Anatomic Abstracts

September 2005

Editors:
Michael Cibull, MD
Subodh Lele, MD
Melissa Kesler, MD

Cetuximab-based therapy in select colorectal cancer patients with tumors
Lymph node-negative breast carcinoma with sentinel lymph node micrometastases detected by IHC
Indication for follow-up surgical excision in breast core needle biopsies
Histologic analysis of Spitz nevi and atypical Spitz nevi/tumors
Lymph node evaluation for colorectal cancer: a population-based study

Cetuximab-based therapy in select colorectal cancer patients with tumors

The authors conducted a study to establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC). The authors reviewed pharmacy computer records to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first three months cetuximab was commercially available. They then reviewed the medical records of these patients to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. A reference pathologist reviewed pathology slides from these patients to confirm EGFR negativity, and a reference radiologist reviewed computed tomography scans during cetuximab-based therapy. Response rates were reported using criteria of the World Health Organization. Sixteen chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting were identified. Fourteen of these patients received cetuximab plus irinotecan, and two received cetuximab monotherapy. In the 16 patients, four major objective responses were seen (response rate, 25 percent; 95 percent confidence interval, four percent to 46 percent). The authors concluded that colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by IHC techniques does not seem to have predictive value, and selecting or excluding patients for cetuximab therapy based on available EGFR IHC does not seem warranted.

Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol. 2005;23(9):1803-1810.

Reprints: Dr. Ki Young Chung, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, H-816, New York, NY 10021; chungk@mskcc.org

Lymph node-negative breast carcinoma with sentinel lymph node micrometastases detected by IHC

The best way to pathologically assess sentinel lymph nodes in patients with breast carcinoma remains controversial. The authors evaluated how detailed assessment of sentinel lymph nodes (SLNs) using immunohistochemistry (IHC) and serial sectioning would affect treatment decisions and outcomes in patients with breast carcinoma who had negative SLNs on standard hematoxylin-and-eosin staining. The SLNs from patients who were treated between June 1998 and June 1999 and who had negative lymph node status determined by hematoxylin-and-eosin staining (n=84 patients) were evaluated further with serial sectioning and cytokeratin IHC. Patients were offered adjuvant therapy based on primary tumor factors. The median patient age was 57 years, and the median tumor size was 1.2 cm. At a median followup of 40.2 months, 81 patients were alive with no evidence of disease, one patient was alive with disease, one patient had died of disease, and one patient had died of other causes. Fifteen patients had micrometastases identified on IHC. Of the 84 patients, information regarding adjuvant therapy was not available for five patients. Of the remaining 79 patients, 10 patients were not offered adjuvant chemotherapy but had positive SLN status determined by IHC. SLN status based on IHC evaluation did not correlate with age (P=0.077), tumor size (P=0.717), grade (P=0.148), estrogen receptor status (P=1.000), or lymphovascular invasion (P=0.274). Furthermore, IHC-detected positive SLN status did not correlate with distant metastasis (P=0.372) or overall or distant metastasis-free survival (P=0.543 and P=0.540, respectively). Although the finding of SLN micrometastases by IHC may change management in more than 12 percent of patients, preliminary results suggest that such micrometastases do not significantly affect outcomes.

Chagpar A, Middleton LP, Sahin AA, et al. Clinical outcome of patients with lymph node-negative breast carcinoma who have sentinel lymph node micrometastases detected by immunohistochemistry. Cancer. 2005;103:1581-1586.

Reprints: Dr. Kelly K. Hunt, Dept. of Surgical Oncology, Unit 444, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; khunt@mdanderson.org

Indication for follow-up surgical excision in breast core needle biopsies

Atypical lobular hyperplasia and lobular carcinoma in situ diagnosed in core needle biopsy are generally regarded as risk indicators for developing invasive ductal or lobular carcinoma in either breast. No well-established guidelines exist for managing these patients. The most common management options are careful observation and endocrine chemoprophylaxis for high-risk patients. Previous studies had contradicting recommendations regarding follow-up surgical excision of core needle biopsy yielding atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS). These studies have been limited by their retrospective nature, small number of patients examined, and association with other high-risk lesions. Only core needle biopsy diagnosed as pure LCIS or ALH (not associated with other high-risk lesions, such as atypical ductal hyperplasia, radial scar, or papilloma) were included in the study. The authors reviewed 33 core needle biopsies (20 ALH and 13 LCIS) with subsequent follow-up surgical excision from 33 patients (age range, 30 to 83 years; mean, 58 years). Eighteen of these patients were prospectively analyzed, where follow-up surgical excision was performed in an unselected fashion. All core needle biopsies were obtained by mammotome (11-gauge, 30 cases; 14-gauge, three cases). Mammography identified calcifications in 29 cases (88 percent) and a mass in four cases (12 percent). Follow-up surgical excision revealed infiltrating ductal or lobular carcinoma, or both, in four of 13 LCIS (31 percent). Follow-up surgical excision of 20 ALH revealed cancer in five cases (25 percent), including four ductal carcinoma in situ (DCIS) and one invasive lobular carcinoma. Seven of these nine cancers were associated with calcifications and two presented as masses. Sampling error and underestimation of cancer (DCIS or invasive carcinoma) was associated with core needle biopsy diagnosis of LCIS or ALH in 27 percent of all cases. Underestimation of cancer was seen in 28 percent of prospectively examined patients, including 20 percent of ALH and 38 percent of LCIS. Core needle biopsy associated with mass lesions or that showed histologic features of pleomorphic LCIS or extensive classic LCIS had a higher rate of cancer underestimation. Despite removal of all abnormal mammographic calcifications by core needle biopsy in six patients, one cancer was detected on follow-up surgical excision. The authors' data strongly suggest that subsequent follow-up surgical excision is warranted in all patients with core needle biopsy diagnoses of LCIS or ALH to exclude the presence of cancer.

Elsheikh TM, Silverman JF. Follow-up surgical excision is indicated when breast core needle biopsies show atypical lobular hyperplasia or lobular carcinoma in situ: a correlative study of 33 patients with review of the literature. Am J Surg Pathol. 2005;29:534-543.

Reprints: Dr. Tarik M. Elsheikh, Pathologists Associated/ Ball Memorial Hospital, 2401 University Ave., Muncie, IN 47303; elsheikht@palab.com

Histologic analysis of Spitz nevi and atypical Spitz nevi/tumors

A subset of Spitz nevi poses substantial diagnostic difficulty, even among experts, due to its resemblance to malignant melanoma. There is a lack of objective criteria for predicting the biologic behavior of these lesions, termed atypical Spitz nevi/tumors. The authors compared the expression of Ki-67, p21, and fatty acid synthase by immunohistochemistry in 10 atypical Spitz nevi, 28 typical Spitz nevi, 19 compound melanocytic nevi, and 18 invasive malignant melanomas. They found a progressive increase in fatty acid synthase cytoplasmic expression with statistically significant differences observed between Spitz nevi and atypical Spitz nevi (P=0.003) and between atypical Spitz nevi and malignant melanoma (P<0.050). Ki-67 nuclear staining was lower in typical and atypical forms of Spitz lesions than in malignant melanoma (P<0.001). The degree of p21 nuclear expression in atypical Spitz nevi was not significantly different than in Spitz nevi but was significantly greater than expression in conventional nevi and approached significance after multiple comparisons corrections for malignant melanoma. Therefore, a high level of p21 expression makes a tumor more likely to be a typical or atypical Spitz nevus than a malignant melanoma, especially when coupled with a low Ki-67 index and weak expression of fatty acid synthase. These immunohistochemical observations support the concept that atypical Spitz nevi are distinct lesions of borderline biologic behavior residing between Spitz nevi and malignant melanoma. The study also compared a large array of histologic features of 16 cases of typical Spitz nevi in children with 12 typical Spitz nevi in adults. The authors found that the adult lesions were significantly more likely to be intradermal and to display dermal fibroplasia but were histologically similar to their pediatric counterparts in all other respects.

Kapur P, Selim MA, Roy LC, et al. Spitz nevi and atypical Spitz nevi/tumors: a histologic and immunohistochemical analysis. Mod Pathol. 2005:18;197-204.

Reprints: Dr. M.P. Hoang, Dept. of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9073

Lymph node evaluation for colorectal cancer: a population-based study

Adequate lymph node evaluation is required for proper staging of colorectal cancer, and the number of lymph nodes examined is associated with survival. Current guidelines recommend that a minimum of 12 lymph nodes be examined to ensure adequate sampling. The authors used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program to determine the proportion of colorectal cancer patients in the United States who receive adequate lymph node evaluation. The authors evaluated 116,995 adults with colorectal adenocarcinoma diagnosed from 1988 through 2001 who underwent radical surgery and did not receive neoadjuvant radiation. They assessed the number of lymph nodes, likelihood of receiving adequate lymph node evaluation—that is, at least 12 lymph nodes examined, and influence of tumor and patient factors on lymph node evaluation. All statistical tests were two-sided. Among all patients, the median number of lymph nodes examined was nine. Only 37 percent of patients received adequate lymph node evaluation. The proportion of patients receiving adequate evaluation increased from 32 percent in 1988 to 44 percent in 2001 (P_trend<.001, Cochran-Armitage test). Advanced tumor stage was statistically significantly associated with adequate lymph node evaluation (odds ratio [OR] of receiving adequate lymph node evaluation, 2.27; 95 percent confidence interval [CI], 2.18 to 2.35). Patients who were 71 years or older (OR, 0.45; 95 percent CI, 0.44 to 0.47) were less likely to receive adequate lymph node evaluation than younger patients, and those with left-sided (OR, 0.45; 95 percent CI, 0.44 to 0.47) or rectal (OR, 0.52; 95 percent CI, 0.50 to 0.54) cancers were less likely to receive adequate lymph node evaluation than patients with right-sided cancers. In all analyses, geographic location was an important predictor of adequate lymph node evaluation, which ranged from 33 percent to 53 percent depending on geographic location. The authors concluded that in 2001, the majority of patients with colorectal cancer still received inadequate lymph node evaluation. The association of demographic variables, particularly patient age and geographic location, with adequate lymph node evaluation indicates that local surgical and pathology practice patterns may affect the adequacy of lymph node evaluation.

Baxter NN, Virnig DJ, Rothenberger DA, et al. Lymph node evaluation in colorectal cancer patients: a population-based study. J Natl Cancer Inst. 2005;97(3):219-225.

Reprints: Dr. Nancy Baxter, MMC 450, Division of Surgical Oncology, Dept. of Surgery, University of Minnesota, 420 Delaware St. SE, Minneapolis, MN 55455; baxte025@umn.edu