later years, to triage for various special studies. In a tabulation of 1355 cases seen at the Memorial Hospital in New York from 1935-1942 (published in the first edition of the AFIP Breast Fascicle), only 201 cases were under 2.0 cm. and more than half were between 2 and 4 cm. (Table I)

TABLE I



The major hazard of doing a breast frozen section diagnosis today is that the requests are uncommon. Hence, experience is not as broad as in previous years. Screening mammography has clearly changed the contemporary evaluation of breast cancer and has brought breast conservation surgery into the clinical mainstream. This has become the primary goal of therapy. Most tumors are now under 2.0 cm. and many are not palpable at all. (Table II).

TABLE II



Small size would be a major disadvantage for frozen section since there is a risk of having to freeze the entire sample and then having to deal potentially with frozen artifact on both the frozen and the paraffin embedded material. Today, definitive therapeutic decisions are seldom made under the urgent conditions of prior years. Treatment decisions take place after an elective needle core biopsy. The patient herself is likely to be consulted about the therapeutic path she wishes to take. Therefore, there is no reason to take immediate clinical action as a result of a malignant diagnosis.

Even the literature reflects that this procedure has fallen from general use. Published studies on breast frozen sections within the last 10 years are uncommon. If it is an accurate reflection of general practice, breast frozen sections as reasons for legal action are also few [1]. For those pathologists who have continued the practice of routine frozen section for breast lesions, success has varied. In a report from the Mayo Clinic, looking at 1490 consecutive mammographic lesions, the accuracy rate was 97.7%. The lesions were small (mean size 1.07 cm.) and the diagnosis was deferred to permanents in only 5.2%. The false negatives were 0.5% [2]. In another study from Case Western Reserve, 181 intraductal carcinomas were evaluated by frozen section. Sampling error was thought to be significant in the high false negative rate of 36%; diagnostic accuracy was correlated with the presence of a palpable mass [3]. The authors recommended against doing frozen sections for macroscopically inapparent lesions.

Nonetheless, in the context of individualizing therapy, there are occasional requests for a frozen section of a breast mass. Employing imprint preparations along with the actual frozen section is a good idea. The importance of a good gross examination, adequate sampling and minimizing potential artifacts, e.g., avoiding fatty areas, using sharp knives and cryostats for which the temperature is properly monitored and maintained, cannot be overstated. The actual frozen section histologic examination employs no special skill or secret maneuver other than attention to traditional morphologic detail: recognition of the standard alterations in low-power growth pattern just as would be appreciated on routine paraffin embedded sections. Cytologic detail, while important, is secondary. Being able to discriminate infiltrating cancer from inflammatory infiltrates, sclerosing adenosis and involutional changes in a papilloma is not always easy, but relies on basic morphology. It is not good practice, not to mention potentially dangerous, for the pathologist to ignore these fundamental morphologic and technical principles. The most important point to remember is that if the frozen is not absolutely diagnostic of cancer, defer the diagnosis.

In Case 1, the patient's specific circumstances led to a request for a frozen section. She had a previous infiltrating ductal carcinoma with known nodal metastases and had been definitively treated by lumpectomy, radiation and chemotherapy in the past. The appearance of an ipsilateral mass several years later raised the possibility of a tumor recurrence. The issues were thoroughly discussed with her and the decision was made with her concurrence, prior to excision of this lesion that a mastectomy would be immediately done if the lesion were malignant. The details of the history were obviously important and were communicated to the pathologist prior to surgery. Grossly, the lesion was firm, stellate and gray-yellow, highly suggestive of invasive cancer. The frozen section showed an infiltrative process in a dense collagenous background, suggestive of an infiltrating lobular carcinoma, different from her original tumor type. Cytologically, the cells were not clearly malignant. In addition, given the patient's history, a florid inflammatory - sclerotic process, possibly related to previous irradiation, could not be confidently excluded. The diagnosis was deferred. On the H & E permanent sections, frozen artifact notwithstanding, it was clearer that this was an inflammatory lesion. This was confirmed by negative cytokeratin and positive CD68 stains. Approximately one year later, the patient developed an invasive ductal carcinoma in the opposite (right) breast and underwent bilateral mastectomies with reconstruction. Examination of the left breast failed to demonstrate any residual malignant tumor.

Breast Cancer and the Sentinel Node Frozen Section (Case 2)
The staging and prognostic parameters used to evaluate each new case of infiltrating breast cancer are many. However, the two most important remain the size of the primary tumor and the status of the regional lymph nodes (Table 1, above). The axillary lymph nodes may be positive in up to 20% of cases in which the primary tumor is < 1.0 cm. (Figure 1)

Figure 1: Positive axillary lymph nodes and primary tumor size



It is widely accepted that nodal involvement cannot be accurately predicted on clinical or imaging grounds alone, histologic assessment is required. The axillary lymph nodes have been traditionally assessed by a complete dissection, which in present practice translates into a low (Level I) dissection accompanying either a mastectomy or a lumpectomy. Postoperatively, the clinical morbidity associated with this procedure includes pain, limitation of motion, lymphedema and infection. The sentinel node biopsy should be regarded as the regional lymph node counterpart to breast conservation surgery and is a concept which has been validated by numerous studies. This procedure allows for the preservation of function and cosmesis without compromising the necessary staging information.

A sentinel node is the first lymph node in a drainage basin to receive lymphatic fluid. As such, metastatic deposits are anticipated first in this location. The node is identified by the injection of radioactive colloid and/or blue dye into the primary breast biopsy site. The affected node or nodes are then excised. This procedure is best applied to small primary tumors, i.e., under 2 cm, and is well suited for mammographically discovered lesions. A multidisciplinary consensus conference in 2001 indicated that a negative sentinel node was a suitable replacement for a complete axillary dissection as a staging and diagnostic procedure for T1 and T2 tumors [4]. This has been supported by data from other more recent studies [5, 6]. At present, it is common practice that patients with a positive sentinel node have a complete (low) axillary dissection. The question is, should the information related to the status of the sentinel node be delivered immediately, by frozen section, or should the diagnosis be made under the usual circumstances of fixation and paraffin embedding?

The answer is, in part, related to the relevance of the size of the metastasis as well as the issue of a false negative frozen section result. With regard to size, most would agree that a metastasis 2 mm or larger is clinically significant. Presently, such a patient will undergo a completion axillary dissection, and it is obviously easier for the surgeon to complete the dissection at the time of the sentinel node excision instead of returning to the operative site several days later. Controversy exists about the clinical significance of metastases between 0.2 mm and 2 mm. and the resulting issue of overtreatment. At the University of Chicago, sentinel node sampling has been an increasing clinical practice since 2000. Adding frozen section to this practice has been common since 2002 and has continued to the present. Acknowledging that missing a small metastasis is much easier than finding it, freezing the entire node will assist in dealing with the sampling issue. Of more than 300 sentinel nodes on an annual basis since 2002, 30-40% are initially examined by frozen section. There have been no false positives. There were 6 false negatives from 2002-2003 and 6 false negatives from December 2004-August 2006. The false negatives in the latter period included only one missed micrometastasis. Other false negatives included artifacts of frozen section or sampling issues. Present practice among the surgeons is that a frozen section demonstrating a micrometastasis (0.2-2.0mm) will also commit a patient to an axillary dissection.

The size of the metastasis is only one of several issues related to handling and reporting that have been raised since the acceptance of the sentinel node concept. The following is a list of some:
  1. Extent of gross sampling.

  2. Use of imprints

  3. Frozen section

  4. Number of H & E sections and the spacing of intervals

  5. Immunohistochemistry for cytokeratin

  6. PCR

  7. Size of the metastatic deposit.

  8. Do patients who have a sentinel node procedure also need an axillary dissection?
The technical preparation of the frozen section can be problematic. The need to examine the entire node can be complicated by nodes of any size which are invested by or infiltrated by fat. The fat is grossly difficult to trim. However, everyone involved should recognize that at some level sampling error is inherent in the accuracy of this procedure, i.e., the chances of missing a small metastasis are greater than finding it. Issues related to professional expertise in interpreting the sections are often raised, but this examination should be well within the ability of a general surgical pathologist. The false negative rate reported in the literature varies, but can be as high as 40%. However, in some of these reviews, it is indicated that the lymph nodes were not entirely examined [7].

In Case 2, the patient had a diagnosis on a prior needle core breast biopsy of invasive ductal carcinoma. The 1.0 cm sentinel lymph node, entirely examined by frozen section, was grossly negative for tumor. Subtle subcapsular and sinusoidal collections of tumor cells were seen, however, on microscopic examination. Permanent sections of the frozen blocks were more clearcut. A complete axillary dissection was done based on the results of the frozen.

Kidney Tumors (Cases 3 and 4)


TABLE III



One urothelial carcinoma (FS) changed to papillary RCC
One RCC (FS), nos, changed to oncocytoma
One chromophobe (FS) changed to clear cell
One benign cyst (FS) changed to papillary RCC (separate lesion, not on frozen)
92 partial nephrectomies, frozen section for margins in 89

Frozen section requests for lesions of the kidney generally focus on three major issues: 1) The identification, or confirmation, of tumor; 2) the cell typing of the tumor; 3) margin of resection as applied to partial nephrectomy (Table III). With the sophisticated imaging techniques currently available, the preoperative diagnosis of tumor, solid or cystic, is not usually problematic. In instances of clinical uncertainty, the confirmation of tumor by frozen section may influence the nature of the surgical procedure, especially whether to remove the kidney or not. Nephron sparing procedures, either open or laparoscopic, need some pathologic evaluation of the parenchymal margin and frozen section has become increasingly employed for this. Potential sources of difficulty in this examination can be at least partially mitigated by actually having a gross specimen containing the excised lesion.

Primary epithelial tumors of the kidney comprise approximately 3% of all solid neoplasms, occurring at a rate of 10 cases per 100,000 population. SEER data suggests an increase in this neoplasm during the years, 1975-1995. This increase may reflect incidental discoveries while pursuing a work-up for other intra-abdominal complaints. Possibly because of this there is increased awareness regarding the historical controversy related to the size criterion of separation between renal adenoma and renal adenocarcinoma (renal cell carcinoma), especially clear cell type. A solitary renal mass discovered incidentally or not, is initially treated surgically since the mass is presumed to be malignant and surgical extirpation remains the primary modality for treating this malignancy as it has been for over 50 years. The standard procedure against which all others are measured is the open radical nephrectomy, i.e., a wide excision of the kidney to include its outside investing fascia, perirenal fat and adrenal gland.

The identification of cell type by frozen section does not often play a role in the surgery for renal tumors. However, if the tumor is urothelial a radical nephrectomy will be extended to a nephroureterectomy. In Case 3, the pre-operative imaging led to strong consideration of a urothelial carcinoma. A nephron sparing procedure was, therefore, not considered and the entire kidney was removed laparascopically. Grossly, the kidney demonstrated multiple, poorly circumscribed, bright orange and reddish-blue friable masses involving both the renal parenchyma as well as the calyceal mucosa. No calculi were present. Because of the preoperative studies, the surgeon requested a frozen section to determine whether this was urothelial cancer. If so, a completion ureterectomy would be done.

The frozen section of the dominant 1.3 cm. lesion demonstrated poorly delineated infiltrates of foamy and pigmented cells with granulation tissue and dense scarring. The frozen specifically included a portion of the adjacent calyceal mucosa, not grossly involved, to determine whether the lesion represented a urothelial tumor. Edema, inflammation and a proliferation of vonBrunn's nests was seen, no tumor was identified. No tumor urothelial or otherwise was seen in permanent sections, either in the frozen or in sections taken from other lesions in the kidney. The predominant cells were siderophagic histiocytes. Although there was no prior history of infection or calculus disease, the diagnosis in this case was felt to represent a form of xanthogranulomatous pyelonephritis. The clinical issue of tumor was, however, definitively resolved.

For the more common renal cell carcinoma, nephron sparing (partial) nephrectomy has become an established procedure with comparable results, i.e., low perioperative morbidity, preservation of renal function and a low local recurrence rate, compared to standard radical nephrectomy [8]. Simple enucleation is not generally indicated; the partial procedure employs a sharp dissection of parenchyma to yield a rim of about 1.0 cm. of normal tissue around the tumor. The indications for partial nephrectomy have included:
  1. A localized tumor in a patient who would be rendered anephric by the procedure (solitary kidney, atrophic or dysplastic contralateral kidney, irreversible benign contralateral disease, e.g., obstruction).

  2. Bilateral kidney tumors

  3. A condition compromising renal function (diabetes, hypertension, glomerulonephritis, reflux, recurrent infection)
Many series of nephron sparing surgery for sporadic renal cell carcinoma have been reported and are summarized in the review article by Uzzo [8]. In over 1800 cases reported from 21 studies, the local recurrence rate ranged from 0-10% over a mean follow up of 49 months. In the analysis of reports comparing partial versus radical nephrectomy, the 5 year survivals were virtually identical. Smaller tumors, especially those under 4.0 cm, did best. Multifocality has been an argument against partial nephrectomy, implying that an independent focus may contribute to local recurrence or be the nidus for subsequent metastatic disease. In sporadic renal cell carcinoma, multifocality is an issue in about 15% of cases but cannot be predicted, especially if the multifocal involvement is occult. Based on the recurrence rates in the summarized large series of partial nephrectomy, the contribution of multifocal or multicentric tumors to subsequent recurrence or metastasis, while not completely resolved, is probably small. Given this current understanding of the biologic behavior of renal adenocarcinoma and the need to assure complete excision of at least the dominant lesion, frozen sections in partial nephrectomies are reasonable requests.

For the pathologist, it is optimal if the entire gross specimen is available for inspection at the time of the frozen instead of separate small biopsies being sent. The parenchymal margin can then be inked and the specimen freshly cut. The question of whether to take a "strip" margin or a representative section perpendicular to the inked edge at the point closest to the tumor has never been formally addressed. I prefer a perpendicular section because it is possible to include grossly obvious tumor and grossly obvious normal tissue. The tissue section should be taken from the point at which the tumor macroscopically most closely approaches the specimen edge. Given that the possible sources of confusion in this setting include sampling, detached atypical cells, crush artifact and the misidentification of normal renal constituents, especially tubules, for tumor [9, 10], having secure gross landmarks is often helpful.

In Case 4, a cystic lesion in a patient with multiple tumors on both sides, a partial nephrectomy was attempted. The knowledge that a solid tumor already existed on this side, plus the yellow color of the cyst walls in the excised tumor made tumor identification less important. The major issue for this lesion was the margin, which was grossly free. The frozen section did, however, establish a tumor diagnosis as well as confirm the negative status of the parenchymal margin.

Prostate Cancer (Cases 5 and 6)
In adenocarcinoma of the prostate, the use of frozen section is divided into two major areas: 1) margins of resection; 2) status of the regional lymph nodes. The two cases presented here deal respectively with each of these issues.

The development of PSA screening and the radical prostatectomy have transformed the detection and treatment of this disease. The American Cancer Society estimates approximately 230,000 new cases of prostate cancer in 2004 with nearly 30,000 deaths. It is the most common malignancy in men and is the second leading cause of death from cancer. The adequacy of resection depends in large measure on the status of the margins, i.e., peripheral capsular margins as well as apex and base. The status of the margins is a major predictive factor in assessing the potential progression of the tumor [11]. The common complications of radical prostatectomy are urinary incontinence and impotence. The latter is related to the usual peripheral location for prostatic adenocarcinoma, the propensity for the tumor to penetrate the poorly defined capsular tissue as well as the known tendency to track along the peripheral nerves. A resection of the neurovascular bundles assures that the patient will be impotent.

The nerve sparing radical prostatectomy is designed for patients with limited disease who are preoperatively potent and attempts to preserve potency without compromising eradication of the tumor and ultimate local control. These two goals are not mutually exclusive [12, 13]. At the time of surgery if there is a palpable abnormality related to the poles of the gland (apex or base) or an unexpected bulge in the peripheral capsule, a frozen section may be requested. In one large series of about 7300 cases equally divided between nerve-sparing and wide excision procedures, the incidence of positive margins (mostly apical and posterior) was about the same in both groups as was the progression-free survival. (Table IV) [13].

Table IV - Positive Margins in Radical Prostatectomy*

Procedure Nerve-sparing Wide excision
N 3741 3527
+ Margin (overall) 27% 31%
Location (%)
Apex 18 25
Posterior 16 19
Base 5 11
Urethra 2 5
Anterior 2 2

*modified from Ward, JF, et al, J Urol 172: 1328-1332, 2004

The relatively recent advent of the laparascopic radical prostatectomy, occasionally done with robotic assistance, has raised additional concerns over the potential for adequate resection of the gland due to the absence of tactile feedback for the surgeon and inadvertent capsulotomy related to the field of view. Frozen sections may be requested to assist in complete removal of the prostate gland as well as to assess whether tumor is present [14]. A potential margin which is positive for tumor will result in additional tissue being submitted, possibly to include a wide resection encompassing the neurovascular bundle. In one series of 101 patients undergoing nerve-sparing surgery with frozen section, 15 samples were positive, 12 of which demonstrated no tumor on additionally submitted tissue [14].

The University of Chicago experience from 2000-2006 (August) is summarized in Table V. A comparison is made between those cases accessioned between 2000-2003 and those examined between 2004 and August of 2006. This grouping parallels the more common practice of robotic assisted laparoscopic radical prostatectomy at the University of Chicago beginning around 2004. The chart demonstrates that not only did the number of cases markedly increase, but frozen section requests also increased for both lymph nodes as well as prostatic margins.

In Case 5, the initial sample submitted from the robotic assisted laparascopic prostatectomy exhibited a perineural infiltrate of artifactually distorted small cells highly suggestive of tumor. Similar areas were seen on the resected prostate but were not apparent on the permanent sections of the frozen. While the permanent preparation is designed to function as a quality control of the actual frozen, issues of sampling inherent to all frozen sections mean that occasionally the lesion or abnormality originally identified will be lost on the permanent. This does not make the original interpretation incorrect, but does emphasize the role of well grounded morphologic analysis. It also means that any additional studies which might have been desirable on permanently prepared material cannot be done on that block.

Since urology residents with advanced training in robotic procedures are entering a variety of non university type practice situations, it is inevitable that there will be an increase in the acquisition and use of robotic devices. Frozen section requests are likely to be encountered by surgical pathologists in these practice settings as well. The University of Chicago experience over the last approximately 6 years has generated more confidence in the interpretation of these frozen sections. No false positives have been discovered; there have been 4 false negatives.

Table V
Radical Prostatectomy: Prostate Frozen Sections University of Chicago 2000-2006 (August)


2000-2003
Total radical prostatectomy 294
Total prostate frozen section 129
Apex 35
Base 27
Peripheral 67
Total positive 5 (4%)
2004-2006 (August)
Total radical prostatectomy 677
Total prostate frozen section 429
Apex 163
Base 89
Peripheral 161
Other 16
Total positive 39 (9%)

The second major issue related to radical prostate surgery is the status of the regional lymph nodes. Since radical prostatectomy has a debatable role in the treatment of metastatic disease, there is an advantage in detecting those patients who would not benefit from this form of surgical treatment. Since there is no form of preoperative staging which is 100% accurate, in earlier years it was common to do routine bilateral pelvic lymphadenectomies with frozen section analysis to identify such patients and not proceed to the prostatectomy if a metastasis were discovered. Unfortunately, no standardized method of examination was ever employed in the analysis of these nodes, so that the reported false negative rate was as high as 70% in some series with very low sensitivities [15].

Mostly, the reason for this figure is related to sampling. In the absence of grossly obvious metastatic disease, the pathologic analysis has varied from freezing everything, freezing a portion of the largest node to imprinting all the nodes. The skills required to do a frozen section in this setting for metastatic disease are no different than those required for the sentinel lymph node for breast cancer, discussed above. No special expertise is required. However, the sentinel node concept has not been developed for prostate cancer; the node-bearing tissue is dissected en bloc by the surgeon and delivered as such to surgical pathology. The pelvic lymph nodes are often large, heavily invested by fat and often multiple. Making a complete examination by frozen section is impractical in most cases. Recent surgical literature argues against doing routine frozen sections on pelvic lymph nodes [15, 16]. Besides the questionable utility of frozen section in this setting, two other factors related to routine pelvic lymphadenectomy are the added costs and post-operative morbidity. The former could be of the nature of several thousand dollars; the latter could involve nerve and vessel injury sustained during the dissection, bleeding, infection, fistulas and genital and lower extremity edema.

In recent years, urologists have begun to use a panel of clinical and pathologic parameters to identify those patients who could undergo a radical prostatectomy without concurrent lymph node dissection. These parameters are a clinical stage T2 or less, a Gleason grade of 6 or less and a serum PSA < 10ng/ml. This group of patients has < 4% chance of having a positive regional lymph node. At the University of Chicago from 2000-2003, 294 radical prostatectomies were done for which there were 61 requests for lymph node frozen sections. Since such requests are often multipe, the lymph node figure corresponds to a fewer number of patients. With the popularity of robotic assisted prostatectomy, between 2004 and August of 2006, there were 677 prostatecomies with requests for lymph node examinations in 299 lymph nodes. The preoperative selection of patients is quite good and explains the very low frozen section positive rate. False negatives were also very low. (Table VI)

Table VI
Radical Prostatectomy and Pelvic Lymph Node Frozen Section
University of Chicago
2000-2006 (August)
2000-2003
Total radical prostatectomy 294
Total lymph node frozen sections 61
Total positive 3 (5%)
False negative 4 (7%)
2004-2006 (August)
Total radical prostatectomy 677
Total lymph node frozen sections 299
Total positive 0
False negative 4 (1%)

Presently, while routine intraoperative analysis of the lymph nodes for every case is not recommended, in the individual assessment of each patient such an examination may be deemed appropriate. For example, a patient with questionably localized disease (T2 or T3) but who may have a PSA > 10ng/ml, any area of Gleason 4 in the biopsy, or any combination of these factors. Case 6 meets several of those criteria. The patient was only 57, but had a recent history of a nephroureterectomy for a urothelial cancer. His serum PSA was high with a Gleason 7 biopsy pattern. The clinical indications were that this could be an aggressive disease and that the patient would not benefit from a radical prostatectomy. Metastatic disease was identified easily, even though grossly the nodes were thought to be negative.

Urothelial Cancer (Case 7)
Urothelium has long been recognized as the most primitive of epithelia, both in its organization and in the individual cytologic characteristics. The simplicity of the cytoplasmic organization aptly suits the cells for fluid transport [17]. In the past, this epithelium has been termed transitional epithelium, possibly because of its ability under inflammatory and neoplastic conditions to demonstrate squamous and/or glandular differentiation. It is now accepted that these cells are not transitional in the sense they represent some intermediate phase of differentiation but do in fact represent a discrete form of epithelium. Hence, the current designation as urothelium.

The individual cell simplicity is also reflected in the histologic organization, since basal to surface maturation is subtle. The key feature in the histologic assessment of urothelial organization is the preservation of a basal layer. Ideally, these are cells with higher nuclear:cytoplasmic ratios and a palisaded arrangement. The presence of "umbrella cells" in the most superficial urothelial layer is not a reliable indicator of a normal maturation sequence, since umbrella cells may persist over dysplastic urothelium. Since there is no meaningful morphologic distinction between high-grade dysplasia and in-situ carcinoma, the frozen section determination is whether dysplasia is present and if so, whether it is low or high grade. The recognition of dysplasia that is less than high grade is difficult due to the difficulty in recognizing the basal layer and the subtleties of urothelial maturation. High-grade dysplasia may be more easily appreciated due to more obvious nuclear pleomorphism, dyscohesion and mitotic activity. Although p53 immunohistochemistry is helpful in identifying examples of carcinoma in situ, obviously this is not available for frozen section use. The clinical implications of these morphologic struggles, i.e., whether additional margins will be submitted and the long term implication(s) of a negative or positive margin, are not entirely clear.

As a matter of practice, the frozen section requests in the process of doing a radical cystectomy almost always involve the ureteral margins (Table VII). Most surgical pathologists would agree that it is difficult enough to assess urothelial dysplasia based on well fixed and cut paraffin embedded samples; doing this by frozen section can be extremely challenging. Especially if the distinction to be made is between something reactive/hyperplastic and a low-grade dysplasia. In addition, there is support for the idea that degrees of dysplasia short of severe (carcinoma in-situ) are not predictive of anything. However, the dynamics of the clinical decision-making process in this context are not clear. Nor are the reasons clear why, if ureteral margins are routinely requested, a urethral margin is not. Assuming the results of the frozen section actually influence the intraoperative management, two questions should be raised: 1) does the frozen section actually influence subsequent clinical behavior of the tumor; 2) if not, then why do we do them?

TABLE VII
Radical Cystectomy/Cystoprostatectomy University of Chicago 2004-2006 (August) Frozen Section Results

N 190
Ureter FS 385 Lymph nodes (FS)
Negative 295 Negative 11
Low-grade dysplasia 5 Positive 4
High-grade dysplasia 69 False negative 1
Tumor/invasive 4
Other 14
Urethra 5
Other 14
False negative 1

The issues of appropriate utilization of frozen section in urothelial disease, especially radical cystectomy, have been discussed largely in the surgical literature. A number of studies spanning the last 15 years or so have indicated that frozen sections of ureteral margins during a radical cystectomy have a very low yield and may, in fact, not be indicated [18, 19, 20, 21]. The University of Chicago figures are shown in Table VII and show more than 75% of ureteral frozen sections are negative or have low grade dysplasia. Very few urethral frozen sections are requested. Whether "field effect" in urothelial cancer is in fact clinically meaningful and should play a role in the intraoperative assessment of margins for radical surgery is a subject which requires some probing on the part of the urologists and the pathologists.

Upper tract recurrences after cystectomy range from 2.4 - 17%, as reported in one large review article; urethral recurrences are highest for males at about 6% [21]. The circumstances under which this procedure may be indicated are: 1) tumor involving the bladder neck; 2) tumor multifocality; 3) extensive carcinoma in situ; 4) involvement of the intramural ureter.

In Case 7, a male patient with multiple co-morbidities including a heavy smoking history had a 9.0 cm high grade urothelial carcinoma of the bladder. It was clinically felt that control of his urothelial disease would require a cystectomy. The frozen sections of his ureteral margins were all interpreted as carcinoma in situ. His cystectomy was completed with an ileal conduit.

References
Breast and Sentinel Node
  1. Troxel, DB, Error in surgical pathology, Am J Surg Pathol 28: 1092-1095, 2004.

  2. Ferreiro, JA, Gisvold, JJ and Bostwick, DG, Accuracy of frozen-section diagnosis of mammographically directed breast biopsies: Results of 1490 consecutive cases, Am J Surg Pathol 19: 1267-1271, 1995.

  3. Cheng, L, Al-Kaisi, NK, Liu, AY, et al, The results of intraoperative consultations in 181 ductal carcinomas in situ of the breast, Cancer 80: 75-79, 1997.

  4. Schwartz, GF, Giuliano, AE, Veronesi, U, et al, Proceedings of the consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast, Hum Pathol 33: 579-589, 2002.

  5. Reitsamer, R, Peintinger, F, Prokop, E, et al, Sentinel lymph node biopsy alone without axillary lymph node dissection - follow up of sentinel lymph node negative breast cancer patients, Eur J Surg Oncol 29: 221-223, 2003.

  6. Vernesi, U, Paganelli, G, Viale, G, et al, A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer, N Engl J Med 349: 546-553, 2003.

  7. Chao, C, The use of frozen section and immunohistochemistry for sentinel lymph node biopsy in breast cancer, Cancer 70: 414-419. 2004.
Kidney
  1. Uzzo, RG and Novick, AC, Nephron sparing surgery for renal tumors: Indications, techniques and outcomes, J Urol 166: 6-18, 2001.

  2. McHale, T, Malkowicz, B, Tomaszewski, et al, Potential pitfalls in the frozen section evaluation of parenchymal margins in nephron-sparing surgery, Am J Clin Pathol 118: 903-910, 2002.

  3. Krishnan, B, Lechago, J, Ayala, G, et al, Intraoperative consultation for renal lesions: Implications and diagnostic pitfalls in 324 cases, Am J Clin Pathol 120: 528-535, 2003.
Prostate
  1. Epstein, JI, Partin, AW, Sauvageot, J, et al, Prediction of progression following radical prostatectomy: A multivariate analysis of 721 men with long-term follow-up, Am J Surg Pathol 20: 286-292, 1996.

  2. Sokoloff, MH and Brendler, CB, Indications and contraindications for nerve-sparing radical prostatectomy, Urol Clin N Am 28: 535-543, 2001.

  3. Ward, JF, Zincke, H, Bergstralh, EJ, et al, The impact of surgical approach (nerve bundle preservation versus wide local excision) on surgical margins and biochemical recurrence following radical prostatectomy, J Urol 172: 1328-1332, 2004.

  4. Goharderakhshan, RZ, Sudilovsky, D, Carroll, LA, et al, Utility of intraoperative frozen section analysis of surgical margins in region of neurovascular bundles at radical prostatectomy, Urology 59: 709-714, 2002.

  5. Beissner, RS, Stricker, JB, Speights, VO, et al, Frozen section diagnosis of metastatic prostate adenocarcinoma in pelvic lymphadenectomy compared with nomogram prediction of metastasis, Urology 59: 721-725, 2002.

  6. Link, RE and Morton, RA, Indications for pelvic lymphadenectomy in prostate cancer, Urol Clin N Am 28: 491-498, 2001.
Urinary bladder
  1. Battifora, H, Eisenstein, R and McDonald, JH, The human urinary bladder mucosa: An electron microscopic study, Inv Urol 1: 354-361, 1964.

  2. Johnson, DE, Wishnow, KI, Tenney, D, Are frozen-section examinations of ureteral margins required for all patients undergoing radical cystectomy for bladder cancer? Urology 33: 451-454, 1989.

  3. Lebret, T, Herve, JM, Barre, P, et al, Urethral recurrence of transitional cell carcinoma of the bladder : Predictive value of preoperative latero-montanal biopsies and urethral frozen sections during prostatocystectomy, Eur Urol 33: 170-174, 1998.

  4. Schoenberg, MP, Carter, HB, Epstein, JI, Ureteral frozen section analysis during cystectomy: A reassessment, J Urol 155: 1218-1220, 1996.

  5. Stenzl, A, Bartsch, G, Rogatsch, H, The remnant urothelium after reconstructive bladder surgery, Eur Urol 41: 124-131, 2002.