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Pathologic Evaluation of Sentinel Lymph Nodes in Colorectal Carcinoma.

Colorectal carcinoma remains a significant cause of morbidity and mortality worldwide, with global estimates of 783 000 new cases and 437000 deaths in 1990.[1] In the United States, colorectal carcinoma is the third most common cancer in both men and women, and is the fourth most common cancer overall, with 129400 new cases and 56 600 deaths estimated for 1999.[2]

The prognosis of colorectal carcinoma is greatly influenced by the stage of the disease at the time of diagnosis. Despite the more favorable prognosis of patients with localized cancer and no regional lymph node metastasis, up to 20% to 30% of patients will develop recurrent disease, despite apparent surgical cure.[3] It is likely that some of these clinical failures are in part due to pathologic under-staging of the tumor at the time of resection.

The accurate identification of lymph node metastasis in colorectal resection specimens is clearly critical for accurate tumor staging. Standard surgical procedures are designed to remove regional lymph nodes as a component of the resection. However, the pathologic identification and sampling of these nodes may be inconsistent and undoubtedly varies between pathologists and among laboratories. Routine pathologic dissection of fresh or fixed colorectal resection specimens yields only a subset for histologic examination of all the lymph nodes resected surgically. Small positive lymph nodes may be missed at the time of gross pathologic examination, and lymph nodes most directly in the path of lymphatic drainage in fact may not be sampled at all. To assure at least a degree of statistical probability to identify regional lymph node metastasis, some studies have suggested a minimum number of lymph node blocks[4] or lymph nodes[5] to be recovered from colorectal resection specimens; Goldstein et al[5] found that at least 17 lymph nodes should be recovered for proper evaluation.

A variety of techniques have been proposed to increase the number of lymph nodes identified in colorectal resections. These have included meticulous methods for stretching, pinning, fixing, and recovering lymph nodes from associated mesenteric fat,[6] as well as a variety of fat clearance techniques to aid in the recognition of lymph nodes.[7,8]

Other studies have focused on immunohistochemical methods to help increase the identification of micrometastases within those lymph nodes recovered[9-12]; some of these methods have been combined with fat clearance techniques.[13,14] Reverse transcriptase--polymerase chain reaction techniques have also been evaluated.[15,16] However, all of these methods again rely on sufficient sampling of lymph nodes in the resection specimen and may be time-consuming and expensive if applied to all of the lymph nodes recovered. If those lymph nodes most directly in the immediate drainage path of the primary tumor (sentinel lymph nodes [SLNs]) could be consistently and unequivocally identified in colorectal resection specimens, and if they, in turn, could be subjected to thorough and meticulous pathologic examination, it is possible that more accurate pathologic staging, particularly of micrometastatic disease, could be achieved. Identification of SLNs allows the pathologist to focus meticulous attention on those nodes most likely to harbor metastasis by combinations of multilevel sections, immunohistochemistry, or molecular diagnostic techniques. Intraoperative mapping of such SLNs was initially proposed by Cabanas[17] for cases of penile cancer. The technique has been well developed for cases of melanoma[18] and breast cancer,[19] and the body of literature on this subject is growing rapidly. The method indeed may be applicable to most solid tumors,[20] and pathologists may expect to see the method extended to additional clinical settings.[21] We evaluated an SLN mapping method in colorectal carcinoma, with an emphasis on the pathologic evaluation of the SLNs. To our knowledge, this article represents the first published series on the pathologic evaluation of SLNs in colorectal carcinoma.

METHODS

From April 1996 through August 1999, 83 consecutive patients with colorectal carcinoma were initially enrolled in the study on an informed consent protocol approved by the Institutional Review Board. A single surgeon (S.S.) performed all surgical procedures. Pathologic evaluation was rotated among the pathologists in the department; all cases were reviewed subsequently by a single pathologist (D.W.). One patient with a rectal primary tumor had undergone neoadjuvant chemoradiation therapy; at surgery, no SLN could be identified. This patient was excluded from the study group.

At the time of surgery, approximately 1 to 2 mL of a 1% solution of isosulfan blue dye (Lymphazurin; Ben Venue Labs, Inc, Bedford, Ohio) was injected circumferentially into the subserosa around the tumor. Within 5 to 10 minutes, the blue dye could be visualized within 1 to 4 lymph nodes in the adjacent pericolic fat or mesocolon. These nodes were uniquely identified with suture tags by the surgeon in the order they were visualized, so that the pathologist could subsequently identify them; they were designated as first, second, third, and/or fourth SLNs. Occasionally, in patients with unusually thick or fatty mesocolic tissue, limited surgical dissection of the mesocolic fat was required to identify the blue-stained lymph nodes. The remainder of the colorectal resection was carried out by standard methods.

The specimen was sent to the pathology department in either the fresh or formalin-fixed state, depending on the need for intraoperative evaluation or additional ancillary studies. On receipt, the pathologist dissected the SLNs free from the specimen. Each of these nodes was blocked individually. Small nodes less than about 3 to 4 mm in diameter were submitted without gross sectioning, while larger nodes were sectioned grossly at 2- to 3-mm intervals and totally embedded. The remainder of the pathologic dissection was performed according to standard methods. Pericolic adipose tissues were often fixed for 2 to 18 hours in Carnoy fluid to aid in the recognition and dissection of non-SLNs.

Paraffin-embedded blocks were sectioned at 4 [micro]m. Sections of each SLN were obtained at a total of 10 representative levels, typically 20 [micro]m apart, and were mounted on separate slides. In each case, at least 1 of the levels, typically the fifth, was immunostained as outlined below. The remaining SLN sections, together with the routine sections from the case, were stained with hematoxylin-eosin. In addition, for the first 25 cases, all non-SLNs that were free of metastatic tumor on the first section were sectioned at 9 additional levels for hematoxylin-eosin staining.

In each case, at least 1 level from each SLN was immunostained for the demonstration of cytokeratins. In some cases, a slide was immunostained for carcinoembryonic antigen. For immunocytochemical staining, paraffin sections were collected on charged slides (Superfrost Plus; Fisher Scientific, Pittsburgh, Pa). Immunocytochemical labeling was performed with an automated immunostainer (Ventana ES; Ventana Medical Systems, Inc, Tucson, Ariz). For cytokeratins, sections were predigested for 8 minutes (Protease 1), followed by a 24-minute incubation at 37 [degrees] C with prediluted cocktail AE1/AE3. For carcinoembryonic antigen labeling, there was no predigestion; the slides were incubated for 16 minutes at 37 [degrees] C with a prediluted anti--carcinoembryonic antigen antibody. The remaining steps followed the vendor protocol; diaminobenzidine was used as the chromogen.

RESULTS

The patients ranged in age from 33 to 97 years with a mean age of 71 years. Of the 82 patients, 36 (44%) were men and 46 (56%) were women. All patients were admitted with clinically or biopsy-proven primary carcinoma of the colorectum. Two patients each had 2 separate synchronous primary tumors, while single primary tumors were present in the other 80 patients. Of the 84 individual tumors, 83 were adenocarcinomas and 1 was a small cell carcinoma. The tumors were graded as well differentiated (n = 7), moderately differentiated (n = 65), or poorly differentiated (n = 12). Well-differentiated tumors were characterized by well-formed glands with low-grade nuclei. Moderately differentiated tumors showed more complex glands and loss of nuclear polarity; nuclei appeared to be higher grade, and a few solid areas were seen. Poorly differentiated tumors contained prominent solid areas with high-grade nuclei throughout the majority of the tumor. The total 84 primary tumors were distributed throughout the colorectum, including the cecum (n = 19), ascending colon (n = 18), transverse colon (n = 12), descending colon (n = 2), sigmoid colon (n = 19), and rectum (n = 14). The primary tumors (Table 1) were staged as T1 (n = 12), T2 (n = 18), T3 (n = 43), and T4 (n = 9). Both patients with dual primaries had T4 lesions, which were combined for the purposes of staging.
Table 1. Pathologic TNM Staging

 Distant
 Lymph Nodes Metastasis

Stage n N0 N1 N2 M0 M1

T1 12 9 3 0 12 0
T2 18 13 5 0 16 2
T3 43 22 14 7 38 5
T4 9 4 3 2 6 3
Total 82 48 25 9 72 10


Lymph node metastases (Table 2) were identified in 34 (41%) of the 82 patients. They were present in 3 (25%) of 12 patients with T1 tumors, 5 (28%) of 18 patients with T2 tumors, 21 (51%) of 43 patients with T3 tumors, and 5 (56%) of 9 patients with T4 tumors.
Table 2. Positive Lymph Nodes Relative to Primary Tumor(*)

 No. of Patients No. of Positive
Tumor With LN Metastases/ LNs/Total LNs
T Stage Total Patients (%) (%)

T1 3/12 (25) 3/111 (3)
T2 5/18 (28) 7/294 (2)
T3 21/43 (49) 65/706 (9)
T4 5/9 (56) 24/164 (15)
Total 34/82 (41) 99/1275 (8)

 No. of Patients
 No. of Positive With Positive
Tumor SLNs/Total SLNs SLNs/Patients With
T Stage (%) LN Metastases (%)

T1 3/21 (14) 3/3 (100)
T2 4/33 (12) 4/5 (80)
T3 25/84 (30) 20/21 (95)
T4 6/14 (43) 4/5 (80)
Total 38/152 (25) 31/34 (91)


(*) LN indicates lymph node; SLN, sentinel lymph node.

A total of 1275 lymph nodes were recovered from the 82 patients (Table 3), for an average of 15.6 lymph nodes per case (range 2-39). A total of 152 lymph nodes, accounting for 11.9% of the total number of lymph nodes, were identified as SLNs, with an average of 1.9 SLNs per patient (range 1-4). Thirty-two patients had 1 SLN, 33 patients had 2 SLNs, 14 patients had 3 SLNs, and 3 patients had 4 SLNs. A total of 99 (7.8%) positive lymph nodes were identified. Of these, 38 represented positive SLNs, for a positive yield in the SLN set of 25%. Two of the 38 positive SLNs were identified only by immunocytochemical staining for cytokeratins. The remaining 1123 non-SLNs yielded 61 positive lymph nodes, or 5.3%. In patients with positive SLNs, 91 (19%) of 474 total lymph nodes and 53 (11%) of 436 non-SLNs were positive. In patients with negative SLNs, 8 (1%) of 801 total lymph nodes and 8 (1.2%) of 687 non-SLNs were positive.

Table 3. Summary Findings in Lymph Nodes From 82 Patients
 Total No. No. Positive
 (No. per Patient) (%)

Lymph nodes 1275 (15.6) 99 (7.8)
Non-sentinel lymph nodes 1123 (13.7) 61 (5.4)
Sentinel lymph nodes 152 (1.9) 38 (25.0)


In the 34 patients with lymph node metastases, the SLNs were the only involved nodes in 17 (50%), while 14 patients (41%) had positive SLNs and non-SLNs (Table 4). Three patients (9%) had positive non-SLNs with negative SLNs, representing skip metastases. One patient had a T2 tumor with 1 of 28 non-SLNs positive and 2 SLNs negative. One patient had a T3 tumor with 4 of 9 non-SLNs positive and 4 SLNs negative. Another patient had a T4 tumor with 3 of 34 non-SLNs positive and 2 SLNs negative.

Table 4. Summary Findings in Patients With Metastasis
Total patients, n (%) 82 (100)
Patients with lymph node metastastasis, n (%) 34 (41.4)
Patients with SLN metastasis only, n (%) 17 (50)
Patients with SLN and non-SLN metastasis, n (%) 14 (41)
Patients with non-SLN metastasis only, n (%) 3 (9)


For the first 25 consecutive patients, both SLNs and all initially negative non-SLNs were sectioned at 10 levels through the tissue blocks. For these 25 patients, a total of 390 lymph nodes were recovered, with an average of 15.6 lymph nodes per patient. A total of 36 (9.2%) of these were identified as SLNs, of which 13 (36%) were positive for metastasis. There were 354 non-SLNs, of which 24 (7%) were positive for metastasis. For cases in which the non-SLNs were initially negative on the first section, regardless of whether the SLN was positive or negative, additional multilevel sections through the non-SLN yielded 2 (0.6%) additional positive nodes of 330 lymph nodes sectioned. One of these was in a patient in whom 3 of 35 other nonSLNs were already positive. The other was in a patient in whom 21 non-SLNs and 1 SLN were initially negative, representing an additional case of skip metastases recognized only by multilevel sectioning of all 21 non-SLNs.

All positive SLNs were reviewed to evaluate at which level metastasis was detected (Table 5). Expressed as a cumulative rate of detection for the 38 positive SLNs, 76% of positive SLNs were detected on the initial section, with 84% detected by 2 levels, 87% by 3 levels, and 92% by 4 levels. This rate stayed constant through the next 4 levels, with 95% of the positive SLNs identified by the ninth and 10th levels. The remaining 2 positive SLNs were detected by cytokeratin immunostains only; careful review of the hematoxylin-eosin-stained sections from these specimens showed no histologic features diagnostic of metastasis, although in retrospect small clusters and single atypical cells corresponding to the cytokeratin-positive elements were noted. When positive SLNs were reviewed per level to evaluate the detection of metastasis for a given patient, rather than for a given SLN, the results were generally similar. Expressed as a cumulative rate of detection for the 31 patients with positive SLNs, 77% were identified on the initial section of the SLN, with 87% detected by the second and third levels, 94% by the fourth through the 10th level, and the remainder detected by cytokeratin immunostain only.

Table 5. Cumulative Detection of Positive Sentinel Lymph Nodes (SLNs) or Positive Patient per Section Examined
 Cumulative Positive Cumulative
 SLN Detected/ Positive Patients/
Section Total Positive Total Positive
Level SLNs (%) Patients (%)

 1 29/38 (76) 24/31 (77)
 2 32/38 (84) 27/31 (87)
 3 33/38 (87) 27/31 (87)
 4 35/38 (92) 29/31 (94)
 5 35/38 (92) 29/31 (94)
 6 35/38 (92) 29/31 (94)
 7 35/38 (92) 29/31 (94)
 8 35/38 (92) 29/31 (94)
 9 36/38 (95) 29/31 (94)
10 36/38 (95) 29/31 (94)
Cytokeratin 38/38 (100) 31/31 (100)


The overall efficacy of the method was evaluated both for the ability to detect metastases per patient and per lymph node (Table 6). Using the status of the SLN (either positive or negative) as the test to detect the presence or absence of metastatic disease in a given patient, the sensitivity is 90%, specificity is 100%, the false-negative rate is 11%, and the overall accuracy is 95%. When the SLN status is applied as the test to detect the presence or absence of metastatic tumor in a given lymph node, the sensitivity is 98%; specificity, 100%; false-negative rate, 6%; and overall accuracy, 99%.

Table 6. Overall Efficacy of Sentinel Lymph Node Mapping With Multilevel Sections and Cytokeratin Immunostaining
 Per Lymph
 Per Patient Node

Sensitivity, % 90 98
Specificity, % 100 100
False negative rate, % 11 6
Overall accuracy, % 95 99


COMMENT

Colorectal carcinoma resections represent a common specimen in the surgical pathology laboratory. Standard methods for evaluating and reporting such specimens are well established.[22] However, the identification and evaluation of locoregional lymph nodes, while critical to the accurate staging of these cases, undoubtedly varies among laboratories and between pathologists.[5]

For the surgical pathologist, 2 major questions in evaluating lymph nodes in colorectal resections remain: How can I identify lymph nodes in the specimen most likely to harbor metastasis, and how many sections should I obtain to assure sufficient sampling of those lymph nodes? The answers to these questions must be tempered by the realistic constraints of time and resources available, particularly in an era of medical cost containment.

The technical application of SLN mapping to colorectal carcinoma is straightforward.[23] The method at surgery is simple and inexpensive, with the cost of the isosulfan blue dye approximately $30 per patient and the procedure adding only 5 to 10 minutes of surgical time. Sentinel lymph nodes were identified in 82 (99%) of the original 83 patients in the series. The one failure to identify an SLN occurred in a patient with rectal carcinoma treated with neoadjuvant chemoradiation, which possibly caused sclerosis of regional lymphatics, such that no dye uptake could be seen in the lymph nodes at the time of surgery. The SLN mapping method does not usually alter the surgical approach, although in 2 cases aberrant lymphatic drainage was recognized, prompting extended resection.

The SLN mapping method appears effective in identifying nodes most likely to harbor metastasis. In fact, when the 1 to 4 SLNs are negative, it is unlikely to find metastatic tumor in any of the other regional lymph nodes. In this series of 51 such SLN-negative patients, only 8 (1%) of 801 total lymph nodes were seen to contain metastatic tumor.

We evaluated the possibility that the increased detection of metastasis in the SLNs might be solely due to the increased sectioning of these nodes. Of interest, a previous report evaluated the simple effect of increased sectioning on the identification of lymph node metastasis in 55 patients with carcinomas of the esophagus, stomach, colon, thyroid, and breast.[24] In that study, 3 additional sections from each of 1698 initially negative regional lymph nodes yielded 10 additional positive nodes (0.6%). In our series, therefore, all of the initially negative non-SLNs for the first 25 consecutive cases were sectioned also at 10 levels, similar to the SLNs. If metastases were randomly (and unexpectedly) distributed through these lymph nodes, multilevel sectioning of the non-SLNs might be expected to yield a percentage of positive lymph nodes similar to that seen for SLNs (about 25%). Instead, of the 330 initially negative non-SLNs only 2 (0.6%) contained metastatic tumor on these numerous additional multilevel sections. One of these was in a patient in whom other non-SLNs were positive. The other was present in a patient in whom all lymph nodes, including SLNs, had been negative, representing a single additional case of skip metastasis uncovered by the more extended sampling. This finding suggests that even if all lymph nodes recovered in colorectal carcinoma resection specimens in SLN-negative patients are sectioned at 10 levels, fewer than 1% of the lymph nodes and only about 4% of the patients would be expected to be staged at a higher level.

We also evaluated the number of sections of the SLNs necessary to assure detection of metastatic disease. In our series, 92% of the positive SLNs and 94% of the patients with positive SLNs were detected by evaluating 4 levels through each SLN submitted. When a single cytokeratin immunostain was added, the detection rose to 97% of the positive SLNs and 100% of the patients with positive SLNs. Six additional levels of each SLN identified only 1 additional positive SLN of the total of 38 positive SLNs in the series. It is therefore recommended that sampling of SLNs in colorectal carcinoma include 4 representative levels together with a single cytokeratin immunostain.

Reports of smaller clinical series in which colorectal SLN mapping was attempted yielded mixed results. In 1 study of 25 patients, SLNs were identified in 24 patients (96%) and were predictive of the node status in 79%.[25] However, in another study of 50 patients, the SLN could be identified in only 35 (70%), 20 of whom had positive lymph nodes.[26] Furthermore, the SLNs were negative in 12 of these patients, representing a rate of skip metastasis of 60% and suggesting possible technical problems in the application of the procedure.

In our series, the SLN mapping approach increased the likelihood that the surgical pathologist would be able to detect metastases in the regional lymph nodes in colorectal carcinoma patients, thereby staging the disease more accurately. Of note, 12 of our patients had very limited local disease (T1 lesions), and yet 3 (25%) of these had lymph node metastases, all detected by the SLN technique. With the SLN approach, the pathologist can be confident that at least 91% of the patients with metastatic disease in lymph nodes will be identified simply by examination of the 1 to 4 SLNs identified and tagged by the surgeon. This approach may lead to greater confidence in techniques such as laparoscopic colorectal tumor resection.

Additional studies are currently underway to combine SLN mapping in colorectal carcinoma with sensitive detection methods, such as reverse transcriptase-polymerase chain reaction, for identification of metastatic tumor. The combination of such techniques may further increase the ability to stage these patients accurately. In the future, it may be possible to focus pathologic evaluation on the SLNs alone in combination with advanced methods for the detection of metastatic disease. The impact that improved detection of nodal micrometastasis has on the clinical course of these patients must also continue to be evaluated, with conflicting conclusions reported to date.[10,11,27-32]

Clearly, there are cases in which SLN mapping is not necessary, such as in patients with overt metastatic disease, or even with clinically obvious lymph node metastasis. However, in most patients with colorectal carcinoma, SLN mapping with focused multilevel sectioning and cytokeratin immunostaining of the SLNs should increase the detection of metastatic disease, improving the accurate staging of colorectal carcinoma.

References

[1.] Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin. 1999;49:33-64.

[2.] Landis SJ, Murray T, Bolden S, Wingo P. Cancer statistics, 1999. CA Cancer J Clin. 1999;49:8-32.

[3.] Cohen AM, Kelsen D, Saltz L, et al. Adjuvant therapy for colorectal cancer. Curr Probl Cancer. 1998;22:5-65.

[4.] Mainprize KS, Hewavasinthe J, Savage A, Mortensen N, Warren BF. How many lymph nodes to stage colorectal carcinoma? J Clin Pathol. 1998;51:165-166.

[5.] Goldstein NS, Sanford W, Coffey M, Layfield LJ. Lymph node recovery from colorectal resection specimens removed for adenocarcinoma: trends over time and a recommendation for a minimum number of lymph nodes to be recovered. Am J Clin Pathol. 1996;106:209-216.

[6.] Crucitti F, Doglietto GB, Bellantone R, et al. Accurate specimen preparation and examination is mandatory to detect lymph nodes and avoid understaging in colorectal cancer. J Surg Oncol. 1992;51:153-157.

[7.] Scott KW, Grace RH. Detection of lymph node metastases in colorectal carcinoma before and after fat clearance, Br J Surg. 1989;76:1165-1167.

[8.] Koren R, Siegal A, Klein B, et al. Lymph node-revealing solution: simple new method for detecting minute lymph nodes in colon carcinoma. Dis Colon Rectum. 1997;40:407-410.

[9.] Davidson BR, Sams VR, Styles J, Deane C, Boulos PB. Detection of occult nodal metastases in patients with colorectal carcinoma. Cancer. 1990;65:967-970.

[10.] Cutait R, Alves VA, Lopes LC, et al. Restaging of colorectal cancer based on the identification of lymph node micrometastases through immunoperoxidase staining of CEA and cytokeratins. Dis Colon Rectum. 1991;34:917-920.

[11.] Greenson JK, Isenhart CE, Rice R, Mojzisik C, Houchens D, Martin EW Jr. Identification of occult micrometastases in pericolic lymph nodes of Duke's B colorectal cancer patients using monoclonal antibodies against cytokeratin and CC49: correlation with long-term survival. Cancer. 1994;73:563-560.

[12.] Sasaki M, Watanabe H, Jass JR, et al. Occult lymph node metastases detected by cytokeratin immunohistochemistry predict recurrence in "node-negative" colorectal cancer. J Gastroenterol. 1997;32:758-764.

[13.] Haboubi NY, Clark P, Kaftan SM, Schofield PF. The importance of combining xylene clearance and immunohistochemistry in the accurate staging of colorectal carcinoma. J R Soc Med. 1992;85:368-388.

[14.] Haboubi NY, Abdalla SA, Amini S, et al. The novel combination of fat clearance and immunohistochemistry improves prediction of the outcome of patients with colorectal carcinomas: a preliminary study. Int J Colorectal Dis. 1998; 13:99-102.

[15.] Mori M, Mimori K, Inoue H, et al. Detection of cancer micrometastases in lymph nodes by reverse transcriptase-polymerase chain reaction. Cancer Res. 1995;55:3417-3420.

[16.] Futamura M, Takagi Y, Koumura H, et al. Spread of colorectal cancer micrometastases in regional lymph nodes by reverse transcriptase-polymerase chain reactions for carcinoembryonic antigen and cytokeratin 20. J Surg Oncol. 1998; 68:34-40.

[17.] Cabanas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456-466.

[18.] Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392-399.

[19.] Guiliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994;220:391-401.

[20.] Bilchik A, Guiliano A, Essner R, et al. Universal application of intraoperative lymphatic mapping and sentinel lymphadenectomy in solid neoplasms. Cancer J Sci Am. 1998;4:351-358.

[21.] Cochran AJ. Surgical pathology remains pivotal in the evaluation of "sentinel" lymph nodes. Am J Surg Pathol. 1999;23:1169-1172.

[22.] Association of Directors of Anatomic and Surgical Pathology. Recommendations for the reporting of resected large intestinal carcinomas. Mod Pathol. 1996;9:73-76.

[23.] Saha S, Wiese D, Badin J, et al. Technical details of sentinel lymph node mapping in colorectal cancer and its impact on staging. Ann Surg Oncol. 2000; 7:120-124.

[24.] Natsugoe S, Aiko T, Shimazu H. A detailed histological study on occult metastasis of the lymph nodes. Jpn J Surg. 1991;21:528-532.

[25.] Cserni G, Vajda K, Tarjan M, Bori R, Svebis M, Baltas B. Nodal staging of colorectal carcinomas from quantitative and qualitative aspects: can lymphatic mapping help staging? Pathol Oncol Res. 1999;5:291-296.

[26.] Joosten JJ, Strobbe LJ, Wauters CA, Pruszczynski M, Wobbes T, Ruers TJ. Intraoperative lymphatic mapping and the sentinel node concept in colorectal carcinoma. Br J Surg. 1999;86:482-486.

[27.] Rodrigeuz-Bigas MA, Maamoun S, Weber TK, Pnetrante RB, Blumenson LE, Petrelli NJ. Clinical significance of colorectal cancer: metastases in lymph nodes [is less than] 5 mm in size. Ann Surg Oncol. 1996;3:124-130.

[28.] Sanchez-Cespedes M, Esteller M, Hibi K, et al. Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence. Clin Cancer Res. 1999;5:2450-2454.

[29.] Adell G, Boeryd B, Franlund B, Sjodahl R, Hakansson L. Occurrence and prognostic importance of micrometastases in regional lymph nodes in Dukes' B colorectal carcinoma: an immunohistochemical study. Eur J Surg. 1996;162:637-642.

[30.] Broll R, Schauer V, Schimmelpenning H, et al. Prognostic relevance of occult tumor cells in lymph nodes of colorectal carcinomas: an immunohistochemical study. Dis Colon Rectum. 1997;40:1465-1471.

[31.] Oberg A, Stenling R, Tavelin B, Lindmark G. Are lymph node micrometastases of any clinical significance in Dukes stages A and B colorectal cancer? Dis Colon Rectum. 1998;41:1244-1249.

[32.] Liefers GJ, Cleton-Jansen AM, van de Velde CJ, et al. Micrometastases and survival in stage II colorectal cancer. N Engl J Med. 1998;339:223-228.

Accepted for publication July 14, 2000.

From the Departments of Pathology (Drs Wiese, Badin, Ng, Gauthier, Ahsan, and Yu) and Surgery (Dr Saha), Michigan State University, College of Human Medicine, McLaren Regional Medical Center, Flint, Mich. Dr Gauthier is currently affiliated with Columbia Clear Lake Medical Center, Webster, Tex.

Presented in part at the US and Canadian Academy of Pathology Meeting, Boston, Mass, March 11, 1997; and at the American Society of Clinical Pathology Fall Meeting, New Orleans, La, September 25, 1999.

Reprints: David A. Wiese, PhD, MD, Department of Pathology, McLaren Regional Medical Center, 401 S Ballenger Hwy, Flint, MI 48532.
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Author:Wiese, David A.; Saha, Sukamal; Badin, Julio; Ng, Peter S.-T.; Gauthier, Jerry; Ahsan, Aamir; Yu, Le
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Dec 1, 2000
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