Morphological changes in atrial appendages removed during the maze procedure: a comparison with autopsy controls.

Atrial fibrillation (AF) is commonly encountered in clinical practice and typically it is treated with pharmacological agents. Some patients whose arrhythmias are resistant to pharmacological therapy undergo the maze procedure, which is a surgical treatment. The atrial appendages are removed as part of the surgical procedure. These appendages often demonstrate mycocyte hypertrophy, vacuolar degeneration and other changes that may be seen in cardiomyopathies. We examined 19 of these appendages and compared them with 17 autopsy controls, 12 of whom had documented coronary atherosclerotic disease and 5 of whom did not. We semiquantitatively measured the amount of vacuolar degeneration, interstitial fibrosis, myocyte hypertrophy and intramyocardial adipose tissue. Univariate and multivariate analysis was performed and revealed that vacuolar degeneration were significantly more common in appendages of patients with arrhythmias than the autopsy controls (P<.0004). The other three histological features studied were not significantly different in the three groups. Ultrastructural studies on atrial tissue excised during the maze procedure, retrieved from the paraffin blocks, revealed degenerative changes similar to cardiomyopathic myocardial tissue. Vacuolar degeneration is commonly seen in atrial appendages removed in patients with chronic AF. Myocyte hypertrophy is a nonspecific finding and may occur in patients with arrhthymias and coronary artery disease.

Regression of fibrosis and hypertrophy in failing myocardium following mechanical circulatory support.

BACKGROUND: The cellular and structural changes that occur during long-term ventricular unloading leading to cardiac recovery are poorly understood. However, we have previously demonstrated that left ventricular assist device (LVAD) support leads to a significant decrease in intracardiac tumor necrosis factor-alpha (TNF-alpha), a protein capable of producing hypertrophy and fibrosis. METHODS: To further define the beneficial effects of long-term ventricular unloading on cardiac function, we determined the effect of mechanical circulatory support on fibrosis and hypertrophy in paired myocardial samples of 18 patients with end-stage cardiomyopathy obtained at the time of LVAD implantation and removal. RESULTS: We determined total collagen as well as collagen I and III by a semiquantitative analysis of positive immune-stained areas in pre- and post-LVAD myocardial samples. We found that total collagen content was reduced by 72% (p < 0.001), whereas collagen I content decreased by 66% (p < 0.001) and collagen III content was reduced by 62% (p < 0.001). Next, we determined myocyte size by direct analysis of cellular dimensions utilizing a computerized edge detection system in pre- and post-LVAD myocardial samples. We found that myocyte size decreased in all patients studied for an average reduction of 26% (33.1 +/- 1.32 to 24.4 +/- 1.64 microm, p < 0.001). CONCLUSION: These data demonstrate that long-term mechanical circulatory support significantly reduces collagen content and decreases myocyte size. We suggest that the reduction of fibrosis and hypertrophy observed may in part contribute to the recovery of cardiac function associated with long-term mechanical circulatory support.

Vulvar hypertrophy with lymphedema. A mimicker of aggressive angiomyxoma.

We report the case of a 43-year-old quadriplegic woman with bilateral vulvar enlargement. The clinical impression was labial hypertrophy, but the microscopic features mimicked aggressive angiomyxoma because of the location, hypocellular proliferation of fibroblastic cells in an edematous-myxoid stroma, and vessels with perivascular collagen deposition, which simulated the thick-walled vessels of aggressive angiomyxoma. Since the lesion lacked true thick-walled vessels and contained ectatic tortuous lymphatics, the pathologic interpretation was lymphedema. This vulvar lesion should be recognized to prevent the misdiagnosis of aggressive angiomyxoma.

The prognostic value of human chorionic gonadotropin expression in colorectal adenocarcinomas. An immunohistochemical study of 102 stage B2 and C2 nonmucinous adenocarcinomas.

Several recent studies have detected human chorionic gonadotropin (hCG) expression in colorectal adenocarcinomas and have concluded that its expression is an adverse prognostic indicator. The patient population and length of follow-up has varied. Therefore, we reviewed a defined group of cases with long-term (> 5 years) follow-up. We studied 102 stage B2 and C2 nonmucinous adenocarcinomas immunohistochemically for the production of hCG. Expression of hCG was detected in paraffin sections, including tumor and adjacent mucosa, using immunolabeling with a polyclonal rabbit antibody and the avidin-biotin-peroxidase complex technique. Cytoplasmic positive staining was evaluated semiquantitatively in every low-power microscopic field containing tumor. Expression of hCG was noted in at least one field in 42% (43/102) of the carcinomas. There was no expression in adjacent mucosa. Although the staining was usually focal (< 5% of tumor cells), some cases did stain diffusely. There was no significant correlation of hCG expression with survival, stage, differentiation, age, race, sex, or site of tumor. We therefore conclude that hCG expression is not a significant prognostic indicator in stage B2 and C2 colorectal carcinomas.

p53 protein immunostaining in routinely processed paraffin-embedded sections.

Mutation of the p53 tumor suppressor gene is the most common genetic alteration in human tumors. The altered protein product of the mutant gene is stabilized in tumor cells and can be detected using monoclonal antibody immunohistochemistry. We report a technique for immunostaining of the altered p53 protein in routinely processed paraffin-embedded tissue sections, comparing this method with a frozen-section immunostain method for concordance. Similarly processed tumor cell lines with known mutations or deletions of the p53 gene served as positive or negative controls. The results in 25 human gliomas and 20 colorectal carcinomas showed a 100% correspondence of positive reactivity in the colorectal carcinomas and an 83% correspondence in the gliomas. In no case did the paraffin-embedded sections react in the absence of frozen section reactivity (that is, there were no false positives). Three of 18 gliomas showed reactivity in frozen sections without reactivity in the companion paraffin-embedded sections. This discrepancy could have been caused by technical factors such as length of fixation time. We propose that this new paraffin-embedded section immunostaining method will be of value as a screening technique for the investigation of p53 mutations in archived human tumors. The data thus obtained may then be correlated with clinical information and perhaps be of value in diagnosis or predicting outcome for various human cancers.

The correlation of two argyrophilic nucleolar organizer region counting methods with bromodeoxyuridine-labeling index: a study of metastatic tumors of the brain.

Bromodeoxyuridine (BrdU) is a thymidine analog that is incorporated into cellular DNA in the synthetic phase. The BrdU-labeling index (BLI) thus reflects the S-phase fraction. The argyrophilic nucleolar organizer regions (AgNORs) are silver-stained granules that have been correlated with ploidy and/or S-phase fraction. Two AgNOR counting methods have been proposed to distinguish between ploidy and S-phase fraction: the mean AgNOR (mAgNOR) count (the mean number of AgNOR granules in 100 cells), which is believed to reflect ploidy, and the AgNOR proliferative index (pAgNOR) (the percentage of cells exhibiting five or more AgNOR granules per nucleus), which is believed to reflect S-phase fraction. To evaluate the latter hypothesis we studied 19 tumors metastatic to the brain in patients who had received preoperative low-dose BrdU injections. Formalin-fixed, paraffin-embedded sections of the resected tumors were stained using the indirect immunoperoxidase technique and a monoclonal antibody to BrdU. The BLI was determined by counting 1,000 tumor cells in each case; AgNOR silver staining was performed on sections of the same blocks studied for BLI. The correlation between pAgNOR counts and BLI was statistically significant (r = .649, P = .003). No statistically significant correlation could be obtained between mAgNOR counts and BLI (r = .421, P = .17). We conclude that the pAgNOR count can reliably reflect the proliferative activity of cells. The method can prove beneficial in situations in which cell kinetic analysis is needed and in which invasive procedures, such as BrdU injection, are not feasible or are contraindicated.

Distribution of p53 protein expression in gliosarcomas: an immunohistochemical study.

The wild-type p53 gene product is a nuclear phosphoprotein that suppresses cell and tumor growth. Mutations of the p53 gene are by now the most frequently recognized genetic alterations in human malignancies and occur in many types of carcinomas as well as in astrocytomas and sarcomas. Wild-type p53 protein has a short half-life, is present in very low quantities in normal cells and cannot be detected immunohistochemically. Mutant p53 proteins have longer half-lives and are usually present in immunohistologically detectable amounts. It is generally agreed that the presence of p53 immunostaining indicates the presence of an abnormal p53 protein and is strongly suggestive of a mutation in the p53 gene. In this study, we stained paraffin sections from eight samples of gliosarcomas from seven patients with an antibody to p53. All tumors contained p53-immunoreactive nuclei in both the glial and the sarcomatous component. In five tumors, a majority of nuclei was positive in the sarcomatous component while only a minority of nuclei was positive in the glial areas. In one tumor, the reverse was seen. In another tumor, approximately half the nuclei were positive in both components and in one tumor, only a minority of nuclei were positive in either component (this lesion was the recurrence of a tumor in which the majority of the sarcoma's nuclei had been positive). These data indicate that p53 mutations may play a role in the pathogenesis of gliosarcomas and suggest an origin of both the glial and sarcomatous components from a common progenitor.

Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas.

Chemoradiation prior to pancreaticoduodenectomy ensures that all patients who undergo resection complete multimodality therapy, avoids resection in patients with rapidly progressive disease, and allows radiation therapy to be delivered to well-oxygenated cells before surgical devascularization. Twenty-eight patients with cytologic or histologic proof of localized adenocarcinoma of the pancreatic head received preoperative chemoradiation (fluorouracil, 300 mg/m2 per day, and 50.4 Gy) with the intent of proceeding to resection; all 28 completed this preoperative therapy. Hospital admission because of gastrointestinal toxic effects was required in nine patients, yet no patient experienced a delay in operation. Restaging was performed 4 to 5 weeks after completion of chemoradiation, and five patients were found to have metastatic disease; the 23 patients without evidence of progressive disease underwent laparotomy. At laparotomy, three patients were found to have unsuspected metastatic disease, three patients had unresectable locally advanced disease, and 17 patients were able to undergo pancreaticoduodenectomy. One perioperative death resulted from myocardial infarction, and perioperative complications occurred in three patients. Histologic evidence of tumor cell injury was present in all resected specimens. Our results suggest that pancreaticoduodenectomy can be performed with a low incidence of complications after chemoradiation for localized adenocarcinoma of the pancreas.

Dermatofibrosarcoma protuberans. A clinicopathologic review with emphasis on fibrosarcomatous areas.

We reviewed 75 cases of dermatofibrosarcoma protuberans (DFSP) from the University of Texas M.D. Anderson Cancer Center. All accessions were examined for areas of giant cell fibroblastoma (GCF), but none was found. The 30 cases having a minimum of 5 years follow-up were studied in more detail. The histologic findings were typical of DFSP in 24 cases, whereas in six cases discrete areas with a fascicular or "herringbone" growth pattern, considered to represent fibrosarcomatous change (DFSP-FS), were evident. The mitotic rate was usually but not always higher in fibrosarcomatous areas, and occasional examples of typical DFSP demonstrated relatively numerous mitotic figures (up to 35 per 10 high-power fields). Other histologic findings of interest were the presence of melanin in two cases of DFSP and the focal presence of a distinctive type of multinucleated giant cell similar to those seen in GCF in six cases. Patients with DFSP-FS differed from those with DFSP in that they had a higher median age (56 years vs. 37 years). Tumor location was similar in both groups, with the trunk being the most common site. No significant difference in either the rate of local recurrence or the interval until recurrence between DFSP and DFSP-FS was evident; the only factor strongly related to local recurrence was adequacy of surgical margins. However, the only two patients who died of tumor, including the sole patient with distant metastasis, had DFSP-FS. We conclude that DFSP-FS deserves recognition as a variant of DFSP.

p53 protein expression in transitional mucosa and adenocarcinomas of the colorectum.

Transitional mucosa, the nonneoplastic mucosa adjacent to colorectal adenocarcinomas, exhibits some morphologic and histochemical abnormalities. It is unclear, however, whether transitional mucosa is a preneoplastic or reactive phenomenon. Though normal p53 functions as a tumor suppressor, p53 gene alterations have been proposed as a step in malignant transformation, and aberrant p53 protein expression has been described in a high percentage of colonic adenocarcinomas. Since p53 protein normally has a short half-life, immunohistochemical detection of the protein is considered to be evidence of abnormal p53 expression. We analyzed p53 protein expression immunohistochemically on frozen tissue samples of transitional mucosa, normal mucosa, and tumor from 20 cases. In all 20 cases the transitional mucosa and normal mucosa failed to express p53, while 13 of 20 adenocarcinomas showed positive immunoreactivity characterized by intense nuclear staining. There was no correlation between tumor stage and p53 expression. The absence of staining for p53 protein in TM does not support the theory that transitional mucosa is a preneoplastic phenomenon.

Mucinous carcinomas of the colon and rectum. An analysis of 62 stage B and C lesions.

The significance of a large extracellular mucinous component in colorectal adenocarcinomas continues to be controversial. We studied 62 stage B and C mucinous carcinomas defined by 60% or greater mucinous component. Sixty of these patients had matched nonmucinous adenocarcinoma controls. Patients with mucinous carcinomas with a residual adenoma had a significantly greater survival than those who did not. Overall, no difference was noted in 5-year survival between patients with mucinous carcinoma and nonmucinous adenocarcinoma (64% each). However, when the stages were considered separately, patients with stage B mucinous carcinoma fared significantly worse and had more local sites of treatment failure. We speculate that patients with stage B mucinous carcinoma may have a worse prognosis owing to the extra-cellular mucin, which may make a complete surgical extirpation more difficult.

Lack of correlation between histologic findings and response to chemotherapy in metastatic breast cancer.

A retrospective analysis was undertaken to assess the prognostic role of histologic findings in response to chemotherapy and survival in patients with metastatic breast cancer. Histologic material was available for 395 of 1587 patients treated for metastatic breast cancer at the M.D. Anderson Cancer Center between 1973 and 1984. Chemotherapy consisted of 5-fluorouracil, doxorubicin, and cyclophosphamide or similar drugs, with or without tamoxifen. Maintenance cyclophosphamide, methotrexate, and 5-fluorouracil was continued for 2 years after a cumulative doxorubicin dose of 450 mg/m2 was administered. The histologic distribution was as follows: infiltrating ductal carcinoma, 353; invasive lobular, 14; mixed histology, ten; mucinous, seven; signet ring, four; tubular, three; papillary, two; sarcomatoid, one; and apocrine, one. Because individual histologic types occurred infrequently, the patients were divided into infiltrating ductal and nonductal groups. Baseline patient characteristics included age, performance status, estrogen-receptor status, prior hormone response, disease extent, and levels of alkaline phosphatase, bilirubin, and lactate dehydrogenase. These were similar in the two groups. Significantly more patients with nonductal histology had greater than three metastatic sites. There were also more patients with hemoglobin less than 10 mg/dl and albumin less than 3.5 mg/dl in the nonductal group of patients. However, statistically these factors did not have an impact on the results. There was a 63% response rate (17% complete and 46% partial) for the ductal group and a 60% response rate (12% complete and 48% partial) for the nonductal group. The time from initiation of chemotherapy to disease progression was identical (12 months) for the two groups. Survival from initiation of chemotherapy was not significantly different (22 months for ductal and 27 months for nonductal). Based on this study, the authors conclude that histologic findings have no bearing on patient response to chemotherapy or survival in metastatic breast cancer.

Exophytic signet-ring cell carcinoma of the colorectum.

Previous studies have assessed colorectal signet-ring cell carcinomas of the linitis plastica variant but not of the exophytic subtype. We retrospectively reviewed 20 cases of colorectal signet-ring cell carcinoma of the exophytic subtype (greater than 50% signet-ring cells). The patients ranged in age from 14 to 79 years (mean, 51.8 years); 10 were male; 17 were white; and three were black. Ten tumors were colonic (eight, right sided; two, left sided) and 10 were rectal; seven were stage B and 12 were stage C. One patient presented with distant metastases. Eleven of 16 tumors assessed by flow cytometry were diploid. Parenchymal hepatic metastases developed in only two patients. The overall 5-year survival rate was 36%, and matched cases did not vary significantly in survival from typical nonmucinous adenocarcinomas. There was a trend toward poorer survival for patients with advanced-stage tumor. Survival was not affected by primary site, ploidy, presence of vascular/lymphatic invasion or residual adenoma, or percentage of extracellular mucin or signet-ring cells. Our cases were somewhat lower stage than literature cases of signet-ring cell carcinoma of the lintis plastica variant.

Lymphoreticular disease masquerading as or associated with an inguinal or femoral hernia.

Twelve patients (eight men and four women) had previously undiagnosed lymphoreticular disease associated with or simulating an inguinal (nine) or femoral (three) hernia. The disease was present on the left side in eight. Four patients (three women and one man) did not have an actual hernia. Two of these women had a preoperative diagnosis of femoral hernia. Seven of the patients, including all of the women, had non-Hodgkin's lymphoma (three diffuse large cell, two follicular mixed cell and two follicular small cleaved cell) and one patient had lymphocytic predominance (nodular lymphocytic and histiocytic) Hodgkin's disease. No stage predominated. Inguinal lymph nodes from two patients showed, histologically, Kaposi's sarcoma and type I human immunodeficiency virus (HIV) associated disease. Each patient was homosexual and HIV seropositive. Changes suggestive of viral cause were present in the lymph node of one patient. The enlarged lymph nodes of the 12th patient showed stellate suppurative granulomas containing cat-scratch bacilli demonstrated by Warthin-Starry stain. Because of the special processing needs for lymphoreticular diseases and potential for misdiagnosis, surgeons, clinicians and pathologists should be aware of the spectrum of lymphoreticular processes occurring in lymph nodes associated with or masquerading as a hernia, particularly in women.