Teri A. Longacre

Mixed hyperplastic adenomatous polyps/serrated adenomas : a distinct form of colorectal neoplasia

We present the clinicopathologic characteristics of 110 colorectal mixed hyperplastic adenomatous polyps (MHAP) that exhibited the architectural but not the cytologic features of a hyperplastic polyp. They are compared with 60 traditional adenomas, 40 hyperplastic polyps, and five colonic polyps that contained admixed but well-defined hyperplastic and adenomatous glands (HP/AD). The patients with MHAP ranged in age from 15 to 88 years (mean, 63 years). Five patients had two or more (up to seven) lesions. MHAP measured 0.2–7.5 cm in diameter. They were distributed throughout the colorectum, but a slight preponderance of large lesions (more than 1.0 cm) occurred in the cecum and appendix. All MHAP were characterized by a serrated glandular pattern simulating that seen in hyperplasia (27% of MHAP were initially diagnosed as hyperplastic polyps). However, MHAP were distinguished by the presence of goblet cell immaturity, upper zone mitoses, prominence of nucleoli, and the absence of a thickened collagen table. Although surface mitotic activity, nuclear pseudostratification, and nuclear cytoplasmic ratio were greater in MHAP than in hyperplastic polyps, they were slightly less than in traditional adenomas. Thirty-seven percent of MHAP contained foci of significant dysplasia; 11% contained areas of intramucosal carcinoma. We conclude that these lesions reflect a morphologically unique variant of adenoma and suggest that they be termed “serrated adenoma” in order to emphasize their neoplastic nature. We further offer the hypothesis that MHAP may arise from the neoplastic transformation of a more differentiated cell in the crypt than the traditional adenoma.

Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers

To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan–Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III–IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I–II (74, 82, and 86%; P<0.0001) and stage III–IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients.

A Correlative Morphologic Study of Human Breast and Endometrium in the Menstrual Cycle

Seventy-five premenopausal women autopsied under medical examiner auspices were selected for a correlative study of breast and endometrial morphology proceeding through the menstrual cycle. Criteria for selection included adequate preservation of the endometrial and breast tissue, relatively even distribution of women by age (range 15-56), menstrual cycle date, and parity status. Hormonal therapy and disease states that might influence pituitary-ovarian cycling were reasons for exclusion from the study. Proliferative phase breast was characterized by small lobules with few terminal duct structures. Terminal duct epithelial mitoses were uncommon. Intralobular stroma was condensed and continuous with interlobular stroma. Secretory phase breasts were characterized by increasing size of lobules and number of terminal duct structures and duct epithelial basal vacuolization and mitoses. Intralobular stroma became increasingly loose and edematous. Stromal lymphocytic population increased toward the end of secretory phase. Perimenstrual breasts underwent lobular contraction with necrosis and sloughing of duct epithelium. There was a concomitant marked increase in lobular stromal lymphocytic infiltrate and metachromasia. These features heralded a return to the proliferative phase appearance. These marked cyclical changes have implications for routine pathologic diagnosis as well as for the newer noninvasive diagnostic techniques.

Ovarian Serous Tumors of Low Malignant Potential (Borderline Tumors): Outcome-Based Study of 276 Patients With Long-Term (???5-Year) Follow-Up

The natural history, classification, and nomenclature of ovarian serous tumors of low malignant potential (S-LMP) (serous tumors of borderline malignancy, atypical proliferating tumors) are controversial. To determine long-term outcome for patients with S-LMP and further evaluate whether S-LMP can be stratified into clinically benign and malignant groups, the clinicopathologic features of 276 patients with S-LMP and ≥5 year follow-up were studied. The histology of the ovarian primary, extraovarian implants, and recurrent tumor(s) were characterized using World Health Organization criteria and correlated with FIGO stage and clinical follow-up. After censoring nontumor deaths, overall survival and disease-free survival for the 276 patients was 95% (98% FIGO stage I; 91% FIGO II-IV) and 78% (87% FIGO stage I; 65% FIGO stage II-IV), respectively. Unresectable disease (P < 0.001) and invasive implants (P < 0.001) were associated with decreased survival. When compared with typical S-LMP, S-LMP with micropapillary features were more strongly associated with invasive implants (P < 0.008) and decreased overall survival (P = 0.004), but patient outcome with micropapillary S-LMP was not independent of implant type. Stromal microinvasion in the primary tumor was also correlated with adverse outcome, independent of stage of disease, micropapillary architecture, and implant type (P = 0.03). There was no association between outcome and lymph node status. Transformation to low-grade serous carcinoma occurred in 6.8% of patients at intervals of 7 to 288 months (58% ≥ 60 months) and was strongly associated with increased tempo of disease and decreased survival (P < 0.001). S-LMP forms a heterogeneous group, morphologically and clinically distinct from benign serous tumors and serous carcinoma. The majority of S-LMP are clinically benign, but recurrences are not uncommon, and persistent disease as well as deaths occur. Progression to low-grade serous carcinoma is highly predictive of more aggressive disease. Other features associated with recurrent and/or progressive disease include FIGO stage, invasive implants, microinvasion in the primary tumor, and micropapillary architecture. These predictors tend to co-occur, and no single clinical or pathologic feature or combination of features identify all adverse outcomes. The small, but significant risk of progression over time to low-grade serous carcinoma emphasizes the need for prolonged follow-up in patients with S-LMP.

Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management

Purpose: To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals. Experimental Design: We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing. Results: We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers. Conclusions: In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.

Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study

BACKGROUND Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. METHODS 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. FINDINGS 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74). INTERPRETATION PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. FUNDING Carraresi Foundation and others.

CDH1 Truncating Mutations in the E-Cadherin Gene: An Indication for Total Gastrectomy to Treat Hereditary Diffuse Gastric Cancer

Background:Approximately 1% to 3% of all gastric cancers are associated with families exhibiting an autosomal dominant pattern of susceptibility. E-cadherin (CDH1) truncating mutations have been shown to be present in approximately 30% of families with hereditary diffuse gastric cancer (HDGC) and are associated with a significantly increased risk of gastric cancer and lobular breast cancer. Methods:Individuals from a large kindred with HDGC who were identified to have a CDH1 mutation prospectively underwent comprehensive screening with stool occult blood testing, standard upper gastrointestinal endoscopy with random gastric biopsies, high-magnification endoscopy with random gastric biopsies, endoscopic ultrasonography, CT, and PET scans to evaluate the stomach for occult cancer. Subsequently, they each underwent total gastrectomy with d-2 node dissection and Roux-en-y esophagojejunostomy. The stomach and resected lymph nodes were evaluated pathologically. Results:Six patients were identified as CDH1 carriers from a single family. There were 2 men and 4 women. The mean age was 54 years (range, 51–57 years). No patient had any signs or symptoms of gastric cancer. Exhaustive preoperative stomach evaluation was normal in each case, and the stomach and adjacent lymph nodes appeared normal at surgery. However, each patient (6 of 6, 100%) was found to have multiple foci of T1 invasive diffuse gastric adenocarcinoma (pure signet-ring cell type). No patient had lymph node or distant metastases. Each was staged as T1N0M0. Each patient recovered uneventfully without morbidity or mortality. Conclusions:CDH1 mutations in individuals from families with HDGC are associated with gastric cancer in a highly penetrant fashion. CDH1 mutations are an indication for total gastrectomy in these patients. This mutation will identify patients with cancer before other detectable symptoms or signs of the disease.

Desmoplastic and spindle-cell malignant melanoma. An immunohistochemical study.

The clinical, histologic, and immunohistologic features of 22 desmoplastic melanomas (DMM), 10 mixed desmoplastic and spindle-cell melanomas (DMM/SMM), and two cellular spindle-cell melanomas (SMM) were studied. Patients ranged in age from 35 to 91 years (mean, 67) and included 23 men and 11 women. Seventeen cases occurred in sun-damaged skin of the head and neck. 11 were on the extremities, and six on the trunk. Except for two cases, all were Clarks level IV or V. Twenty-two (65%) cases were associated with a recognizable overlying pigmented lesion. Thirty of 32 (94%) DMM and DMM/SMM were clearly positive for S100. S100 staining was limited to < 5% of the spindle cells in two DMM/SMM. All DMM were negative when stained with HMB45. Three DMM/ SMM were immunoreactive with HMB45, as were both SMM. CD68 staining was limited to < 5% of the spindle cells in two of 32 DMM and DMM/SMM and 20% of the cells in one of two SMM. Nine (32%) DMM and DMM/SMM contained significant numbers of spindle cells immunoreactive for SMA but not desmin. In five cases, the number of actin-positive spindle cells. Two color stains for SMA and S100 demonstrated that these smooth-muscle actin positive cells constituted a separate spindle-cell population, consistent with reactive myofibroblasts. This study indicates that the immunohistologic features of desmoplastic melanoma differ from those of conventional melanoma. If a problematic spindle-cell skin lesion is a suspected melanocytic process, HMB45 is unlikely to provide confirmatory (or exclusionary) evidence for the diagnosis of DMM. Similarly, because of the variability in S100 expression in this neoplasm, the absence of S100 staining should not be relied on too heavily to exclude DMM if the clinical and histologic features favor that diagnosis. Caution should be exercised in the interpretation of numerous actin-positive spindle cells in isolation of additional confirmatory or exclusionary data as desmoplastic melanomas may contain significant numbers of these cells.

BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays

A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.

Atypical fibroxanthoma: multiple immunohistologic profiles

The clinical, histologic, and immunohistochemical features of 37 cases of atypical fibroxanthoma (AFX) are presented. Patients ranged in age from 13 to 95 years (mean, 69). Thirty AFXs occurred on the head and neck, and seven lesions developed on the trunk or extremities. The morphologic spectrum varied from a predominant spindle cell pattern with focal cellular pleomorphism to numerous bizarre epithelioid cells with multinucleated giant cells. The spindle cell component in these lesions ranged from 10 to 90% of the constituent cells. Most (31 of 37) AFXs also contained pleomorphic giant cells. Small numbers of S-100-positive dendritic cells were present in 11 cases. Five cases showed variable reactivity with antifactor- XIIIa. Fifteen (41%) of the AFXs stained for muscle- specific actin or smooth muscle actin and 21 (57%) expressed CD68 (detected with monoclonal KP1), a monocyte-macrophage marker. Reactivity for these antigens was seen in all lesional cell types (spindled, epithelioid, and bizarre). Four immunologic profiles were observed: CD68 only (13 cases), actin only (7 cases), double positives (8 cases), and double negatives (9 cases). No significant differences in staining characteristics were observed in the head and neck versus the trunk and extremity lesions. These results expand the immunohistochemical spectrum of AFX, suggest the concept of heterogenous bimodal “fibrohistiocytic” and “myofibroblastic” phenotypes, and provide further evidence that an integrative, nonalgorithmic approach is necessary in the analysis of these and other spindle cell cutaneous lesions.