Novel surveillance and cure of a donor-transmitted lymphoma in a renal allograft recipient.

BACKGROUND: In this report we describe a malignant lymphoma of donor origin inadvertently transplanted into two renal allograft recipients, despite standard comprehensive donor screening. The successful clearance of the tumor from both patients and a novel method of surveillance are detailed. METHODS: Initial management consisted of withdrawal of immunosuppression to promote rejection of the allograft and the transplanted tumor in both patients, followed by graft removal. Peripheral blood microchimerism was assessed in both recipients using nested polymerase chain reaction to detect the DYZ3 gene on the Y chromosome (donor male, recipients female). RESULTS: Although microchimerism was detected on day 6 after transplantation and day 1 after explantation, repeat peripheral blood examination at 1, 3, and 6 months after explantation demonstrated no microchimerism. Both patients remain well at 12 months and have been relisted for transplantation. CONCLUSION: Despite inadvertent transplantation of a previously undiagnosed malignancy of donor origin, the recipients' immune response was able to eliminate donor tumor cells after the withdrawal of immunosuppression. Repeated surveillance of peripheral blood from both recipients, using a novel application of the technique of nested polymerase chain reaction to amplify donor DNA, demonstrated no persistence of donor cells, supporting effective eradication of the donor malignancy.

Advanced donor-origin melanoma in a renal transplant recipient: immunotherapy, cure, and retransplantation.

BACKGROUND: A kidney transplant recipient inadvertently contracted donor-origin melanoma, which was found to be very advanced at presentation. Withdrawal of immunosuppression failed to induce rejection, and interferon-alpha was required. When florid allograft rejection was in progress, the allograft was removed, before it was recognized that the transplanted melanoma was not being simultaneously rejected. METHODS: Subsequent immunotherapy was required, which largely recapitulated treatment of recognized value in autologous melanoma and included interferon-alpha, use of cultured melanoma cells as tumor vaccine, pooled allogeneic cell vaccination, and adoptive immunotherapy using lymphokine-activated killer cells. RESULTS: Prolonged immunotherapy eradicated the widespread malignancy, and the patient went on to a successful second renal transplant, with follow-up of over 24 months. CONCLUSIONS: This unique case demonstrates the successful cure of advanced transplanted melanoma through the use of immunotherapy, which did not require sophisticated tumor vaccine technology, and successful retransplantation.

Malignant sacrococcygeal germ cell tumour in an adult.

In adults, malignant sacrococcygeal germ cell tumour is a rare cause for a presacral tumour, with only 17 cases having been reported in the literature since 1907. We report the case of a 34 year old male who presented with a 6 month history of symptoms relating to a malignant presacral tumour which required en bloc excision including the lower sacrum and rectum. He died with lung and mediastinal metastasis 7 months following surgical excision and adjuvant chemotherapy using Cisplatin, Bleomycin and Etoposide. Prior to his death, he had a severe polyarthritis of his peripheral joints and evidence of hypertrophic osteo-arthropathy. The literature indicates that adults with these tumours have a poor prognosis, with only one reported long-term survivor. Surgical excision offers the only chance of cure, with the role of adjuvant therapy not having been defined because of the small numbers.

Donor-related secondary haemorrhage complicating renal transplantation.

We report two cases of secondary haemorrhage in renal transplant recipients that would appear to relate to their common donor. Our experience confirms the inadequacy of arterial repair in this setting. One patient, a middle aged diabetic male, required excision of his external iliac artery, but recovered without reconstructive surgery. In the second case nephrectomy was performed on day 8 because of accelerated rejection. This was followed by recurrent sepsis due to E. coli, which was implicated in the previous case. Haemorrhage from the donor aortic wall patch occurred 3 weeks later. We now recommend that if secondary haemorrhage occurs, recipients of other organs from the donor should be carefully monitored for evidence of infection. If this is found and a similar organism cultured, consideration to transplant nephrectomy should be made with removal of all donor tissue to avoid the risk of subsequent secondary haemorrhage.

Invasive squamous cell carcinoma of the conjunctiva.

A 73-year-old man had been treated for a sore, red, left eye for 4 months before a clinical diagnosis of squamous cell carcinoma of the limbus was made. This diagnosis was confirmed on examination of a biopsy specimen, but after an initial surgical attempt to fully excise the tumor, there was clinical evidence of intraocular spread. An extensive corneoscleral resection and iridocyclectomy appeared to completely excise the tumor, as indicated by frozen section review. However, 1 year later, the patient re-presented with obvious residual squamous cell carcinoma of the iris and trabecular meshwork, well away from the original tumor site. Subsequent exenteration has resulted in a tumor-free patient for 1 year. Apparent surgical clearance of an extensive squamous cell carcinoma does not ensure total intraocular clearance of residual tumor, which may be remote from the original tumor site.

International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology.

A group of renal pathologists, nephrologists, and transplant surgeons met in Banff, Canada on August 2-4, 1991 to develop a schema for international standardization of nomenclature and criteria for the histologic diagnosis of renal allograft rejection. Development continued after the meeting and the schema was validated by the circulation of sets of slides for scoring by participant pathologists. In this schema intimal arteritis and tubulitis are the principal lesions indicative of acute rejection. Glomerular, interstitial, tubular, and vascular lesions of acute rejection and "chronic rejection" are defined and scored 0 to 3+, to produce an acute and/or chronic numerical coding for each biopsy. Arteriolar hyalinosis (an indication of cyclosporine toxicity) is also scored. Principal diagnostic categories, which can be used with or without the quantitative coding, are: (1) normal, (2) hyperacute rejection, (3) borderline changes, (4) acute rejection (grade I to III), (5) chronic allograft nephropathy ("chronic rejection") (grade I to III), and (6) other. The goal is to devise a schema in which a given biopsy grading would imply a prognosis for a therapeutic response or long-term function. While the clinical implications must be proven through further studies, the development of a standardized schema is a critical first step. This standardized classification should promote international uniformity in reporting of renal allograft pathology, facilitate the performance of multicenter trials of new therapies in renal transplantation, and ultimately lead to improvement in the management and care of renal transplant recipients.

Glomerular abnormalities in children undergoing orthotopic liver transplantation.

A prospective study of renal function was undertaken on an unselected group of 8 children with chronic progressive liver disease on whom a renal biopsy was performed subsequently at the time of orthotopic liver transplantation. Two patients had abnormal urinalyses and 2 elevated urinary albumin/creatinine ratios. The remainder had no clinical evidence of renal dysfunction. All had normal serum creatinine concentrations. Glomerular abnormalities were present in all renal biopsies and were of two types: hepatic glomerulosclerosis (n = 5) and minor glomerular abnormalities (n = 3). IgM immunofluorescence was present in all biopsies and IgA in 6. Elevated serum immunoglobulin levels were observed in all patients, with IgM elevation in 6, IgA in 4 and IgG in 6. C3 and/or C4 were reduced in 5 patients and increased circulating immune complexes containing IgM were noted in 4. The clinical significance of these cirrhosis-associated glomerular abnormalities can only be established by long-term follow-up studies after orthotopic liver transplantation.

Universal occurrence of glomerular abnormalities in patients receiving liver transplants.

We conducted a prospective study of renal histology and function in 18 consecutive nonalcoholic patients who underwent orthotopic liver transplantation (OLT). Despite well-preserved renal function, all patients had abnormal renal biopsies. Four patterns of glomerular injury were identified: minor glomerular abnormalities (eight patients), hepatic glomerulosclerosis (seven), membranoproliferative glomerulonephritis (one), and IgA nephropathy (one). In one patient there was insufficient tissue to allow classification. There was a trend toward lower plasma bilirubin and higher plasma albumin in patients with minor glomerular abnormalities than in the group of patients with more severe forms of glomerular injury (29 v 82 mumol/L, 35.5 v 30 g/L; P = 0.1, 0.1 greater than P greater than 0.05, respectively). Glomerular changes persisted in the three patients who died within 7 weeks post-OLT. IgM immunofluorescence was present in all biopsies and IgA in 11. IgM-containing circulating immune complexes occurred in five patients, suggesting a pathogenic role for IgM immune complex deposition. The significance of cirrhosis-associated glomerular abnormalities is not yet known. They may contribute to the hepatorenal syndrome and the renal dysfunction that occurs in up to 94% of patients post-OLT.

Effects of hypoxia on morphological and biochemical characteristics of renal epithelial cell and tubule cultures.

Apoptotic cell death plays an important role in the pathogenesis of renal atrophy in diseases of the kidney involving chronic mild ischemia. The present study constitutes an in vitro model of these diseases and assesses the modes of cell death involved after hypoxic treatment of renal epithelium. Cultures of MDCK cells or primary cultures of rat renal parenchymal tubules were treated in either a physiological or a hypoxic atmosphere. Cultures were collected before treatment and at 24 h and 48 h, for morphological and biochemical studies. Both apoptosis and necrosis were observed at significantly increased levels by 48 h of hypoxia in the MDCK cell cultures. DNA gel electrophoresis patterns supported these findings. Experiments using tubule cultures demonstrated that, during the 48 h of study, tubular epithelial cells in the center of the control tubule structures died by apoptosis, possibly as a result of mild oxygen and/or nutrient depletion. With added hypoxic treatment, however, the entire tubule structure became necrotic. Results are similar to those found during in vivo studies, thus providing in vitro models that may be developed further to define factors in the pathogenesis of some renal diseases.

Intravascular large cell lymphoma: diagnosis on renal biopsy.

The case is reported of a woman aged 60 yrs who presented with systemic symptoms and who was found to have proteinuria of 3.5 g per day. A renal biopsy revealed numerous neoplastic cells filling many of the glomerular capillary lumina. Immunoperoxidase stains revealed that the phenotype of the malignant cells was LCA+, L26+, MB2+, UCHL1-, CD43-, CAM5.2- and S100-, indicating that they were of lymphoid origin and B-cell lineage. The diagnosis of intravascular large cell lymphoma was therefore made. Remission was induced by chemotherapy with CAVP (cyclophosphamide, adriamycin, vincristine and prednisone). A subsequent relapse was treated with cyclophosphamide, VP16 and prednisone, and again remission occurred. This is the first case known to the authors in which the diagnosis of intravascular large cell lymphoma was made on renal biopsy. We confirm the experience of others that chemotherapy with regimens utilized in other varieties of large cell lymphoma may also be appropriate for this unusual neoplasm.

Functioning lipoadenoma of the parathyroid gland.

A lipoadenoma of the parathyroid gland was discovered at autopsy as the result of a search for the cause of terminally detected hyperparathyroidism in an elderly man who had suffered cerebral infarction. It is the only case known to the authors in which this uncommon cause of hyperparathyroidism was found at post-mortem examination after hypercalcemia and raised levels of serum immunoreactive parathormone were documented during life.

Granulomatous lobular mastitis: report of a case with previously undescribed histopathological abnormalities.

A 41-yr-old multiparous woman presented with a discrete breast lump which proved histologically to be an example of granulomatous lobular mastitis. The clinical and histological features were similar to those noted in previous reports. Additional histological features in the present case were an intense mononuclear cell infiltration of lobular and ductal epithelium, associated with nuclear fragments morphologically suggestive of apoptosis. These appearances, which have not previously been described, are illustrated, together with the more classical features of the condition well demonstrated by the present case. The novel histological features noted here suggest that the development of granulomatous lobular mastitis may be at least in part immunologically mediated, and that the cellular infiltrates seen may be a manifestation of cell-mediated destruction of mammary epithelium.

Scrotal calcinosis: origin from dystrophic calcification of eccrine duct milia.

Scrotal calcinosis is a rare benign disorder considered idiopathic by most recent authors, although an origin from dystrophic calcification of epidermoid cysts has been proposed. In 3 of 4 cases which were otherwise typical of scrotal calcinosis, there was calcification of the contents of small cysts lined by stratified squamous epithelium. These structures were identified as eccrine duct milia because some of them communicated with eccrine ducts and there were ultrastructural features of eccrine duct differentiation in one case. The eccrine nature of the milia was confirmed using the immunoperoxidase technique for the demonstration of carcinoembryonic antigen (CEA) which serves as a marker of eccrine sweat glands. Since a transition could be seen between degenerating calcified milia and typical nodules, it appeared that the calcific deposits of scrotal calcinosis result from the breakdown of such lesions. Staining of deposits unassociated with cyst walls with the technique for the demonstration of CEA supported this conclusion. An advanced stage of evolution of the disease could account for the absence of visible cysts in many cases. We propose the term "hidrocalcinosis of the scrotum" for this distinctive form of cutaneous calcification.

Renal and urinary tract complications following the intravesical instillation of formalin.

The case is reported of a 10-yr-old girl who developed intractable hematuria from hemorrhagic cystitis following chemotherapy for a malignant lymphoma. Following the intravesical instillation of formalin, which controlled the hematuria, she developed oliguria attributable to ureteric stenosis and fibrotic contraction of the renal pelves. Bilateral nephrostomies were constructed, but recurrent pyelonephritis and further renal pelvic obstruction developed. A series of renal biopsies and ultimately bilateral nephrectomy revealed severe, chronic interstitial nephritis, massive renal interstitial accumulation of deposits probably containing Tamm-Horsfall protein and, in the left nephrectomy specimen, a florid interstitial chronic granulomatous inflammatory reaction. Although ureterohydronephrosis has been described by others as a complication of the intravesical instillation of formalin, fibrotic contraction of the upper urinary tract and the florid interstitial nephritis with granulomata as described herein have not previously been reported. It is proposed that vesicoureteric reflux of formalin, perhaps accompanied by intrarenal reflux, caused or contributed to these pathological changes.

Glomerular transplant rejection: a distinctive pattern of early graft damage.

Five hundred seventy-six consecutive biopsy or nephrectomy specimens obtained during the first 6 months of transplantation from 300 grafts in 431 recipients were examined by light microscopy for focal or diffuse endocapillary hypercellularity. Forty-seven (8.2%) of the 576 specimens obtained from 37 (12.3%) of the 300 grafts exhibited segmental or global occlusion of capillaries by swollen cells in 40-100% of glomeruli per biopsy. The lesions occurred at any time after transplantation, but 34 (72.3%) were present by day 60 and 7 (14.9%) before day 10. Immunofluorescence in 39 affected biopsies revealed focal or segmental glomerular staining in 18 (46.2%), among which IgM was found most frequently, and was considered to be non-specific. Electron micrographs of 17 biopsies from 14 grafts revealed that glomerular capillaries were narrowed or occluded by mononuclear cells of uncertain type, possibly monocytes, as well as lymphocytes and a few neutrophils. Complement-fixing antibody titers to cytomegalovirus rose at least fourfold in 10 (45.5%) of the 22 patients studied, but glomerular lesions were no more severe in the seroconverters than in the non-converters, and there was no consistent temporal relationship between the occurrence of glomerular changes and seroconversion. Cellular or vascular rejection was present in most biopsies. One year graft survival was 34% among 35 accessed grafts with glomerular lesions, compared to 55% among 243 biopsied grafts with no glomerular changes. We consider that these lesions do not have a consistent association with cytomegalovirus infection and that they represent a distinctive form of glomerular rejection. Whether they indicate a poor graft survival, as the present results suggest but do not prove, requires further studies of other series of cases.

Recurrent focal glomerulosclerosis in renal transplants.

Among 431 renal transplants in 380 patients, 4 patients were identified with focal glomerulosclerosis characterized by presentation with corticosteroid-resistant nephrotic syndrome, early development of histological lesions, mesangial proliferation and rapid progression into chronic renal failure. After transplantation, all patients had early proteinuria and the 4 grafts surviving beyond 3 months developed recurrent glomerular lesions with severe nephrotic syndrome and progression to graft failure. In one patient, recurrent disease developed in two successive grafts. Focal glomerulosclerosis is a nonspecific glomerular lesion, but identification of specific clinical and pathological features may provide guidelines that will predict the risk of its recurrence in transplanted kidneys.

Bilirubin-associated renal papillary necrosis in the homozygous Gunn rat: light-and electron-microscopic observations.

Homozygous members of the mutant Gunn strain of Wistar rats suffer an inherited autosomal recessive deficiency of glucuronyl transferase resulting in unconjugated hyperbilirubinaemia and jaundice. Unconjugated bilirubin visibly accumulated in the interstitium of the renal papillary tip. The deposit is followed by necrosis, first of intersitital cells, loops of Henle and vasa recta and later of collecting ducts. The necrotic, acellular papillary tip eventually separates. Cortical scars correlate with established papillary necrosis. The bilirubin occurs in two ultrastructural forms, crystalline and fibrillar. The deposit is found initially in the interstitium and around but not within basement-membranes. It is accompanied by cytoplasmic adaptive or degenerative changes and loss of cells by desquamation and coagulative necrosis. The lesion can be regarded as a chronic, progressive papillary necrosis similar in its evolution to the papillary necrosis of analgesic nephropathy.

Calcification in the renal medulla; a classification based on a prospective study of 2261 necropsies.

Kidneys from 1864 necropsies performed in Brisbane, Australia, and from 397 necropsies performed in Christchurch, New Zealand, were examined macroscopically and microscopically. Three zonal and three focal patterns of renal medullary calcification were defined: (1) Outer medullary cortical calcification seen in hypercalcemic conditions. (2) A band of calcification at the boundary of the inner and outer medullar associated with degenerative changes and correlated with aging and arteriolar disease. (3) Calcification concentrated around the loops of Henle in the papilla, sometimes a striking finding in children and common at all ages. Heavy calcification in this region was injurious to the loops. (4) Fine focal calcification in random distribution throughout the medulla. This lesion was seen in virtually all adult necropsies to some degree. (5) Coarse focal deposits in the papillary region, more common in males and in a hotter climate. (6) Randall's plaques also were common in males and in a hotter climate.