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  Anatomic Abstracts

 

 

 

 

February 2010

Editors:
Michael Cibull, MD
Melissa Kesler, MD
Rouzan Karabakhtsian, MD
Megan Zhang, MD

Confirmatory tumor biopsy and management of breast cancer patients with distant metastases Confirmatory tumor biopsy and management of breast cancer patients with distant metastases

Decisions about the systemic treatment of women with metastatic breast cancer are often based on estrogen receptor, progesterone receptor, and HER2 status of the primary tumor. The authors reported on a study to prospectively investigate concordance in receptor status between primary tumors and distant metastases and to assess the impact of discordance on patient management. For the study, biopsies of suspected metastatic lesions were obtained from patients and analyzed for estrogen receptor/progesterone receptor and HER2. Receptor status was compared for metastases and primary tumors. Questionnaires were completed by the oncologist before and after biopsy to determine whether biopsy results changed the treatment plan. Forty women were enrolled in the study; 35 of them underwent biopsy, yielding 29 samples sufficient for analysis. Three of 29 biopsies (10 per-cent) showed benign disease. Changes in hormone receptor status were observed in 40 percent (P=.003) of women, and changes in HER2 status in eight percent. Biopsy results led to a change in management for 20 percent of patients (P=.002). The authors concluded that this prospective study demonstrated the presence of substantial discordance in receptor status between primary tumors and metastases, which led to altered management in 20 percent of cases. Tissue confirmation should be considered in patients with clinical or radiological suspicion of metastatic recurrence.

Simmons C, Miller N, Geddie W, et al. Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Ann Oncol. 2009;20(9):1499–1504.

Correspondence: Dr. M. J. Clemons at mark.clemons@uhn.on.ca
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Mutation of FOXL2 in granulosa-cell tumors of the ovary Mutation of FOXL2 in granulosa-cell tumors of the ovary

Granulosa-cell tumors are the most common type of malignant ovarian sex cord-stromal tumor. The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging, and there is no curative treatment beyond surgery. The authors analyzed four adult-type granulosa-cell tumors (GCTs) using whole-transcriptome paired-end RNA sequencing. They identified putative GCT-specific mutations that were present in at least three of these samples but were absent from the transcriptomes of 11 epithelial ovarian tumors, published human genomes, and databases of single-nucleotide polymorphisms. The authors confirmed these variants by direct sequencing of complementary DNA and genomic DNA. They then analyzed additional tumors and matched normal genomic DNA using a combination of direct sequencing, analyses of restriction fragment length polymorphisms, and TaqMan assays. All four index GCTs had a missense point mutation, 402C’G (C134W), in FOXL2, a gene encoding a transcription factor known to be critical for granulosa-cell development. The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97 percent), three of 14 thecomas (21 percent), and one of 10 juvenile-type GCTs (10 percent). The mutation was absent in 49 sex cord-stromal tumors of other types and 329 unrelated ovarian or breast tumors. The authors concluded that whole-transcriptome sequencing of four GCTs identi-fied a single, recurrent somatic mutation (402C’G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs.

Shah SP, Köbel M, Senz J, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med. 2009;360(26):2719–2729.

Correspondence: Dr. D. G. Huntsman at dhuntsma@bccancer.bc.ca
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Sperm-associated antigen 9 as a biomarker for early cervical carcinoma Sperm-associated antigen 9 as a biomarker for early cervical carcinoma

Cervical cancer is the second most common malignancy in women, with nearly half a million cases diagnosed annually worldwide. Recent studies by the authors have suggested an association of the cancer testis antigen sperm-associated antigen 9 (SPAG9) in ovarian carcinomas. The authors conducted a study to evaluate the clinical utility of SPAG9 expression and humoral immune response in cervical carcinomas. They assessed SPAG9 mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ RNA hybridization. The authors also investigated SPAG9 protein expression by immunohistochemistry and analyzed its association with various stages and grades of cervical cancer in patients. And they tested the humoral immune response against SPAG9 in cervical cancer patients. The authors found that RT-PCR, in situ RNA hybridization, and im-munohistochemical analyses revealed that SPAG9 expression was significantly associated with tumor grade in 82 percent of early stage cervical cancer specimens. SPAG9 antibodies were detected in approximately 80 percent of cervical cancer patients but not in healthy control subjects. Statistical analysis revealed that a significant proportion of early stage cancer patients with a high SPAG9 immunoreactivity score exhibited significantly higher antibody response against SPAG9 compared with those who had moderate SPAG9 immunoreactivity scores, suggesting a close relationship between SPAG9 protein expression and humoral immune response. The authors concluded that in early stage cervical cancer, a substantial number of patients exhibited SPAG9 expression and generated SPAG9 antibodies, supporting a potential role for SPAG9 in detecting and diagnosing cervical cancer in the early stages. Furthermore, these findings provide leads for the future development of noninvasive serologic biomarkers for early detection, diagnosis, and treatment of cervical cancer.

Garg M, Kanojia D, Salhan S, et al. Sperm-associated antigen 9 is a biomarker for early cervical carcinoma. Cancer. 2009;115:2671–2683.

Correspondence: Dr. Anil Suri at anil@nil.res.in
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Selecting gross sampling methods for radical prostatectomy specimens Selecting gross sampling methods for radical prostatectomy specimens

Widespread use of the serum prostate-specific antigen test has increased the early detection of prostate cancer and, consequently, reduced grossly definable prostate cancers. The authors conducted a study to find the most efficient gross sampling method for radical prostatectomy specimens, which would preserve important prognostic factors and be cost-effective. The authors initially analyzed clinicopathologic features of entire prostate sections from 148 radical prostatectomy specimens, which then were used to examine the impact of five partial sampling methods on tumor stage, Gleason score, extraprostatic extension, resection margin status, and paraffin block numbers. The methods included submission of alternative slices, alternative slices plus biopsy-positive posterior quarters, every posterior half, every posterior half plus one midanterior half, and alternative slices plus the peripheral 3-mm rim of the remaining prostate. The authors found that the prostate cancers and their extraprostatic extension and resection margin involvement were commonly located in the right posterior portion of the prostate. The method that involved alternative slices plus the peripheral 3-mm rim of the remaining prostate was most efficient. It detected all cases with extraprostatic extension and resection margin involvement and reduced 25 percent of paraffin blocks compared with the entire sampling of the prostate. Gleason scores were retained in most of the cases, except two (one percent), which had reversal of the primary and secondary Gleason grade component. Four cases (three percent) were downstaged within the same T2 stage. The authors concluded that these results demonstrate that sampling of alternative slices plus the peripheral rim of the remaining prostate is the most efficient partial sampling method for radical prostatectomy specimens.

Kim K, Pak PJ, Ro JY, et al. Limited sampling of radical prostatectomy specimens with excellent preservation of prognostic parameters of prostate cancer. Arch Pathol Lab Med. 2009;133(8):1278–1284.

Correspondence: Dr. Yong Mee Cho at yongcho@amc.seoul.kr
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Role of cytomorphology and proliferative activity in predicting behavior of pancreatic neuroendocrine tumors Role of cytomorphology and proliferative activity in predicting behavior of pancreatic neuroendocrine tumors

The biologic behavior of pancreatic neuroendocrine tumors is difficult to predict in the absence of metastases or invasion into adjacent organs. The authors retrospectively evaluated the cytopathology and proliferative activity in cytology specimens obtained by endoscopic ultrasound-guided fine-needle aspiration (FNA). They retrospectively studied, between 2002 and 2007, 35 patients who were diagnosed with pancreatic neuroendocrine tumors based on endoscopic ultrasound-guided FNA. They reviewed cytopathology and proliferative activity (Ki-67) in cytology specimens. Patients were divided into two groups: group A, which was made up of patients with simultaneous, suspicious, metastatic masses (unresectable tumors), and group B, which was made up of patients with a final histopathologic diagnosis. The patients in group B were further classified into four risk sub-groups according to the 2004 World Health Organization (WHO) classification—subgroups 1a, 1b, 2, and 3. Thirteen of 35 patients who were diag-nosed with unequivocally malignant tumors were placed in group A, and 22 of 35 patients were placed in group B. In group A, more than two percent of Ki-67–positive cells were present in 12 of 13 patients (92.3 percent). In group B, more than two percent of Ki-67–positive cells were present in zero of six patients in WHO subgroup 1a, three of seven patients in WHO subgroup 1b (42.86 percent), seven of seven patients in WHO subgroup two (100 percent), and two of two patients in WHO subgroup three (100 percent). The authors observed nuclear pleomorphism/multinucleation in eight of 13 patients in group A (61.53 percent). They observed nuclear pleomorphism/multinucleation in four of seven patients in WHO subgroup two (57.14 percent) and in two of two patients in WHO subgroup three (100 percent). In group A, nucleoli were present in seven of 13 patients (53.85 percent); whereas, in group B, nucleoli were present in six of seven patients in WHO subgroup two (85.7 percent) and in two of two patients in WHO subgroup three (100 percent). None of the remaining cytologic features that were evaluated—necrosis, mitoses, spindle cells, and molding/crush artifact—were observed consistently in malignant neuroendocrine tumors. The results indicate that Ki-67 evaluation in routine endoscopic ultrasound-guided FNA cytology specimens can be used as a potential prognostic marker in pancreatic neuroendocrine tumors. Nuclear pleomorphism/multinucleation and the presence of nucleoli also are reliable for predicting malignant pancreatic neuroendocrine tumors.

Chatzipantelis P, Konstantinou P, Kaklamanos M, et al. The role of cytomorphology and proliferative activity in predicting biologic behavior of pancreatic neuroendocrine tumors: a study by endoscopic ultrasound-guided fine-needle aspiration cytology. Cancer Cytopathol. 2009;117(3):211–216.

orrespondence: Dr. Paschalis Chatzipantelis at pchatzipantelis@yahoo.com
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Use of p16 expression to differentiate between desmoplastic Spitz nevi and desmoplastic melanomas Use of p16 expression to differentiate between desmoplastic Spitz nevi and desmoplastic melanomas

Desmoplastic melanoma is a spindle-cell malignant neoplasm with malignant cells found between collagen boundless and fibrotic stroma. It is sometimes difficult to distinguish it from desmoplastic Spitz nevi on hematoxylin-and-eosin-stained sections. P16 protein is a product of the CDKN2A gene. Its loss of expression has been reported in invasive and metastatic melanomas. The authors conducted a study in which they immunohistochemically evaluated 15 cases of desmoplastic nevi and 11 cases of desmoplastic melanomas using p16 staining. They also performed immu-nostaining for nestin, a neural stem cell marker. The result showed that all 15 (100 percent) desmoplastic Spitz nevi were moderately and strongly positive for p16, while only two (18.2 percent) desmoplastic melanomas were weakly stained for p16. Complete loss of p16 expression was noted in nine of 11 (81.8 percent) cases of desmoplastic melanomas. The nestin staining was nondiscriminative and expressed in all desmoplastic Spitz nevi and all desmoplastic melanomas. The authors concluded that p16 immunohistochemical staining in conjunction with other tools, such as S100 staining and Ki67 proliferation index, may help distinguish these two entities in difficult cases. Nestin staining does not differentiate desmoplastic Spitz nevi from desmoplastic melanomas.

Hilliard NJ, Krahl D, Sellheyer K. P16 expression differentiates between desmoplastic Spitz nevus and desmoplastic melanoma. J Cutan Pathol. 2009;36(7):753–759.

Correspondence: Dr. Klaus Sellheyer at ksellheyer@uab.edu
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SLN biopsy and completion axillary lymph node dissection for node-positive breast cancer SLN biopsy and completion axillary lymph node dissection for node-positive breast cancer

The medical community has questioned the role of completion axillary lymph node dissection after identification of nodal metastases by sentinel lymph node biopsy in women with breast cancer. The authors conducted a study to assess national nodal evaluation practice patterns and examine differences in recurrence and survival for sentinel lymph node biopsy (SLNB) alone versus SLNB with completion axillary lymph node dissection (ALND). The authors identified from the National Cancer Data Base (1998 to 2005) women with clinically node-negative breast cancer who underwent SLNB and who had nodal metastases. They examined practice patterns and outcomes for patients who underwent SLNB alone versus SLNB with completion ALND (median followup, 63 months). Of 97,314 patients, 20.8 percent underwent SLNB alone and 79.2 percent underwent SLNB with completion ALND. In 2004 and 2005, patients were significantly more likely to undergo SLNB alone if they were older, had smaller tumors, or were treated at non-National Cancer Institute-designated cancer centers. The authors found that in patients with macroscopic nodal metastases (n=20,075 during 1998 to 2000), there was a nonsignificant trend toward better outcomes for completion ALND versus SLNB alone after analysis was adjusted for differences between the two groups: axillary recurrence (hazard ratio [HR], 0.58; 95 percent confidence interval [CI], 0.32–1.06) and overall survival (HR, 0.89; 95 percent CI, 0.76–1.04). In patients with microscopic nodal metastases (n=2,203 from 1998 to 2000), there were no significant differences in axillary recurrence or survival for patients who underwent SLNB alone versus completion ALND. The authors concluded that compared with SLNB alone, completion ALND does not appear to improve outcomes for breast cancer patients with microscopic nodal metastases. However, there was a nonsignificant trend toward better outcomes with completion ALND for those with macroscopic disease.

Bilimoria KY, Bentrem DJ, Hansen NM, et al. Comparison of sentinel lymph node biopsy alone and completion axillary lymph node dissection for node-positive breast cancer. J Clin Oncol. 2009;27(18):2946–2953.

Correspondence: David P. Winchester at dwinchester@facs.org
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Anatomic pathology abstracts editors: Michael Cibull, MD, professor and vice chair, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington; Melissa Kesler, MD, and Rouzan Karabakhtsian, MD, assistant professors of pathology and laboratory medicine, University of Kentucky College of Medicine; and Megan Zhang, MD, visiting fellow, Division of Dermatopathology, University of California, San Francisco.