Retrospective and observational analyses suggest that occult lymph-node metastases are an important prognostic factor for disease recurrence and survival among patients with breast cancer. Prospective data on clinical outcomes from randomized trials with respect to sentinel-node involvement have been lacking. The authors conducted a study in which they randomly assigned women with breast cancer to sentinel lymph-node biopsy plus axillary dissection or sentinel lymph-node biopsy alone. Paraffin-embedded tissue blocks of sentinel lymph nodes obtained from patients with pathologically negative sentinel lymph nodes were centrally evaluated for occult metastases deeper in the blocks. Routine staining and immunohistochemical staining for cytokeratin were used at two widely spaced additional tissue levels. Treating physicians were unaware of the findings, which were not used for clinical treatment decisions. The initial evaluation at participating sites was designed to detect all macrometastases larger than 2 mm in greatest dimension. The authors found that occult metastases were detected in 15.9 percent (95 percent confidence interval [CI], 14.7–17.1) of 3,887 patients. Log-rank tests indicated a significant difference between patients in whom occult metastases were detected and those in whom no occult metastases were detected with respect to overall survival (P=0.03), disease-free survival (P=0.02), and distant disease-free interval (P=0.04). The corresponding adjusted hazard ratios for death, any outcome event, and distant disease were 1.40 (95 percent CI, 1.05–1.86), 1.31 (95 percent CI, 1.07–1.60), and 1.30 (95 percent CI, 1.02–1.66), respectively. Five-year Kaplan-Meier estimates of overall survival among patients in whom occult metastases were detected and those without detectable metastases were 94.6 percent and 95.8 percent, respectively. The authors concluded that occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination. However, the magnitude of the difference in outcome at five years was small (1.2 percentage points). These data do not indicate that additional evaluation, including immunohistochemical analysis, of initially negative sentinel nodes in patients with breast cancer is of clinical benefit.
Weaver DL, Ashikaga T, Krag DN, et al. Effect of occult metastases on survival in node-negative breast cancer. N Engl J Med. 2011;364:412–421.
Correspondence: Dr. D. L. Weaver at firstname.lastname@example.org
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Oncotype DX is a reverse transcriptase polymerase chain reaction-based assay for predicting chemotherapy benefit in patients with estrogen receptor-positive breast cancers. The authors were interested in determining if pathologic parameters that were routinely available could predict Oncotype DX recurrence scores in subsets of patients. They identified 173 breast cancers with available recurrence scores and used 104 of those as a test set and 69 cases as a validation set. Pathologic characteristics, including size, histologic type, Nottingham grade, and lymphatic invasion were recorded. Test set cases were stained for estrogen receptor, progesterone receptor, HER2, Ki67, cyclin D1, BCL2, D2-40, and p53. Statistical correlations with recurrence score and regression tree analysis were performed. The validation set was subjected to analysis on the basis of grade, progesterone receptor, and Ki67. In the test set, grade, progesterone receptor levels, and Ki67 had the strongest correlation with recurrence score (P=0.0002–0.0007). Regression tree analysis showed grade and progesterone receptor as factors that could segregate cases into recurrence score categories, with Ki67 adding value in certain subsets. A subset of cancers with a high likelihood of having a low recurrence score (0–18) was identified with the following characteristics: grade 1, strong progesterone receptor expression (Allred score, five or more), and Ki67 of 10 percent or less. No cases with these characteristics had a high recurrence score (31 or more), and 73 percent had a low recurrence score. Cancers likely to have a high recurrence score were grade 3, low to absent progesterone receptor expression (Allred score, less than five), and Ki67 greater than 10 percent. Eighty percent of cases with these characteristics had a high recurrence score, and no cases had a low score. The authors’ validation set had similar findings in these two subsets. The authors concluded that when cost and time are a consideration and the added value of Oncotype DX testing is in question, it may be reasonable to assume the results of this test in two specific subsets of breast cancers: grade 1, high progesterone receptor, low Ki67 cancers (low recurrence score), and grade 3, low progesterone receptor, high Ki67 cancers (high recurrence score).
Allison KH, Kandalaft PL, Sitlani CM, et al. Routine pathologic parameters can predict Oncotype DX recurrence scores in subsets of ER positive patients: who does not always need testing? [published online ahead of print March 3, 2011]. Breast Cancer Res Treat. 2011;March 3. doi:10.1007/S10549-011-1416-3.
Correspondence: K. H. Allison at email@example.com
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Lichen sclerosus is considered a precursor lesion of vulvar squamous cell carcinoma, of which only two percent to five percent progress to squamous cell carcinoma. Differentiated vulvar intraepithelial neoplasia (VIN) has been proposed to be the direct precursor lesion, but it has only recently been recognized and is difficult to diagnose. It can also easily be mistaken for a benign dermatosis. The authors tested the hypothesis that some lesions that had been previously diagnosed as lichen sclerosus might now be diagnosed as differentiated VIN. They also sought to identify histopathological differences between lichen sclerosus lesions with and without progression to vulvar squamous cell carcinoma. For the authors’ analysis, two expert gynecopathologists reviewed all lichen sclerosus slides and documented histopathological characteristics. After reviewing lichen sclerosus biopsies without progression (n=61), the experts reclassified 58 as lichen sclerosus. Review of lichen sclerosus biopsies with progression yielded concordant diagnoses in 18 of 60 cases (30 percent). Of 60 lesions, 25 (42 percent) were reclassified as differentiated VIN. The median time from differentiated VIN to vulvar squamous cell carcinoma was shorter (28 months) than that from lichen sclerosus to vulvar squamous cell carcinoma (84 months; P<0.001). The authors found that lichen sclerosus that progressed to squamous cell carcinoma, but that did not meet the criteria for differentiated VIN, more often showed parakeratosis (P=0.004), dyskeratosis (P<0.001), hyperplasia (P=0.048), and basal cellular atypia (P=0.009) compared with lichen sclerosus without progression. The authors concluded that differentiated VIN diagnoses frequently have been missed and are associated with rapid progression to squamous cell carcinoma. Patients with lichen sclerosus with dyskeratosis and parakeratosis, hyperplasia, and/or basal cellular atypia should be kept under close surveillance as these lesions also tend to progress to squamous cell carcinoma.
Van de Nieuwenhof HP, Bulten J, Hollema H, et al. Differentiated vulvar intraepithelial neoplasia is often found in lesions, previously diagnosed as lichen sclerosus, which have progressed to vulvar squamous cell carcinoma. Mod Pathol. 2011;24:297–305.
Correspondence: Dr. H. P. van de Nieuwenhof at firstname.lastname@example.org
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Cellular angiofibroma represents a rare benign mesenchymal tumor that occurs primarily in the superficial soft tissue of the genital region. The authors believe that involvement of 13q14 in some cases confirmed the morphological suggested link with spindle cell lipoma and mammary-type myofibroblastoma. The authors analyzed the clinicopathological and immunohistochemical features of 25 cases and, in a number of cases, performed additional molecular studies. The cases were 17 female and eight male patients (age, 27 to 83 years); females tended to be younger. The authors observed a marked predilection for the vulva (n=13). They also noted that neoplasms in males were predominantly located in the inguinal region (n=4), with one case each in the scrotum, perianal area, knee, and upper eyelid. The tumors typically arose in the superficial soft tissue and were well circumscribed in all but two cases. Tumor size ranged from 1 to 9 cm. All lesions were composed of spindle-shaped cells associated with numerous small- to medium-sized blood vessels. However, a broad morphological variation with foci of lipogenic differentiation in nine cases and sarcomatous transformation in one case was found. Using immunohistochemistry, 11 of 22 cases expressed CD34. A focal reaction for α-smooth muscle actin was observed in nine of 22 cases, and two cases each stained weakly and focally positive for epithelial membrane antigen and CD99. In all seven cases tested, a monoallelic deletion of RB1 was detected by fluorescence in situ hybridization analysis. Followup, available in 14 patients, showed neither local recurrence nor metastasis. The authors concluded that their study affirms the link between cellular angiofibroma, spindle cell lipoma, and mammary-type myofibroblastoma, showing a spectrum of one entity with morphological variations dependent on anatomic location.
Flucke U, van Krieken JH, Mentzel T. Cellular angiofibroma: analysis of 25 cases emphasizing its relationship to spindle cell lipoma and mammary-type myofibroblastoma. Mod Pathol. 2011;24:82–89.
Correspondence: Dr. U. Flucke at email@example.com
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PAX (paired box) genes encode a family of transcription factors that regulate organogenesis in a variety of organs. Very little is known about the role of PAX8 in endocrine cell development and the expression of PAX8 in neuroendocrine tumors. The authors conducted a study to analyze PAX8 immunohistochemical expression in gastroenteropancreatic and pulmonary well-differentiated neuroendocrine tumors in order to determine whether PAX8 can reliably distinguish pancreatic neuroendocrine tumors from neuroendocrine tumors of other anatomic sites and other pancreatic nonductal neoplasms. For the study, they evaluated 221 well-differentiated neuroendocrine tumors: 174 primary neuroendocrine tumors (66 pancreatic, 31 ileal, 21 pulmonary, 20 gastric, 17 rectal, 11 appendiceal, and 8 duodenal) and 47 neuroendocrine tumors metastatic to the liver (31 pancreatic, 11 ileal, 2 pulmonary, 2 duodenal, and 1 rectal). They also evaluated 15 solid-pseudopapillary neoplasms and six acinar cell carcinomas of the pancreas. PAX8 was positive in 49 of 66 (74 percent) primary pancreatic neuroendocrine tumors. PAX8 expression did not correlate with World Health Organization categorization, grade, size, functional status, or the presence of liver or lymph node metastasis. PAX8 expression was not identified in any of 31 ileal or any of 21 pulmonary tumors. It was identified in two of 20 (10 percent) gastric, five of 17 (29 percent) rectal, one of 11 (nine percent) appendiceal, and six of eight (75 percent) duodenal neuroendocrine tumors. PAX8 was positive in four of 15 (27 percent) solid-pseudopapillary neoplasms of the pancreas, whereas all acinar cell carcinomas (zero of six) lacked immunoreactivity. Among liver metastases, only pancreatic neuroendocrine tumors (20 of 31; 65 percent) were PAX8 positive, whereas no ileal (zero of 11), pulmonary (zero of two), duodenal (zero of two), or rectal (zero of one) neuroendocrine tumor metastases were PAX8 positive. The authors concluded that PAX8 is expressed in primary and metastatic pancreatic well-differentiated neuroendocrine tumors, and its expression can reliably distinguish pancreatic from ileal and pulmonary well-differentiated neuroendocrine tumors. Duodenal neuroendocrine tumors and a subset of rectal, gastric, and appendiceal neuroendocrine tumors may also express PAX8. PAX8 expression can distinguish pancreatic neuroendocrine tumors from acinar cell carcinomas, but it has limited utility in distinguishing neuroendocrine tumors from solid-pseudopapillary neoplasms.
Sangoi AR, Ohgami RS, Pai RK, et al. PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma. Mod Pathol. 2011;24:412–424.
Correspondence: Dr. Reetesh K. Pai at firstname.lastname@example.org
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Assessing the biological potential of smooth muscle tumors can be difficult and depends primarily on tumor site, stage, and histologic parameters. The authors conducted a study in which they examined the clinicopathologic and immunohistochemical features of 55 noncutaneous inguinal smooth muscle tumors of women (age range, 20 to 82 years; median, 57 years). Histologically, 23 tumors were considered to be leiomyomas. They showed low mitotic activity (range, zero to six mitoses per 10 high-power fields without atypical mitotic figures), minimal cytologic atypia, and absence of coagulative necrosis. Fifteen of the tumors resembled conventional uterine leiomyomas from a histological perspective, and eight resembled their variants: lipoleiomyomas (n=2) and epithelioid variants (n=6). The mean size of the tumors was 7.8 cm, and half of those with a specified location arose in association with the round ligament. Immunohistochemical expression of estrogen receptor or Wilms tumor protein (WT1), or both, was detected in most cases (83 percent), supporting Mullerian derivation. Followup data (range, 10 to 29 years; median, 13 years) for 11 patients showed that all were alive without disease or death from unrelated causes. The second group, classified as leiomyosarcomas, consisted of 32 mitotically active smooth muscle tumors, almost invariably with atypical mitotic figures and exhibiting significant cytologic atypia. These patients were older than those with leiomyomas, and their tumors were mostly subcutaneous, with a mean tumor size of 5.4 cm. Two leiomyosarcomas showed a femoral vein origin, but none were associated with the round ligament. All but three leiomyosarcomas were negative for estrogen receptor. Followup data on 13 patients (range, two months to 30 years; median, 4.5 years) showed that five died of metastatic sarcoma. Six individuals were alive without disease (median, 16 years) and two died of unrelated causes. The authors concluded that inguinal smooth muscle tumors in women are a dichotomous group. They consist of estrogen receptor/WT1-positive Mullerian-type leiomyomas resembling uterine leiomyomas with an excellent prognosis and conventional leiomyosarcomas that are usually estrogen receptor/WT1 negative and show a variable malignant course. Separating these two categories is important for prognostication and optimal patient management and is aided by immunohistochemical studies of estrogen receptor and WT1.
Patil DT, Laskin WB, Fetsch JF, et al. Inguinal smooth muscle tumors in women—a dichotomous group consisting of Mullerian-type leiomyomas and soft tissue leiomyosarcomas: An analysis of 55 cases. Am J Surg Pathol. 2011;35:315–324.
Correspondence: Dr. M. Miettinen at email@example.com
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