Henry D. Tazelaar

Ovarian epithelial tumors of borderline malignancy: A clinical and pathologic study of 109 cases

One hundred nine cases of ovarian tumors of low malignant potential (borderline tumors) diagnosed at Stanford University Medical Center from 1958 to 1982 were reviewed. The patients ranged in age from 10 to 79 years (mean, 40.5 years). The histologic types and corresponding stages of these neoplasms were 73 serous (Stage IA: 35 patients; Stage IB+C: 16 patients; stage II: 8 patients; Stage III: 14 patients), 30 mucinous (Stage IA: 27 patients; Stage IB+C: 3 patients), and 6 mixed seromucinous (all Stage IA). Borderline endometrioid, clear cell, and Brenner tumors were excluded. Follow‐up information from 3 to 27 years from the time of initial diagnosis (mean, 7.6 years; median, 7.1 years) revealed that 89 patients are alive without further evidence of neoplasm, and three patients died of unrelated disease without recurrent tumor. Seventeen patients have developed persistent or recurrent neoplasms in the contralateral ovary (six patients) and/or elsewhere within the peritoneal cavity (15 patients) at 5 to 226 months (mean, 61 months) after the initial excision. All of the second neoplasms were borderline serous or seromucinous tumors histologically identical to the original tumor; none of the borderline mucinous tumors recurred. Patients who initially had Stage III borderline serous tumors developed persistent or recurrent neoplasms more commonly (64%) than did patients with lower stage tumors (12%). No correlation was found between the development of a subsequent serous neoplasm and patient age, the primary tumor size, or any single histologic feature. Following treatment of the subsequent neoplasms, 13 patients are free of neoplasm, one patient is alive with tumor, one patient has died of intercurrent disease with tumor, and two patients have died with widespread abdominal tumor 53 and 232 months after their initial diagnosis. These findings confirm the excellent prognosis for patients with borderline serous tumors, despite involvement of the peritoneal cavity and the development of recrudescent tumor, although long‐term follow‐up is indicated. Mucinous borderline tumors, as defined by published criteria, almost invariably present as localized (low‐stage) tumors and, in our experience, do not recur when confined to the ovary.

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction http://ow.ly/AZmbr

Leukocytic infiltrates in idiopathic dilated cardiomyopathy. A source of confusion with active myocarditis

The histologic criteria for the endomyocardial biopsy diagnosis of idiopathic dilated cardiomyopathy (IDCM) and active idiopathic/viral myocarditis are unclear. The present study was undertaken to characterize the nature of the inflammatory cell infiltrates in IDCM and thereby refine the differential diagnostic criteria for distinguishing IDCM from myocarditis using endomyocardial biopsy. We examined a mean of 6.2 large random sections from excised hearts of all cardiac transplant recipients at Stanford University with a diagnosis of IDCM, from June 1968 through June 1984. The 108 cases were evaluated for inflammatory cell type, extent, and location. Thirteen percent had no infiltrate, 32.5% had 1-5 foci of at least five inflammatory cells, 47% had 6-30 foci, and 7.5% had 30 or more foci. The infiltrates were primarily lymphocytic; while they were usually in the myocardial parenchyma, infiltrates were also located in zones of fibrosis, the endocardium, the epicardium, and surrounding vessels. Pretransplant biopsies in 56 of the 108 cases were available for review, and 55% of these contained inflammatory cell infiltrates. Agreement between the presence of infiltrates in the biopsy and the resected heart was obtained in 64%. This study highlights the high incidence of inflammatory cell infiltrates in the hearts of patients with IDCM. It reinforces the need for interpreting lymphocytic infiltrates in an endomyocardial biopsy with caution, as their mere presence does not necessarily imply a diagnosis of active myocarditis.

AIRWAY PATHOLOGY IN THE TRANSPLANTED RAT LUNG

Bronchiolitis obliterans has emerged as the most significant long-term complication of human heart-lung transplantation. Possible causes include rejection, infection, altered bronchial circulation, and denervation. We attempted to assess the role of some of these possibilities by reviewing the airway histology in nonimmunosup-pressed orthotopic rat left lung allografts in three strain combinations: BN-to-LEW (major histocompatibility complex [MHC]-incompatible) n=27; (LEW × BN)Fi-to-LEW, n=11; and F344-to-LEW (minor loci-incompatible) n=18. Fifteen syngeneic transplants (LEW-to-LEW) served as controls. After assigning the lungs to a rejection phase (latent, vascular, alveolar, or destructive), the airway pathology was specifically examined. In the latent phase, only changes attributable to transplantation per se were identified. In the vascular phase in the BN-to-LEW rats and (LEW × BN)F1-to-LEW rats, the bronchioles were surrounded by dense cuffs of activated lymphocytes. The lymphocytic infiltrate then progressively involved the lamina propria and epithelium, where it became associated with focal epithelial cell necrosis. Eventually the epithelium became ulcerated (alveolar phase), and the submucosa and luminal surface became replaced by granulation tissue, which frequently protruded into the lumen in a bronchiolitis obliterans pattern. In the destructive phase the changes were similar to those in the alveolar phase, but were more severe. In the F344-to-LEW rats the airway changes were less prominent, although the remainder of the lungs was at comparable phases of rejection. These changes were not observed in the right (nontransplanted) lungs or the control (LEW-to-LEW) lungs. The findings in these animals suggest that the process of rejection affects the airways and may result in posttransplantation bronchiolitis obliterans.

Intravascular lipoleiomyomatosis: A report of two cases

Two cases of intravascular leiomyomatosis (IVL) with histologic features of a lipoleiomyoma (LPL) are reported. Both tumors arose from preexisting uterine leiomyomata. One tumor was found incidentally in a uterus removed for leiomyomata. The other tumor extended up the inferior vena cava into the right side of the heart and presented as a cardiac mass. Although LPL is considered to be a benign lesion, IVL recurs in approximately 10% of reported cases, and must be distinguished from low-grade endometrial stromal sarcoma and leiomyosarcoma with vascular invasion. The combination of features in these cases lends support to the theory that IVL may arise by intravascular extension of a preexisting leiomyoma.

Myocyte hypertrophy in the transplanted heart: a morphometric analysis

In order to better define long-term changes in the transplanted heart with respect to the effects of cyclosporine and the ischemic time of the donor heart, endomyocardial biopsies were examined ultrastructurally from 20 cardiac transplant recipients three years posttransplantation. The biopsies were divided into four groups of five based on the donor heart ischemic time in on-site versus distantly procured hearts and on the immunosuppression protocol: group A: on site donor hearts and cyclosporine-based immunosuppression; group B: on site donor hearts with conventional immunosuppression (azathioprine-based immunosuppression without cyclosporine); group C: distantly procured donor hearts treated with cyclosporine; and group D: distantly procured donor hearts treated with conventional immunosuppression. All four groups showed a significant increase in the average width of myocytes when compared with normal myocardium, (group A, P less than 0.05; groups B, C, D, P less than 0.01). Also, there was a significant difference between the average widths of myocytes from on-site donor hearts and distantly procured donor hearts (P less than 0.04). There was no significant difference between the average myocyte widths of groups treated with cyclosporine and those with conventional immunosuppression. This study shows that despite the hypertension induced by cyclosporine, myocyte hypertrophy at 3 years posttransplantation does not appear to be significantly greater than in patients treated with conventional immunosuppression. Distantly procured donor hearts have more hypertrophy. Due to the increasing evidence that cardiac hypertrophy per se may predispose to serious ventricular arrhythmias, this study supports the use of on-site as opposed to distantly procured donor hearts.

Collagen profile in the transplanted heart

To substantiate the finding of interstitial myocardial fibrosis in the transplanted heart and to characterize the collagen profile of the transplanted heart, we studied endomyocardial biopsy specimens from 30 heart transplants and four heart-lung transplants at 1 to 82 months after transplantation. Indirect immunofluorescent techniques with affinity-purified antibodies for collagen types I, III, IV, and V were used. The degree of interstitial collagen present was scored. The amount of type I collagen was increased in transplants from distant donors (mean ischemia time, 154 minutes) compared with those from on-site donors (mean ischemic time, 59 minutes): collagen scores 1.1 and 1.7, respectively (P less than .01). There was a trend toward a positive correlation, not statistically significant, between cyclosporine dose and collagen III deposition (r = .35), collagen IV (r = .38), and collagen V (r = .56). There was a negative correlation between number of rejection episodes and mean cyclosporine dose (r = -.41) and amount of collagen III (r = -.42) or collagen IV (r = -.42). No correlations were found between collagen deposition and any other variables studied. These results confirm the mixed nature of the collagen deposited and suggest that some fibrosis is related to cyclosporine administration rather than to the number of prior healed rejection episodes.

Combined heart-lung transplantation in the rat: comparison of thoracic and abdominal operation techniques

Recently, we developed two techniques for the combined transplantation of heart and the left lung into the left hemithorax of rats. One technique, with two vessel anastomoses, comprised the microsurgical repair of aorta, anterior vena cava, and left main bronchus. With the other, single vessel technique, only the aorta and bronchus were anastomosed. In this study, we determined the function and histology of syngeneic and cy-closporine (CsA)-treated allogeneic grafts transplanted with both techniques, and compared the results with those of heterotopic heart-lung grafts transplanted with a. previously described technique for transplantation into the rats abdomen. The survival rate of rats operated with either of the thoracic transplantation techniques was high (83%). Lungs and hearts of the grafts functioned well for over two months and had normal morphology when the double vessel technique was used. With the single vessel technique, the function of the lungs started to deteriorate from the third postoperative week onward, probably secondary to congestion. The results of thoracic grafts were superior to those of abdominal transplants, where the nonventilated lungs–especially during immunosuppression–wesre frequently infected. We conclude that these new techniques for thoracic transplantation are most suitable for research of combined heart-lung transplantation.

Minimal lung pathology in long-term primate survivors of heart-lung transplantation

Etude de 2 singes Rhesus ayant survecu longtemps (+ de 5 ans et + de 7 ans) a une transplantation cœur-poumons. Les alterations pulmonaires sont peu importantes; on note une fibrose pulmonaire progressive, probablement due a la toxicite de la cyclosporine, un epaississement de la plevre, mais pas de bronchiolite obliterante (complication frequente chez lhomme)