Nodal staging accuracy for colorectal carcinoma is under

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1 Colorectal Carcinoma Nodal Staging Frequency and Nature of Cytokeratin-Positive Cells in Sentinel and Nonsentinel Lymph Nodes Roderick R. Turner, MD; Dean T. Nora, MD; Steven D. Trocha, MD; Anton J. Bilchik, MD, PhD Context. Nodal staging accuracy is important for prognosis and selection of patients for chemotherapy. Sentinel lymph node (SLN) mapping improves staging accuracy in breast cancer and melanoma and is being investigated for colorectal carcinoma. Objective. To assess pathologic aspects of SLN staging for colon cancer. Design. Sentinel lymph nodes were identified with a dual surgeon-pathologist technique in 51 colorectal carcinomas and 12 adenomas. The frequency of cytokeratin (CK) positive cells in mesenteric lymph nodes, both SLN and non-sln, was determined along with their immunohistochemical characteristics. Results. The median number of SLNs was 3; the median number of total nodes was 14. The CK-positive cell clusters were detected in the SLNs of 10 (29%) of 34 SLN-negative patients. Adjusted per patient, SLNs were significantly more likely to contain CK-positive cells than non-slns (P.001). Cell clusters, cytologic atypia, and/or coexpression of tumor and epithelial markers p53 and E-cadherin were supportive of carcinoma cells. Single CK-positive cells only, however, could not be definitively characterized as isolated tumor cells; these cells generally lacked malignant cytologic features and coexpression of tumor and epithelial markers and in 2 cases represented mesothelial cells with calretinin immunoreactivity. Colorectal adenomas were associated with a rare SLN CK-positive cell in 1 (8%) of 12 cases. Conclusions. Sentinel lymph node staging with CK-immunohistochemical analysis for colorectal carcinomas is highly sensitive for detection of nodal tumor cells. Cohesive cell clusters can be reliably reported as isolated tumor cells. Single CK-positive cells should be interpreted with caution, because they may occasionally represent benign epithelial or mesothelial cells. (Arch Pathol Lab Med. 2003;127: ) Nodal staging accuracy for colorectal carcinoma is under scrutiny because of its importance for prognosis and the selection of patients for postoperative chemotherapy. Comparative analysis of treatment strategies in clinical studies requires accurate nodal staging. Several factors contribute to variation in nodal staging accuracy, including the amount of mesentery resected, fixative, diligence of search for nodes, and number of histologic levels examined. 1 The small size of many mesenteric nodes, including some with micrometastatic carcinoma, increases the risk of missing metastases. 2 4 Recent studies 1,2,5 demonstrated that 10 to 15 lymph nodes are needed for reliable staging, but this number may be substantially higher to attain greater predictive value. 6,7 The sentinel lymph node (SLN) procedure, now standard for selected patients with melanoma 8 and breast carcinoma, 9 appears feasible for colorectal carcinoma and may improve nodal staging accuracy Peritumoral injection of blue dye alone or with radioactive colloid permits the surgeon to identify the first lymph nodes on the Accepted for publication January 24, From the Department of Pathology, Saint John s Health Center (Dr Turner), and Department of Surgery, John Wayne Cancer Institute at Saint John s Health Center (Drs Nora, Trocha, and Bilchik), Santa Monica, Calif. Reprints: Roderick R. Turner, MD, Saint John s Health Center, nd St, Santa Monica, CA ( r.turner@stjohns.org). direct drainage pathway from the primary tumor and resect them; it also highlights for the pathologist the lymph nodes most likely to contain metastases. Combined with cytokeratin (CK) immunohistochemical (IHC) analysis, SLN examination provides a highly sensitive method for the detection of early metastatic carcinoma cells. We studied our institutional experience with SLN identification in colorectal carcinoma to determine the frequency and specificity of CK-positive cells in SLNs and non-slns. We also assessed the number of histologic levels needed to detect CK-positive tumor cells for a practical approach to accurate staging. METHODS Patient Selection and Surgical Procedures We reviewed the John Wayne Cancer Institute database to find 51 consecutive colorectal carcinoma cases and 12 adenoma cases with segmental colectomy and successful SLN identification between 1996 and Informed consent for lymphatic mapping had been obtained per our institutional review board. Some of these patients and procedures have previously been described in surgical studies. 10,13,14 The patients in this series represent the early experience with dye-directed SLN mapping for 9 surgeons and 9 pathologists at 2 hospitals. Identification of SLNs with a vital blue dye was a combined effort between surgeon and pathologist. The surgeon tagged all observed blue-stained nodes before resection of the primary tumor (Figure 1); within 1 to 4 hours after resection, a pathologist assistant or pathologist dissected the mesentery of the surgical specimen and looked for additional blue- Arch Pathol Lab Med Vol 127, June 2003 Colorectal Carcinoma Nodal Staging Turner et al 673

2 Figure 1. Lymphatic mapping of blue dye in vivo leads to sentinel lymph node. stained nodes. Manual techniques were used for dissection; no fat-clearing fixative was used. Blue-stained nodes identified by either surgeon or pathologist were counted as SLNs; unstained nodes were considered non-slns. All slides were reviewed by a single pathologist (R.R.T.). Primary Tumors Diagnoses were confirmed for 51 invasive colorectal carcinomas and 12 adenomas. Histologic data recorded included tumor type, grade, stage, 15 anatomic location, and extramural lymphatic vascular invasion. Lymph Node Examination Mesenteric lymph nodes, both SLNs and non-slns, were grossly sectioned at 2-mm thickness and entirely embedded. Standard hematoxylin-eosin (HE) stained sections included 2 levels (separated by 200 m) for SLNs and 1 level for non-slns. For this study, non-sln blocks were recut at 2 additional levels separated by 200 m. Data recorded included the number and histologic status (HE) of SLNs and non-slns. The maximal dimension of each patient s largest SLN was recorded. If SLNs or non-slns per case were negative on HE examination, CK-IHC analysis was performed on unstained sections of 2 levels separated by 200 m. All SLNs that were negative by HE examination were further examined at 2 additional (total of 4) CK-IHC levels, each approximately 200 m deeper into the block. The SLNs with CK-positive cells were immunostained (adjacent, 4- m sections) for p53, E-cadherin, and calretinin; a section of corresponding primary tumor was similarly stained. The CK stains were considered positive for tumor cells if cell clusters with a minimum of 2 to 3 cells were present; rare single CK-positive cells were considered negative. IHC Stains The IHC stains were prepared on the Ventana ES Automated System (Ventana Medical Systems, Inc, Tucson, Ariz) with commercial antibodies and standardized reagents. Cytokeratin stains (AE-1/AE-3; Dako Corporation, Carpinteria, Calif; 1:200, 32 minutes) were pretreated with Protease 1 (8 minutes). Other immunostains, including p53 (Dako, 1:100, 32 minutes), E-cadherin (Dako, 1:50, 32 minutes), and calretinin (Ventana, undiluted, 32 minutes), were pretreated in a vegetable steamer (Decloaking Chamber, Biocare Medical, Walnut Creek, Calif; 5 minutes). RESULTS Patient and Primary Tumor Data Patients and tumors represented a common spectrum of colorectal adenocarcinomas (Table 1). Tumor types included 47 usual adenocarcinoma, 3 mucinous, and 1 large cell neuroendocrine carcinoma. One patient (node negative) had received neoadjuvant chemotherapy. Primary carcinomas in the 10 patients with SLN CK-positive tumor cell clusters showed immunoreactivity for p53 (60% or 6/10) and E-cadherin (100% or 10/10) but not calretinin (0% or 0/10). SLN Identification At least one SLN was identified by the surgeon in 42 (82%) of 51 cases and by the pathologist in 30 (59%) of Arch Pathol Lab Med Vol 127, June 2003 Colorectal Carcinoma Nodal Staging Turner et al

3 Figure 2. Cluster of isolated tumor cells in sentinel lymph node. A, Cytokeratin stain (original magnification 100). B, Hematoxylin-eosin stain (original magnification 1000). C, p53 stain positive (original magnification 1000). Figure 3. Cluster of isolated tumor cells in sentinel lymph node. A, Cytokeratin stain (original magnification 1000). B, Hematoxylin-eosin stain (original magnification 1000). C, E-cadherin stain positive (original magnification 1000). cases; in all cases (51/51), at least one SLN was found (Figure 1). Lymph node counts are shown in Table 2. Maximal size of the largest SLN per patient ranged from 0.1 to 2.5 cm, with a median of 0.6 cm. In general, large SLNs were replaced and expanded by metastatic carcinoma (Table 3). For patients (n 14) with small SLNs (0.4 cm or less maximal size), 6 were HE stain positive, 2 were IHC stain positive, and 6 were negative. Lymph Node Findings Standard HE examination revealed metastatic carcinoma in 23 (45%) of 51 cases: 12 with positive SLNs and non-slns, 5 with positive SLNs only, and 6 with positive non-slns only (Table 4). Two-level IHC stains of SLNs and non-slns revealed CK-positive clusters in 8 (29%) of 28 previously node-negative cases: 5 had pos- Arch Pathol Lab Med Vol 127, June 2003 Colorectal Carcinoma Nodal Staging Turner et al 675

4 Figure 4. Isolated tumor cells in sentinel lymph node. A, Cytokeratin stain (original magnification 1000). B, Hematoxylin-eosin stain (original magnification 1000). C, E-cadherin stain positive (original magnification 1000). D, Calretinin stain also positive for a few mesothelial cells (original magnification 1000). Figure 5. Single cell without cytologic atypia. A, Cytokeratin stain (original magnification 1000). B, Calretinin stain positive for rare mesothelial cells (original magnification 1000). itive SLNs only, and 3 had positive SLNs and non-slns. Additionally, 2 of 6 SLN false-negative cases based on HE findings had CK-positive cell clusters in SLNs for a total of 10 cases with SLN CK-positive tumor cell clusters. Retrospective review of parallel HE-stained sections of CK-positive clusters in lymph nodes revealed atypical cells compatible with carcinoma cells. Based on 2-level CK-IHC results, SLN accuracy was 92% (47/51), with a false-negative rate of 13% (4/31). A common odds ratio test 16 that compared the percentage of positive SLNs with non-slns adjusted for case showed that carcinoma cells were significantly more likely in SLNs 676 Arch Pathol Lab Med Vol 127, June 2003 Colorectal Carcinoma Nodal Staging Turner et al

5 Table 1. Patient and Primary Tumor Characteristics* Characteristic No. of Patients Age, median (range), y 76 (41 97) Sex Male Female Location Right Transverse Left or sigmoid Rectum Tumor stage T1 T2 T3 T4 Tumor grade I II III Lymphovascular invasion 9/51 (18%) Nodal stage N0 N1 N * All data are number of patients unless otherwise indicated. Nodal stage based on standard hematoxylin-eosin examination. Table 2. Lymph Node Type Sentinel lymph nodes Identified by surgeon Identified by pathologist Total Nonsentinel lymph nodes Total lymph nodes Lymph Node Counts Per Patient Median (Range) 1 (0 4) 1 (0 12) 3 (1 13) 11 (1 42) 14 (2 45) Table 3. Sentinel Lymph Node Maximal Size Status Median (Range), cm Negative Immunohistochemical stain positive Hematoxylin-eosin stain positive 0.6 ( ) 0.6 ( ) 1.0 ( ) Table 4. Lymph Node Positivity per Patient by HE Examination Alone or With CK-IHC Analysis* Lymph Node All lymph node negative Non-SLN only positive SLN only positive Both SLN and non-sln positive HE Examination CK-IHC Analysis * HE indicates hematoxylin-eosin; CK-IHC, cytokeratin-immmunohistochemical; and SLN, sentinel lymph node. than non-slns (P.001). The odds ratio was 9.64 (95% confidence interval, ). For patients with a CK-positive SLN (n 10), 4-level immunostain positivity was recorded on an aggregate basis per patient for each level: L1-8, L2-9, L3-10, L4-10 positive. Eight (80%) of 10 patients with any CK-positive cell clusters in SLN 4-level examination had at least one CKpositive cell cluster in one SLN at level 1, and 9 (90%) of 10 were positive in levels 1 and 2. Specificity of CK-Positive Cells Adjacent sections of each SLN with CK-positive cell clusters (n 10 patients) were stained for p53, E-cadherin, and calretinin. Tumor and epithelial marker expression was observed within nodal sinuses of 5 cases: 1 expressed p53, 2 expressed E-cadherin, and 2 expressed both markers (Figures 2 through 4). In one of these cases, mesothelial marker expression (calretinin) was observed as a few benign-appearing single cells along with E-cadherin immunoreactive tumor cell clusters (Figure 4). Eight other patients had only single CK-positive cells (no clusters) cytologically indeterminate for malignancy; these cases were considered CK negative. These cases lacked coexpression of p53 and E-cadherin, and in 2 cases calretinin-positive mesothelial cells were identified (Figure 5). Colorectal adenomas lacked CK-positive cell clusters. One (8%) of 12 patients had a single CK-immunoreactive cell, which was cytologically benign; immunostains for p53, E-cadherin, and calretinin were negative. The villous adenoma from this patient demonstrated focal high-grade dysplasia but no apparent adenocarcinoma. COMMENT This report represents the early experience of multiple surgeons and pathologists with SLN staging for colorectal carcinoma. Our approach combined the surgeon s visualization in vivo and the pathologist s examination in the laboratory. Nodal dissection was accomplished within the routine workflow of our medium-sized hospital laboratory. Other investigators have used in vivo or ex vivo surgeon only 11,12,17,18 or ex vivo pathologist only methods with mixed success. Prior reports 19,20,22 24 suggest that ex vivo examination alone may be less accurate than in vivo surgeon only or combined surgeon-pathologist approaches. Our overall SLN accuracy was 92%, with a false-negative rate of 13%. Statistical analysis demonstrated that SLNs were significantly (P.001) more likely to contain tumor cells than non-slns (P. 001; odds ratio, 9.64; 95% confidence interval, ). However, further improvements in surgical techniques are under investigation to improve accuracy and facilitate general acceptance. The high sensitivity of the SLN technique places the focus on a few lymph nodes, which may help to decrease the current emphasis on the total number of mesenteric nodes examined. However, for node-positive patients, the total number of positive lymph nodes may also be an important prognostic parameter. 25,26 The small size of many of our SLNs (median maximal dimension, 0.6 cm) supports the value of the SLN technique, because some of these SLNs may not have been found in a standard dissection. Eight patients with positive SLNs had small SLNs ( cm). The major focus of this study was to evaluate the frequency and nature of CK-positive cells in SLNs and non- Arch Pathol Lab Med Vol 127, June 2003 Colorectal Carcinoma Nodal Staging Turner et al 677

6 SLNs. The SLN-negative patients had CK-positive cell clusters in 10 (29%) of 34 cases, a higher frequency of immunohistochemically detected tumor cells in SLNs than our institutional experience with breast cancer (10% 15%) 27 or melanoma (8% 10%; Roderick R. Turner, MD, unpublished data, 2000). All IHC stain positive cases represented isolated tumor cells ( 0.2 mm) 15,28 as currently defined in the AJCC system, with the largest deposit measuring 0.1 mm. However, we considered cases with rare single CK-positive cells node negative because of lack of specificity. Prior IHC and molecular studies on standard node dissections have also demonstrated that isolated tumor cells are common in mesenteric nodes of colorectal carcinoma patients, with conversion rates from 25% to 76% The common occurrence of CK-positive cells and their presence at multiple levels of SLN paraffin blocks indicate that they can be reliably identified with examination of only 1 or 2 levels of nodal paraffin blocks. If 2- level CK-IHC analysis had been performed only on SLN blocks of our HE node-negative patients, accuracy of detection of isolated tumor cell clusters would have been 96% (27/28); one patient had a CK-positive cluster identified in the SLN at level 3 of the paraffin block, and in no case did non-sln only have CK-positive clusters. The CK-positive cells identified as cell clusters in SLNs can be confidently interpreted as isolated tumor cells. Cell clusters demonstrated supportive cytologic atypia or coexpression of tumor and epithelial markers p53 and E-cadherin. 37,38 Single CK-positive cells, however, may not invariably represent carcinoma cells. Intra-abdominal lymph nodes may occasionally contain CK-positive hyperplastic mesothelial cells 39 and possibly benign epithelial cells. In 3 (9%) of 34 of our SLN-negative colorectal carcinoma patients, morphologic findings along with CK and calretinin immunoreactivity suggested that CK-positive cells represented mesothelial cells. In 1 of these 3 cases, a few carcinoma cell clusters were also identified with CK positivity and E-cadherin immunoreactivity, but in 2 cases the few single CK-positive cells appeared to represent only mesothelial cells. Further, nonneoplastic colorectal lesions may infrequently be associated with nodal CK-positive cells. 40 We found a single CK-positive cell in an SLN of 1 (8%) of 12 colorectal adenoma cases. We could not determine whether that cell represented a normal or dysplastic epithelial cell or a mesothelial cell. Because of the lack of complete specificity of CK-IHC stains in the setting of colorectal neoplasms, caution is advised in labeling single CK-positive cells as isolated tumor cells. Stricter criteria with cell clusters improves specificity. The clinical significance of CK-positive cells in mesenteric lymph nodes of colorectal carcinoma patients continues to be debated. Some studies 31,35,36 have shown significantly worse outcomes for these patients, but other studies 29,30,32 34 have not demonstrated survival differences. A few CK-positive cells in mesenteric lymph nodes may represent degenerating tumor cells incapable of implantation and metastasis or reactive mesothelial cells. Until long-term follow-up studies are available and show outcome differences, CK-IHC analysis should be considered investigational and the results used cautiously in clinical management decisions. At this time, use of CK-IHC analysis for colon cancer nodal staging should not be considered standard practice; its use outside approved research studies should be limited to confirmation of suspicious cells identified on HEstained sections. A National Cancer Institute sponsored multi-institutional trial is in progress. 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