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IS HEPATIC ANGIOMYOLIPOMA ASSOCIATED WITH TUBEROUS SCLEROSIS?
R.Colombari, F.Bonetti, M.Pea,G.Martignoni, A.Mombello, E.Manfrin, W.M.S Tsui1,B.C. Portmann2, S.N.Thung3, L.D.Ferrell4, Y.Nakanuma5, D.C.Snover', G.M.Mariuzzi and International Liver Pathology Study Group. Istituto di Anatomia Patologica,Universita di Verona, Italy; 'Caritas Medical Center, Hong Kong;2Kings College Hospital, London,UK; 3Mt Sinai Hospital, New York; 4University of California, San Francisco; 5Kanazawa University, Japan;' University of Minnesota, Minneapolis, USA. Background: Angiomyolipoma (AML) is a benign mesenchymal tumor which rarely occurs in the liver. Since its first description by Ishak in 1976, about 60 cases had been reported in the English literature until the end of the Eighties. However, more cases are now being diagnosed as a result of modern radiologic imaging techniques. Most AMLs occur in the kidney, being associated with tuberous sclerosis complex (TSC) in about 20% of the cases. Contrary to renal AML, the association of hepatic AML with TSC is not well defined. As in the kidney, hepatic AML is composed of proliferating blood vessels, mature adipose tissue and smooth muscle cells, the proportion of fat being highly variable. Fine needle aspiration and minute biopsy are routinely used in the diagnosis of liver tumors, leading to serious problems in differential diagnosis, especially in those tumors in which the amount of adipous tissue is low. Materials: A series of 22 cases of hepatic AML has been collected from the files of five different institutions from Eastern and Western countries. Clinico-morphological features have been examined and an immunocyto chemical study with a panel of antibodies, including HMB45, cytokeratins CAM 5.2 and AEl-AE3, S-100,muscle-specific actin HHF35 and desmin has been performed. Results Clinical features are summarized in Table 1. A female predominance (19/22) was found. 9 patients were Caucasian, 8 Asian and 1 Afro-American; in 4 patients no information about their race was available. 2 patients(#5,11) had clinical evidence of TSC and in both cases the association of hepatic AML and renal AML was documented. The follow-up was available in 80% of the cases: in these cases the clinical behavior is that of a benign tumor, in no case recurrence or significant tumor growth after biopsy being observed. Grossly in most cases, the resected specimen contained a well circumscribed, non-encapsulated, soft, variegated yellow-brown mass with a variable extension of haemorrhagic areas. In 3cases (#4,5,19) the AML was multifocal within the liver. The non tumorous liver parenchyma was non-cirrhotic in all cases. Histologically, the tumor was characterized by an admixture of mature fat cells, bloodvessels and smooth muscle cells. In most cases, the smooth muscle component mainly consisted of epithelioid cells distributed in sheets and bundles particularly around vessels. Occasionally the vessels showed a scierous and thick wall. The epithelioid muscle cells were polygonal with a clear or granular eosinophilic cytoplasm. Eosinophilic condensation around the nucleus was common. Bizarre giant cells were found only focally in aminority of cases. Areas with spindle muscle cell were an unusual finding. The proportion of fatty tissue was very variable; the mature lipocytes were observed either as large fat areas or as individual cells scattered throughout the tumor; more, 2 cases were composed exclusively of oxyphilic epithelioid cells, the adipous tissue component being virtually absent. 3 cases exhibited a purely mphangioleio myomatous pattern in which trabecula of epithelioid muscle cells were intermingled with highly anastomosing vascular channels. Sometimes foci of extramedullary hematopoiesis were present, showing islands of erythroblast and megacaryocytic elements. Mitotic figures were virtually absent. Areas of necrosis or haemorrhage, sometimes giving a peliotic appearance, were seen in most of the resected tumors. All cases demonstrated a strong and diffuse HMB4S positivity of epithelioid musclecells. HHF3S actin was focally expressed in only 6 cases. With HMB45, the staining was cytoplasmic and granular with a perinuclear accentuation whereas actin staining showed a perimembranous pattern. The HMB45 positive cells showed no staining with 5- 100.The other immunomarkers were not expressed. 11 patients out of 22 had aninitial histopathologic misdiagnosis of sarcoma (case#9) or epithelialprimary liver tumors, either benign or malignant (Table 1). Conclusions The association of hepaticAML with clinically evident TSC(10%) is not very much different from that reported for renal AML (about 20%). Both TSC patients in our series showed a concomitant renal AML and one of these exhibited a multifocal growth within the liver as well as in other organs. In two more patients, without clinical evidence of TSC, multifocaI hepatic AML was found. As postulated in multifocal AMLs of the kidney, these two cases might represent form efruste of TSC. Therefore every patient with hepatic AML, in particular multifocal AILLS, should be thoroughly examined for the presence of other signs of TSC. No definite morphologic pattern correlates with tumor size and presence of TSC. In general, we observed that the hepatic AML differs morphologically from renal AML in the prevalence of epithelioid muscle cell component over the spindle muscle cell one and in the number of vessels with sclerotic and thick walls within the tumor mass, which is smaller-in the hepatic AML. These epithelioid cells exhibit a morpho-phenotype overlapping that of perivascular epithelial cell (PEC) described in renal AML and in 'sugar' tumor. Pathologists are not very familiar with this rare type of liver tumor, and the histopathologic differential diagnosis with epithelial primary liver tumors and sarcomas represents a very difficult problem, at least until the introduction of HMB4S immuno-marker allowed a better recognition and characterization of epithelioid muscle cells. In fact, only 45 % of the cases in our series had a correct initial diagnosis. Therefore the immunocytochemical analysis, including HMB4S antibody, seems to be necessary for a reliable diagnosis in such types of lesion. Finally, the high frequency of wrong diagnoses in such lesions suggests that the incidence of hepatic AML is actually underestimated. THE NATURAL HISTORY OF RENALDISEASE IN TUBEROUS SCLEROSIS F.J.O'Callaghan, D.W.Webb,M.Noakes, J.Kabala, J.P.Osborne. The Bath Unit for Research intoPaediatrics, Royal United Hospital, Combe Park, Bath, U.K. Renal angiomyolipomata and cysts can occur as a complication of Tuberous Sclerosis (TS). The natural history of these lesions is poorly understood due to a lack of population based longitudinal studies. This study is the first follow-up study of the renal complications of TS on a community based sample. In the Bath Health District in March 1992 there were 23 patients with a confirmed diagnosis of TS. 21 of these patients (10 male, 11 female)underwent detailed investigation for renal manifestations of TS. Investigation included renal ultrasonography, patient interview, measurement of blood pressure. and urinalysis. 7 out of2lhad renal angiomyolipomata and these were bilateral in 6. Maximum size of renal angiomyolipomata ranged from 1 to 9 cm. 2 out of the 7 gave a history of renal symptoms (i.e. flank pain ) and another 2 had +++ microscopic haematuria. 3 out of 21 had cystic disease: I of the 3 had bilateral polycystic disease. This population was followed up at an interval of4 years. They were subjected to the same process of investigation as previously. Examination will be complete by the Summer of 1996 and will provide longitudinal information about the renal complications of TS based upon a population based sample for the first time. PROGESTERONE RECEPTORS IN RENAL ANGIOMYOLIPOMAS G.Martignoni, M.Pea, F.Bonetti,G.Zamboni, E.Manfrin, C. Colato, A Mombello, GM.Mariuzzi.Istituto di Anatomia Patologica, Universita di Verona, ITALY Background Angiomyolipoma comprises a broad clinical spectrum ranging from an isolated unilateral lesion in its mildest form, to massive bilateral and also extrarenal involvement. Whilst most cases show an indolent clinical course, some can occasionally develop to large bilateral tumors, causing symptoms and haemorrhage. In these cases, the surgical treatment can be problematical and renal transplantation has been considered. We have recently demonstrated the morphological and immunophenotypical similarities ofangiomyolipomas1 to other lesions related to tuberous sclerosis, like pulmonary lymphangioleio myomatosis2 , showing that both lesions share the same peculiar cell type, namely a muscle cell with markers of melanogenesis, such as HMB45. It is well known that some patients with lymphangioleio myomatosis can take advantage of hormonal manipulation and this therapeutic approach finds its biological basis in the detection of progesterone receptors in lymphangioleio myomatosis. Design On the basis of the phenotypical similarities of angiomyolipoma and lymphangioleio myomatosis, we have considered the possibility that they might also share the progesterone receptors content. Results We have immuno histochemically tested 25 cases of renal angiomyolipoma, from the files of Istituto diAnatomia Patologica at Verona University, using the standard Abbott procedure on parraffln sections. Six of the 25 cases showed the presence of progesterone receptors-positive cells. The pattern of immuno reactivity is overlapping that of pulmonary lymphangioleio myomatosis. A strong immuno reactivity was present in the nuclei of smooth muscle spindle cells and rarely inepitheloid muscle cells. No immunoreactivity was present in the other cell components, namely adipose tissue and blood vessels. Conclusions These findings stress the similarities of angiomyolipomas with lymphangioleiomyomatosis and provide the biological basis for a hormonal manipulationfor some patients with renal angiomyolipoma. Hormonal therapy in lymphangioleio myomatosis has led to prolonged survival and stabilization of the disease4. References 1. Melanocyte markerHMB45 is regularly expressed in angiomyolipoma of the kidney. Pea M, Bonetti F, ZamboniG et al Pathology 1991 23:185-188 2. Transbronchial biopsy inLymphangioleiomyomatosis of the Lung. HMB45 for diagnosis. BonettiF, Chiodera P Pea M et at. Am J Surg Pathol. 1993; 17(l), 1092-1102 3. Lymphangioleiomyomatosis.Clinical course in 32 Patients. Taylor JR, Ryu J, Colby TV, RaffinTA: N.Engl. J. Med, 1990, 323:1254-1260 4. Lymphangioleiomyomatosis and tuberous sclerosis: Where is the border? Bonetti F & Chiodera PL.Eur. Resp. J, 1996; 9: 399-401 RENAL INVOLVEMENT IN TUBEROUSSCLEROSIS (TSC) M.Ignatova, 0. Katysheva, E.Charina, M.Dorofeeva, V.Bosin, P. Temin, E.Osipova Moscow, Russia It is well known that renal polycystic changes are typical in TSC. On the basis of a linkage study, it was established that, for some patients, the locus of the mutant gene is localized on chromosome 16 (TSC2) near the gene for Autosomal Dominant Polycystic Kidney Disease at 16p13.3. Other variants of renal pathology in TSC are not so well known. The aim of the present study is to show different variants of renal pathology in children with TSC and to analyze the success of Xydiphone treatment. There were 21 children in our study from 19 families with typical skin and brain symptoms of TSC. There was renal pathology in 17 children. We used Xydiphone (X) as a treatment. Xydiphone (an analogue of Disodium Etidronate, Londronat, Bonefos, Clodronate) which is well known as a stabilizer of Ca metabolism and a membranostabiliser. It is produced by the Moscow Chemical-Pharmacological Company in Russia. The X dosage was 10mg/kg every 8 hours for 2-3weeks. Among the patients were two typical pedigrees. In the first family the mother had polycystic kidneys and died from CR1, and an elder sib had mental retardation and adenoma sebaceum. Both younger sisters, age 5 and 7,had typical cutaneous lesions, adenomasebaceum, hypo-and hypermelanotic macules and shagreen patches and the youngest was mentally retarded. Cranial CT showed the existence of multiple calcified subependymal tubers. Ultrasound investigation revealed multiple cysts in the kidneys in both cases. In the second family we examined a six year old boy with typical TSC cutaneous lesions and polycystic kidneys. He had no mental retardation and seizures, but cranial CT revealed calcifications in a typical position. BEG showed a focus of pathological slow wave activity in the left occipital region and a high possibility of paroxysms. His maternal grandmother had polycystic kidneys; other relatives of his mother had a lot of neoplasms (lipomas, fibromas and myomas) and hypomelanotic macules. The proband and these relatives had the same blood group. In the other families with TSC there were other forms of renal involvement: angiolipomatosis in 2 cases; anatomical abnormalities of the urinary system in two children; metabolic nephropathies with oxalate or urate calciumcrystalluria in 9 patients. Similar disorders were found in their families: metabolic disease which included urolithiasis in 3; anatomical abnormalities in 2 and angiolipomatosis in 2 families. The probands and their relatives had similar clinical pictures in the eases of polycystosis, angiolipomatosis and metabolic dysfunctions. After Xydiphone usage brain calcifications decreased or disappeared in almost all cases, but kidney polycystosis was the same. So not only were typical renal polycystic changes found in children with TSC but there were also different variants of renal involvement, and this study will continue. The Xydiphone treatment will be repeated because of the first positive results. REPORTED RENAL CELL CARCINOMAS TUBEROUS SCLEROSIS (TS) COMPRISE A HETEROGENEOUS GROUP OF TUMORS. M.Pea', G.Martignoni1, F.Bonetti1, C.Colato', & J.Bernstein2. Istituto di Anatoinia Patologica, Universita di Verona, Italy' & ResearchInstitute, William Beaumont Hospital, Royal Oak, Michigan, USA2 Introduction Carcinoma of the kidney has been reported in tuberous sclerosis with higher frequency than expected. However the recent identification of a monophasicepitheijoid variant of angiomyolipoma (ANIL) closely simulating carcinoma has cast doubts on the real incidence of renal carcinoma in TS. Immunohistochemical analysis with a panel of antibodies, including melanogenesis marker HMB4j, constantly positive in the perivascular epithelloid cells (PEC) of AML, can discriminate between epithelial cells of carcinomas and epithelioid cells of AML. We have considered the possibility that some tumors reported in the literature as carcinoma is TS may be tumors composed of perivascular epithelioid cells present in AML. Materials and Results We had the opportunity to study five cases from the approximately 30reported renal call carcinomas in TS. The histopathological features are summarized in the following table: All the PEC tumours (#2,3,&4) showed necrosis, high mitotic rate, and mild to severe nuclear atypia. Tumour 5 was composed of plump eosinopiiiiiccells arranged in a solid pattern with intermingled cysts. These features do not fulfil the criteria for any described histopathologic type renal cell carcinoma. Conclusions 1. Some cases reported in the literature as renal cell carcinoma are PEC tumors related to AML. 2. Two of the three patients with PEC morphology and HMB43 positivity died of metastatic disease(Patients 3 & 4). Therefore we conclude that some malignant renal tumoursare related to AML. 3. Although the PEC tumors in this study exhibited malignant morphologic features, more cases are neededo assess the histopathologic spectrum, because at! our cases had been retrieved from a selected series. 4. Patient S seems to have had a novel epithelial renal tumor probably related to the cells lining the cysts of TS kidneys. This tumor resembles the kidney neoplasms of the Ekerrat, the animal prototype of TS. 5. Finally, immunoreactivity for the neural-related cell marker HMB45 in renal tumors associated with an inherited neurologic syndrome, such as TS, warrants further investigation. TUBEROUS SCLEROSIS- ASSOCIATED RENAL CELL CARINOMA: CLINICAL, PATOLOGIC AND GENETIC FEATURES. Elizabeth Petri Henske1 M. Priscilla Short2, David J. Kwiatkowski, and Johannes Bjornsson3 Divisions of Experimental Medicine and Hernatology-Oncology, Brigham and Women's Hospital, Boston, MA1; Department of Neurology, University of Chicago Medical Center, Chicago'L2; Department of Pathology, Mayo Clinic, Rochester MN3 The tuberous sclerosis complex (ISC) is a multisystem autosomal dominant disorder characterized by seizures, mental retardation, and hamartomas. Patients with TSC have been reported to develop renal cell carcinomas (RCC) with increased frequency, an observation which is supported by the Eker rat model. To address the role of the tuberous sclerosis tumor suppressor genes in the pathogenesis of renal cell carcinoma, we studied six TSC-associated RCCs. Our findings suggest that some TSC-associated RCCs have clinical, pathologic, or generic features which may distinguish them from sporadic RCC. Clinically, the TSC-associated tumors occurred at a younger age (mean 37 years) than sporadic tumors and occurred primarily in women. Four of the 6 patients died of metastatic disease. Pathologically, five tumors displayed clear cell morphology. Of those five, two had high-grade spindle cell areas and one had granular cell histology in addition to the clear cell areas. The sixth tumor was anaplastic throughout. Four of the six tumors inimuno stained positively for a melanocyte-associated marker, HMB-45. HMB-45 positivity has been seen in two other TSC lesions: renal angiomyolipomas and pulmonary lymphangiomyomatosis. Loss of heterozygosity (LOH) analyses were performed on five of the tumors. Two had LOH on chromosome 9q34 and one had LOH on chromosome I6p13. We conclude that TSC-associated RCCs occur at an earlier age than sporadic RCCs, that some TSC-associate drenal carcinomas have a different immuno phenotype than sporadic RCCs, and that the TSC tumor suppressor genes may play a specific pathogenic role in these tumors. CYSTIC RENAL DISEASE AND TUBEROUS SCLEROSIS IN INFANTS David B. Glazier M.B..Kenneth B. Cummings M D.. Niichael H. Fleisher M.D.. David P. Murphy, M.D. and Joseph C. Barone M.D. Division of Urology, Dept. Of Surgery, Robert WoodJohnson Medical School, New Brunswick, New Jersey'. USA Approximately l-2% of patients present with angiomyolipomas or renal cysts as the first sign of tuberous sclerosis. Renal cysts maybe the first or only manifestation of tuberous sclerosis in children, but they can also be present in other systemic diseases. Patients are frequently labeled as having adult polycystic kidney disease until they develop skin lesions or seizures.. We have encountered two infants with tuberous sclerosis who presented with multiple renal cysts. The first case is a 7 month old boy referred for bilaterally enlarged kidneys and pigmented skin lesions (biopsy confirmed ash leaf macules). On last follow-up he was33 months old and renal Ainction was essentially normal. The second case is an 8 month old female presenting with focal seizures and signs consistent with tuberous sclerosis on physical examination. She was noted to have bilaterally enlarged kidneys.. She is 15 months old and stable. In both patients, echocardiogram revealed aright ventricular rhabdomyoma, MRI of the brain revealed evidence of conical tubers and both were hypertensive, Children with renal cysts and tuberous sclerosis normally present under three years of age with a gradually enlarging abdomen. Others present as teenagers with renal impairment, or painless gross hematuria. Most are hypertensive at presentation, Ultrasound "ill not differentiate autosomal dominant polycystic kidney disease from tuberous sclerosis. Intravenous pyelography and radio isotoperenal scan will help evaluate the extent of renal involvement. Serial CT scanning and MIQI may help detect small angiomyolipomas, Renal isotope scans delineate renal parenchymal damage. About 40 percent of children 'with cystic disease associated with tuberous sclerosis develop renal failure in their second and third decades. Those co-existing with angiomyolipoma have a poorer prognosis. In children with tuberous sclerosis presenting 'with renal cystic disease, diagnosis may be difficult, as typical manifestations of tuberous sclerosis are often absent. Bilateral renal cysts in an infant requires thorough assessment with history and investigations before a definitive diagnosis can be made. Diagnosis is often based on the extra-renal manifestations of the disease in this challenging group of patients, THE U.K. REGISTRY OF RENAL COMPLICATIONS OF TUBEORUS SCLEROSIS. Dr.J.C.Kingswood & Mrs.S.Hunt. TS Renal Registry, Renal Unit, The Royal Sussex CountyHospital, Eastern Road, Brighton BN2 5BE. The Renal Registry was started in 1996with the aims of documenting the types of renal lesions that occur in TS, their natural history & the effects of treatment. It also aims to act as a resource to provide up-to-date information for patients, their carers & health care professionals & to promote research by putting research groups in contact with patients interested in participating. The information is gathered by means of a questionnaire completed by patients or their carers. Further information is obtained from patients own doctors if necessary (with the patients/families permission). The data is recorded on EPI INFOVersion 6, an epiderniological programme written by the United States Center for Disease Control & tailored for use in TS by Dr.N.J.Lenn (Dept of Pediatric Neurology, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York) who runs the USA TS Registry. Currently the database holds 42 patient records, a further 24 completed questionnaires are expected. 23 patients did not wish to participate. There have been 26 requests from patients/carers or their doctors for information about renal complications. Most of the patients/carers have asked us to discuss their renal problems further with their doctors. Renal complications recorded so far are:- Polycystic Kidney Disease - 2 AML's -18 Other Cysts - 9 Carcinoma -o Flank Pain -10 Microscopic Haematuria - 8 Macroscopic Haematuria - 3Anaemia - 5 Unexplained Fevers - 10 Hypertension - 7 Urinary Tract Infections - 8 Dialysis - 1 Kidney Transplant - 1 Kidney operations/Embolisation - 9 Six patients/carers replied saying they had not been screened for renal problems. It is planned to follow up each patient annually. One collaborative research project is planned so far. In Conclusion: The registry is already fulfilling its aims of assisting in research &acting as an information resource. As data accrues more will be learn about the natural history of renal complications & their treatment. The registry is not a true prevalence study. The information will be complimentary to such studies (e.g. The Bath Prevalence Survey). Care is being taken not to record the same patients in both studies. For further information pleasecontact:- TS Registry. The Royal Sussex County Hospital, Eastern Road,Brighton BN2 5BE. Tel: 01273 696935 Ext: 4282. Fax:- 01273 679788. Acknowledgements : - We wish to express our gratitude to the UK TSA who have sponsored & supported this work. RENAL CELL CARCINOMAIN PATIENTS WITh TUBEROUS SCLEROSIS COMPLEX (TSC) C.W.Shepherd, Craigavon Area Hospital, Northern Ireland and M.R.Gomez, Mayo Clinic, Rochester, Minnesota, USA In the Mayo Clinic study(1930-89) of 343 patients with TSC, there were 3 cases of renal cell carcinoma. All the patients had 1 of the primary diagnostic features of TSC and in all cases the kidneys showed clear pathological evidence of renal cell carcinoma and accompanying angiomyolipomas. Two of the patients were female. The patients were younger than the average age of renal cell carcinoma in patients without TSC. This suggests a higher incidence of renal cell carcinoma in patients with TSC at a younger age. RENAL INVOLVEMENT IN TSC: PRELIMINARY RESULTS OF THE GERMAN PROSPECTIVE SURVERY(TSCPRO). M.Rehm, L.B.Zimmerhackl, T.Rhner, A.Brecht, G.Wiegele, M.Brandis and the members of the German TSC-study group. Universitats-Kinderklinik, Albert-Ludwigs-Universitat, Mathlldenstr. 1, D791O6, Freiburg, Germany The German Prospective Survey concerning visceral involvement in Tuberous Sclerosis was initiated in 1994. During an evaluation period of 26 months, data on 88patients has been acquired. Over a follow-up period of 5 years we want to investigate the natural history of renal involvement. The last update in March 1996 revealed a 65% frequency of renal involvement (57 patients).The incidence of angiomyolipoma was21/37 (37%). Renal cysts were found in 34% of patients and the combination of both lesions in 17%. In 55 patients control examinations of kidney morphology were performed. The imaging technique used in most cases is renal ultrasound. A progression of angiomyolipoma in number and size was found in 10 cases, progression of cystic lesions in 5 and progression of the combination of both lesions in 6. Regression of cysts was reported in 2 patients. Unchanged pathology was found in 13 examinations. Thus is 38% of the control investigations, a progression of renal morphologic alterations could be observed. Two patients with renal angiomyolipoma died during the observation with clinical signs of shock caused by renal haemorrhage. Unfortunately no postmortem examination could be obtained. These findings emphasize the importance of a frequent re-evaluation of the kidney situation at least by renal ultrasound. This home page is intended to be a family resource for families affected by Tuberous Sclerosis. It does not intend to constitute medical advise. Viewers are warned not to take any action with regard to medical treatment relying on the information provided on this page without first consulting the patient's physician.
Deanna Runyan-Wall E-mail address: deannadawn@lukets.org Last updated: April 5, 2008 Created: December 5, 1996 |
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