Apoptosis of bile duct epithelial cells in hepatic allograft rejection.

Liver biopsy remains the 'gold standard' for monitoring rejection in liver transplant patients. Portal inflammation, bile duct damage and endothelialitis are recognized features of hepatic allograft rejection. The pathogenesis of the bile duct injury during rejection, however, remains unclear. To define the mechanism of bile duct damage, we studied the light- and electronmicroscopic appearance of hepatic tissue from selected patients in whom allograft failure was solely due to rejection. Of the 25 orthotopic liver transplant rejection cases examined, 17 were mild, seven were moderate and one was severe rejection. Light microscopy examination of the damaged bile duct epithelium revealed evidence of apoptosis which was confirmed by electronmicroscopy. Furthermore, there appeared to be a positive correlation between the grade of rejection and the number of apoptotic cells. Also included in the study were 13 cases of chronic active hepatitis and 10 normal livers which showed the least apoptotic cells. We conclude that the identification of apoptotic cells in damaged bile ducts in allograft biopsies might be helpful in the diagnosis of rejection and in assessment of the severity of rejection.

Detection of human papillomavirus DNA by in situ hybridization and polymerase chain reaction in human papillomavirus equivocal and dysplastic cervical biopsies.

One hundred twenty-one paraffin-embedded cervical biopsy specimens were tested for the presence of human papillomavirus (HPV) DNA by in situ hybridization and polymerase chain reaction. By in situ hybridization using probes for HPV types 6/11, 16/18, 31/33/35, 42/43/44, 51/52, and 45/56, HPV DNA was found in none of 20 normal/squamous metaplasia biopsy specimens, in one of 76 HPV equivocal biopsy specimens, in seven of 12 condyloma/mild dysplasia biopsy specimens, and in 12 of 13 moderate/severe dysplasia biopsy specimens. Polymerase chain reaction using HPV L1 consensus sequence primers followed by filter hybridization of the amplification products was positive for HPV DNA in two of 20 normal/squamous metaplasia biopsy specimens, in 23 of 76 HPV equivocal biopsy specimens, in eight of 12 condyloma/mild dysplasia biopsy specimens, and in 12 of 13 moderate/severe dysplasia biopsy specimens. Among biopsies that tested positive by polymerase chain reaction but that were negative by in situ hybridization, the most commonly identified HPV was type 16. We conclude that although HPV equivocal biopsy specimens contain HPV DNA more frequently than histologically normal tissue, the majority of biopsy specimens in this category test negative for HPV DNA. The clinical significance of a positive test for HPV, in the absence of unequivocal histologic changes, remains to be determined.

Cytologic diagnosis of human papillomavirus infection: spindled nuclei.

The classic cytologic criteria, koilocytotic atypia and dyskeratocytosis, fail to identify most cases with colposcopic and histologic evidence of cervical condylomata. The purpose of this study was to identify a novel cytologic diagnostic criterion, spindled nuclei, to predict the presence of human papillomavirus (HPV) infection of the cervical epithelium. Review of the hospital records of 100 consecutive cases with spindled nuclei on Papanicolaou smear identified 36 patients in whom a colposcopic examination and/or cervical biopsy had been performed between January 1, 1988, and March 31, 1989. Ninety-seven percent of these 36 cases were positive by colposcopy and 89% of the cases were positive by cervical biopsy for changes of condyloma or intraepithelial neoplasia. HPV DNA hybridization in situ was positive in 16 of 36 patients, and the probe for types 31/33/35 most often stained histologic sections showing condylomatous change without concurrent dysplasia. Electron microscopy of spindled nuclei showed evidence of HPV-type viral particles in the five cases examined.

Histopathology of early and late human hepatic allograft rejection: evidence of progressive destruction of interlobular bile ducts.

Cholestasis and injury of interlobular bile ducts occur during rejection of human hepatic allografts. However, knowledge of the nature and progression of bile duct injury during rejection remains incomplete. To define the role of inflammation in bile duct damage, we assessed the light microscopic appearance of hepatic tissue from selected patients in whom allograft failure was solely due to rejection. Nine patients with rejection were easily separated into two groups based on the duration of the allograft survival. The first group (early rejection) consisted of five patients in whom rejection occurred between 13 and 36 days. The second group (late rejection) consisted of four patients in whom rejection occurred between 170 and 912 days. Early rejection was characterized by distortion of bile ducts by adjacent inflammatory cell infiltrates, cytological changes of bile duct epithelial cells and occasionally by frank mononuclear cell inflammation of the epithelium with destruction of the duct. Late rejection was characterized by nonsuppurative destructive cholangitis culminating in the disappearance of interlobular bile ducts. Both groups exhibited histological cholestasis, intact limiting plates, preservation of hepatocytes and positive orcein stains for copper-binding protein. We conclude that the dominant histopathological feature of hepatic allograft rejection is progressive, nonsuppurative destructive cholangitis.

Electron microscopy of rejected human liver allografts.

Recognition by biopsy of liver allograft rejection has been less successful than diagnosis of rejection of cardiac and kidney allografts. In a study of 138 failed liver allografts, we recognized damage to small interlobular bile ducts by lymphocytes as the most useful indicator of the presence of rejection. This is a report of the electron microscopic features of three patients with unequivocal allograft rejection. Lymphocytes and occasional granulocytes penetrated the epithelia of interlobular bile ducts. Ducts with diameters of 30 to 60 microM were preferentially affected but ducts up to 120 microM were also occasionally involved. Point contacts between infiltrating inflammatory cells and bile duct epithelial cells were observed occasionally. Degenerative changes of bile duct epithelial cells were conspicuous and involved nuclei and cellular organelles. Degeneration was often accompanied by aggregation of dense bundles of filaments in the cytoplasm. In severely affected ducts, epithelial cell disintegration was noted. In all involved bile ducts, the basement membrane was markedly thickened. Hepatocytes were well-preserved but contained lipid vacuoles, pigment granules, and blunted canalicular microvilli. The similarity between these observations and those seen in primary biliary cirrhosis and chronic graft-versus-host disease is striking.

Relationship of pretransplant hepatobiliary disease to bile duct damage occurring in the liver allograft.

Histopathological features of nonsuppurative destructive cholangitis have been described in primary biliary cirrhosis, chronic graft-vs-host disease, and chronic rejection of human liver allografts. To determine whether or not susceptibility to injury of interlobular bile ducts was related to the original hepatobiliary disease requiring transplantation, we compared the histopathology of allografts transplanted into two groups of patients. The first group consisted of patients whose original hepatobiliary diseases primarily affect bile ducts: primary biliary cirrhosis, sclerosing cholangitis, and biliary atresia. The second group consisted of patients whose original hepatobiliary diseases do not result in injury to interlobular bile ducts. In 32 liver allografts studied histopathologically, the original disease did not recur. Interlobular bile duct damage occurred, however, in 17 of the 32 and resembled that seen in primary biliary cirrhosis. The spectrum of bile duct injury included mononuclear inflammation of the bile duct epithelium, destruction of the bile duct epithelium, and dissolution of the bile duct. There was no relationship between the frequency or severity of bile duct damage and original hepatobiliary disease, age, sex, duration of allograft survival, or cause of death. We conclude that nonsuppurative destructive cholangitis occurs frequently in liver allografts and represents one component of allograft rejection. This lesion resembles, in many respects, that seen in primary biliary cirrhosis so that histopathological differentiation may be difficult.

A developmental view of endometrial hyperplasia and carcinoma based on experimental research.

On the basis of experimental research, using rabbit uterine epithelium as a model, it is postulated that human endometrial hyperplasia or carcinoma may be due to derangement of intrinsic growth mechanisms such as cell proliferation, migration, loss and differentiation. Ovarian hormones, estrogen inhibitor or amplifying factors, prostaglandins, stroma-epithelial interactions, proteolytic activity and hormone receptors, all regulate the described intrinsic growth mechanisms, and their excess or lack could result in altered growth patterns. It is also proposed that different types of endometrial carcinoma could result from neoplastic transformation of cells at different stages of differentiation. Since cells at those stages could respond to various hormones in different ways, it would seem of therapeutic value to know the cell of origin in each type of endometrial carcinoma.

Primary carcinoma of the fallopian tube.

The present report of 16 new cases of fallopian tube carcinoma also includes 2 new cases of adenoacanthoma, an exceedingly rare tumor. The histologic evaluation of tubal carcinoma is discussed. A meticulous search at surgery for occult disease is urged, because penetration of the tubal serosa seems to be the most important determinant of prognosis. Suggestions are made for adjunctive therapy, although the authors believe the time has come for a multicentered attempt to evaluate treatment protocols randomly.

Excisional treatment of cavernous hemangioma of the liver.

Fifteen patients had hepatic hemangiomas removed with liver resections that ranged in extent from local excision to right trisegmentectomy. There was no mortality and little morbidity. The propriety and feasibility of extirpative treatment of such liver tumors has been emphasized by this experience.

Liver transplantation: the pathologist's perspective.

In the years 1963--1977, the pathology department of the University of Colorado Medical School did 93 autopsies of patients with liver transplants. Fifteen of these patients had received a second graft. Sepsis was the greatest single cause of death or failure, and fungi and other organisms often considered opportunistic were frequent pathogens. Problems relating to removal of the liver from the donor, emplacement of the graft in the new host, and maintenance of the graft during the prolonged procedures together offer a monstrous challenge to the transplantation surgeon. All of these problems, classed as technical, include as complications infarction of the graft as the result of prolonged ischemia and blood loss or shock due to various causes, and all may produce alteration in structure of the liver; such changes may be misinterpreted as rejection. Rejection was a major cause of failure in only 5 patients, although the immunosuppression employed to control it contributed to the sepsis that so often was lethal. Hyperacute rejection was not observed in any of these transplanted livers, although 15 of these patients received a second transplant. Two of the patients whose grafts failed due to rejection had changes that indicated progression to an early stage of cirrhosis. We conclude that despite the persistent problems the liver is an organ peculiarly favorable for transplantation.

Microinvasive carcinoma of the uterine cervix.

MICA is the transition stage from intraepithelial growth to clinical invasive cancer. The early invasive growth must be accepted as an indication that the lesion is significant; it may be self-healing but it is objective evidence of progression and invasion remains the most significant indication of malignancy. The subjective changes of CIS, nuclear enlargement, pleomorphism of nuclei, altered nuclear-cytoplasmic ratio, etc., are transcended and the recognition and diagnosis of MICA should be facilitated for the pathologist. Treatment which tends to be conservative is more widely accepted, but the disease can be lethal and the most serious complication appears to be, like CIS, vaginal recurrence.

Pathology of liver transplantation.

Experience with renal transplantation indicates failure of the graft is usually due to immunological rejection. In a previous study of human liver transplantation, rejection was the major cause of transplant failure in 4 of 17 patients )24%); in this review of 76 liver transplantations, 64 of which survived the first postoperative week, rejection was the primary cause of graft failure in only 4 of these 64 cases (6%). The two most common causes of transplant failure were technical difficulties with the operative procedure and sepsis; these accounted for 47 (62%) graft failures of the total of 76 transplants. Biliary obstruction and sepsis are more common causes of liver failure than rejection, and patients with recurrent jaundice are now studied intensively for evidence of obstruction. Only after obstruction is excluded, is immunosuppression intensified. These results are a basis for optimism concerning the future of liver transplantation in management of potentially fatal liver disease.

Latent carcinoma and carcinoma in situ.

Lesions exist in the cervix that are diagnosed as carcinoma in situ; some may progress to invasive carcinoma and some may regress. Many are probably overdiagnosed, may represent effects of promoting agents rather than intiating agents, and may entail risk for the patient in that the lesion may be an unusualy good target in carcinogenesis. Latent carcinomas are small foci of initated cells unable to express their malignant phenotype because of environmental controls. Latent cells are produced in experimental carcinogenesis and occur in spontaneous tumors as G-O stem cells.