College of American Pathologists
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  Anatomic Abstracts





January 2010

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

Evidence for a latent precursor to serous endometrial intraepithelial carcinoma Evidence for a latent precursor to serous endometrial intraepithelial carcinoma

Serous intraepithelial carcinoma and endometrial glandular dysplasia are associated with uterine serous carcinoma. A candidate serous cancer precursor containing p53 mutations (p53 signature) has been described in the fallopian tube. The authors analyzed normal and neoplastic endometrium for a similar entity. They studied 10 endometrial polyps involved by intraepithelial or invasive carcinoma, or both, and 137 benign polyps. All were stained for p53 and MIB-1. A subset of p53 signatures and carcinomas were analyzed for y-H2AX and p53 mutations. P53 signatures were identified in seven of 10 cases of intraepithelial carcinoma and were multicentric in two. In one case, the signature showed continuity with intraepithelial carcinoma. Of the 137 benign polyps (four percent), six contained p53 signatures. The MIB-1 fraction in most signatures was less than five percent and ranged from 50 percent to 90 percent in carcinomas. DNA damage (y-H2AX) was demonstrated in p53 signatures and adjacent carcinomas but not in benign polyps. Shared identical p53 mutations were found in paired signatures and carcinomas in two of three cases analyzed, including one case with multiple signatures. In one, a coexistent invasive serous cancer was not found to contain a p53 mutation. In another, a p53 signature and an invasive cancer harbored two different p53 mutations. The authors concluded that this description of p53 signatures adjacent to carcinoma suggests a role for this entity in the genesis of serous malignancy. The significance of p53 sig-natures in benign conditions remains to be determined.

Jarboe EA, Pizer ES, Miron A, et al. Evidence of latent precursor (p53 signature) that may precede serous endometrial intraepithelial carcinoma. Mod Pathol. 2009:22(3):345–350.

Correspondence. Dr. C. P. Crum at
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HPV-associated p16<sup>INK4A</sup> expression and squamous cell carcinoma of the head and neck HPV-associated p16INK4A expression and squamous cell carcinoma of the head and neck

A subset of head and neck cancers is associated with human papillomavirus. Viral infection is closely correlated with expression of p16INK4A in these tumors. The authors evaluated p16INK4A as a prognostic marker of treatment response and survival in a well-defined prospective cohort of patients treated solely with conventional radiotherapy in the Danish Head and Neck Cancer Group (DAHANCA) 5 trial. They analyzed the immunohistochemical expression of p16INK4A in pretreatment paraffin-embedded tumor blocks from 156 patients treated with conventional primary radiotherapy alone. The authors then evaluated the influence of p16INK4A status on locoregional tumor control, disease-specific survival, and overall survival after radiotherapy. The authors found p16INK4A positivity in 35 tumors (22 percent). Tumor-positivity for p16INK4A was significantly correlated with improved locoregional tumor control (five-year actuarial values, 58 versus 28 percent; P=.0005), improved disease-specific survival (72 versus 34 percent; P=.0006), and improved overall survival (62 versus 26 percent; P=.0003). In multivariate analysis, p16INK4A remained a strong independent prognostic factor for locoregional failure (hazard ratio [HR], 0.35; 95 percent confidence interval [CI], 0.19–0.64), disease-specific death (HR, 0.36; 95 percent CI, 0.20–0.64), and overall death (HR, 0.44; 95 percent CI, 0.28–0.68). The authors concluded that expression of p16INK4A has a major impact on treatment response and survival in patients with head and neck cancer treated with conventional radiotherapy.

Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol. 2009;27:1992–1998.

Correspondence: Dr. Pernille Lassen at
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Study of atypical and malignant hidradenomas Study of atypical and malignant hidradenomas

The histological features of atypical hidradenoma may signal increased risk of recurrence and possible mal-ignant potential; however, earlier studies with immunohistochemistry or patient followup have not been reported. Immunohistochemical analysis of hidradenocarcinoma is reported in the literature mainly as case reports and as a single series of six cases. The authors compared the histological features and Ki-67, phosphorylated histone H3, epidermal growth factor receptor, and HER2/neu expression profiles of 15 atypical and 15 malignant hidradenomas with those of benign hidradenoma and metastasizing adnexal carcinomas. Among the features of hidradenocarcinomas are infiltrative growth pattern, deep extension, necrosis, nuclear pleomorphism, and four or more mitoses per 10 high-power fields. A significant difference in mean Ki-67 percentage was observed between benign and malignant hidradenomas (P<.001), benign and metastasizing adnexal carcinomas (P<.002), atypical and malignant hidradenomas (P<.001), and atypical hidradenomas and metastasizing adnexal carcinomas (P<.002). A significant difference in mean phosphorylated histone H3 percentage was observed between benign and malignant hidradenomas (P<.001), benign and metastasizing adnexal carcinomas (P<.003), atypical and malignant hidradenomas (P<.001), and atypical hidradenomas and metastasizing adnexal carcinomas (P<.001). Mean epidermal growth factor receptor total score was significantly different in benign and atypical hidradenoma when compared with that for metastasizing adnexal carcinoma (P=.014 and .019, respectively). Equivocal or 2+ HER2/neu positivity was observed in one hidradenocarcinoma and two metastasizing adnexal carcinomas. Receiver operating characteristic curve analysis for Ki-67 and phosphorylated histone H3 percentage positivity revealed statistically significant criterion values of more than 11.425 and more than 0.7, respectively, for distinguishing malignant hidradenomas from atypical hidradenomas. The authors concluded that despite the presence of some worrisome histological features, atypical hidradenomas are unlikely to metastasize. A tumor with Ki-67 greater than 11 percent or phosphorylated histone H3 greater than 0.7 percent, or both, would likely be a malignant rather than an atypical hidradenoma. Infrequent HER2/neu overexpression in hidradenocarcinoma suggests its limited therapeutic role.

Nazarian RM, Kapur P, Rakheja D, et al. Atypical and malignant hidradenomas: a histological and immunohistochemical study. Mod Pathol. 2009;22:600–610.

Correspondence: Dr. M. P. Hoang at
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Sebaceous neoplasms and hereditary DNA mismatch repair deficiency Sebaceous neoplasms and hereditary DNA mismatch repair deficiency

Although sebaceous neoplasms have been linked to hereditary DNA mismatch repair deficiency, how best to utilize immunohistochemical detection of DNA mismatch repair proteins has not been established. The authors conducted a study in which they stratified a series of 27 patients with one or more sebaceous neoplasms based on the pattern of immunohistochemical expression of MLH1, MSH2, MSH6, and PMS2. They also performed a comparative analysis of clinical and pathologic characteristics, including pattern of tumor-infiltrating lymphocytes and peritumoral lymphocytic response using CD3 immunohistochemical stain. The study tissue samples included 30 sebaceous carcinomas, 14 sebaceous adenomas, and seven sebaceous hyperplasias, as well as eight concurrent nonsebaceous lesions from six patients. The authors identified abnormal staining for mismatch repair proteins in 12 of the 27 (44 percent) patients. The most common abnormality was a concurrent loss of MSH2 and MSH6 in eight of 12 patients (67 percent). Sebaceous adenomas and carcinomas occurring in the same patients showed an identical staining pattern, as did hereditary nonpolyposis colorectal cancer-related nonsebaceous tumors in the same patients. When compared with subjects who had normal expression of mismatch repair proteins, the patients with abnormal expression tended to be younger (median age, 56.5 years versus 68 years) and were more likely to have a positive family history, and the tumors were more likely to involve sites outside the head and neck (9 of 12 versus 0 of 15) and more likely to have synchronous or metachronous visceral malignancies (8 of 12 versus 3 of 15). Further-more, the intensities of tumor infiltrate of CD3-positive lymphocytes and peritumoral lymphocytic response were significantly stronger in the sebaceous tumors with abnormal expression. The aforementioned factors—age less than 60 years, involvement of sites outside the head and neck, visceral malignancy, family history that at a minimum fulfills Bethesda guidelines, and lymphocytic infiltration—were of value in predicting abnormal expression of DNA mismatch repair proteins. However, the sensitivities were only modest, being 58 percent, 75 percent, 67 percent, 78 percent, and 75 percent, respectively. Given that sebaceous neoplasms are encountered infrequently and immunohistochemistry is readily available and reasonably reliable, the authors recommended routine immunohistochemical staining for DNA mismatch repair proteins in all sebaceous neoplasms, regardless of a patient’s age or other clinical characteristics, to identify hereditary DNA mismatch repair deficiency.

Orta L, Klimstra DS, Qin J, et al. Towards identification of hereditary DNA mismatch repair deficiency: sebaceous neoplasm warrants routine immunohistochemical screening regardless of patient’s age or other clinical characteristics. Am J Surg Pathol. 2009;33(6):934–944.

Correspondence: Dr. J. Shia at
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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.