Treatment of testicular intraepithelial neoplasia (intratubular germ cell neoplasia unspecified) with local radiotherapy or with platinum-based chemotherapy: a survey of the German Testicular Cancer Study Group.

BACKGROUND: The treatment of testicular intraepithelial neoplasia (TIN), the progenitor of testicular germ cell tumours (GCTs), is based on little data. PATIENTS AND METHODS: Two hundred and twenty-eight GCT patients with contralateral TIN were retrospectively enrolled. Ten had surveillance, 122 radiotherapy to testis with 18-20 Gy, 30 cisplatin-based chemotherapy (two cycles), 51 chemotherapy (three cycles), and 15 carboplatin. The study end point was a malignant event (ME), defined as detection of TIN upon control biopsy or occurrence of a second GCT. The Secondary end point was hypogonadism during follow-up. RESULTS: Numbers, proportions of ME, and median event-free survival (EFS) times were: radiotherapy N = 3, 2.5%, 11.08 years; chemotherapy (two cycles) N = 15, 50%, 3.0 years; chemotherapy (three cycles) N = 12, 23.5%, 9.83 years; carboplatin N = 10, 66%, 0.9 years; surveillance N = 5, 50%, 7.08 years. EFS is significantly different among the groups. Hypogonadism rates were in radiotherapy patients 30.8%, chemotherapy (two cycles) 13%, chemotherapy (three cycles) 17.8%, carboplatin 40%, surveillance 40%. CONCLUSIONS: Local radiotherapy is highly efficacious in curing TIN. Chemotherapy is significantly less effective and the cure rates are dose-dependent. Though hypogonadism occurs in one-third of patients, radiotherapy with 20 Gy remains the standard management of TIN.

Testicular biopsy for early cancer detection--objectives, technique and controversies.

This review highlights the usefulness of testicular biopsy for early detection of testicular germ cell tumour (GCT). GCT develops through a precursor stage, called testicular intraepithelial neoplasia (TIN; also called intratubular germ cell neoplasia or carcinoma in situ, CIS), which is present many years before invasive malignancy occurs. TIN/CIS is safely detected histologically. TIN is usually widely but non-randomly distributed within the testicle, thus, a biopsy of 3 mm size usually indicates the presence of TIN. Surgically, testicular biopsy should be performed at the cranial pole. Two-site biopsies provide an 18% diagnostic yield over single biopsy. Surgical complications occur in about 2.8%, most of which are managed conservatively. Serial scrotal imaging studies after biopsies revealed significant early changes. Eighteen months thereafter, less than 5% of cases have changes detectable. False-negative biopsies are extremely rare. Biopsy also provides information regarding spermatogenesis. In case of diagnosis of TIN, orchiectomy is rarely required. Low-dose radiotherapy eradicates TIN. In conclusion, testicular biopsy is useful in patients with unilateral GCT to explore the opposite testis, and in patients with retroperitoneal GCT to look for occult testicular primary. Further candidates for biopsy are selected patients with sonographic testicular microlithiasis. Despite its usefulness, the procedure has been implemented in clinical routine only in few countries thus far.

[Results of the randomised phase III study of the German Testicular Cancer Study Group. Retroperitoneal lymphadenectomy versus one cycle BEP as adjuvant therapy for non-seminomatous testicular tumours in clinical stage I]. / Ergebnisse der randomisierten Phase-III-Studie der "German Testicular Cancer Study Group". Retroperitoneale Lymphadenektomie vs. 1 Zyklus PEB als adjuvante Therapie beim nichtseminomatösen Hodentumor im klinischen Stadium I.

OBJECTIVE: As 30% of non-seminomas in clinical stage I will progress during active surveillance, alternative adjuvant strategies of 2 cycles of bleomycin, etoposid, cisplatin (BEP) or nerve sparing retroperitoneal lymphadenectomy (RPLND) can be offered. The risk of relapse is reduced to 2% and 10%, respectively. Without prognostic markers and with lowered toxicity it is postulated that only one cycle of BEP could significantly reduce the recurrence rate in comparison to RPLND. MATERIALS AND METHODS: Between 1996 and 2005, 382 patients were randomly assigned to receive either RPLND (n=191) or 1 cycle of BEP (n=191). In accordance with the protocol, 174 patients were treated with 1 cycle of BEP and 173 underwent RPLND. The primary study end-point was a reduction of recurrence from 10% after RPLND to a maximum of 3% after 1 cycle of BEP. RESULTS: After a mean follow-up of 4.7 years, there were 2 and 13 recurrences in the according-to-protocol population with chemotherapy and surgery, respectively. The difference between chemotherapy (1.15%) and surgery (7.5%) was statistically significant (p=0.0033). The tumor-specific survival was 100%. CONCLUSION: This largest randomized trial investigating treatment strategies in clinical stage I non-seminomas (AUO AH 01/94) showed the superiority of one cycle BEP over RPLND. The data obtained represent the basis for a reduced chemotherapy.

Visual estimation of the tumor volume in prostate cancer: a useful means for predicting biochemical-free survival after radical prostatectomy?

Absolute and relative (ratio absolute tumor volume to gland volume) tumor volumes were visually estimated in 528 prostatectomy specimens. Surveying a mean post-surgical follow-up of 49 months, both parameters were analyzed regarding their aptitude for prognostication. We found relative tumor volumes exceeding 25% to independently predict biochemical recurrence reflected by post-surgical prostate-specific antigen progression, which was also determined to be increased to 28% when absolute tumor volumes exceeded 10 cm(3). However, this cutoff failed to be an independent prognosticator. Because the visual estimation of both parameters can easily be performed, they are felt to be formidable candidates for deriving prognostic information during routine procedures.

Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms.

PURPOSE: Testicular intraepithelial neoplasia ([TIN], so-called carcinoma in situ of the testis) is hypothesized to be the precursor of testicular germ cell neoplasms. According to previous studies, it can be detected by testicular biopsy. Since patients with a unilateral testicular tumor are at high risk of a second testicular tumor, it seemed feasible to examine the prevalence of contralateral TIN in patients with testicular germ cell cancer and correlate it with the known prevalence of bilateral testicular tumors. The aim was to provide more evidence for the role of TIN as the preinvasive stage of testicular cancer. PATIENTS AND METHODS: Nineteen hundred fifty-four consecutive patients with a unilateral testicular germ cell tumor underwent contralateral biopsy. All specimens were examined immunohistologically. RESULTS: TIN was observed in 4.9% (95% confidence interval [CI], 3.95% to 5.91%). Testicular atrophy and a history of undescended testis were more frequently observed in patients with contralateral TIN, but only atrophy was shown to be independently associated by multivariate analysis. Patients with testicular atrophy have a 4.3-fold increased risk of having contralateral TIN. Sixty-four percent of TIN cases were found in normal testes. Patients with TIN were significantly younger than those without (P < .0017). Three patients developed a second testicular tumor despite a negative biopsy for TIN. CONCLUSION: The prevalence of contralateral TIN corresponds well to the known prevalence of bilateral testicular tumors. Testicular atrophy is a strong indicator for the presence of TIN, but approximately 60% of TIN cases occur without atrophy. The present data are in accordance with the theory that TIN is an early step in the histogenesis of testicular germ cell neoplasms.

Contralateral biopsies in patients with testicular germ cell tumours: patterns of care in Germany and recent data regarding prevalence and treatment of testicular intra-epithelial neoplasia.

The precursor of testicular germ cell tumours (GCTs), called testicular intra-epithelial neoplasia (TIN/CIS), is safely diagnosed immunohistologically. Testicular biopsy provides a valuable tool for early detection of GCTs in risk groups. Although this knowledge is undisputed, testicular biopsies are utilized poorly. The patterns of care regarding the use of biopsies remain unknown. Uncertainty exists about the prevalence and specific treatment of TIN/CIS. We asked clinical urologists in Germany whether or not they employed contralateral biopsies in GCT patients. We evaluated the prevalence of contralateral TIN/CIS in a retrospective analysis of 780 consecutive GCT patients. All had contralateral double biopsies. Discordance of TIN/CIS findings among biopsy pairs as well as age, histology of the primary tumour and clinical stage was noted. Evaluation of data comprised descriptive statistical methods. To evaluate treatment options for TIN/CIS, we performed a literature search. 52.1% of German urologists always perform the biopsy, 17% do it mostly, 27.3% in select cases, 3.5% never. Curiously, there was a geographic north-south gradient regarding biopsy use. Contralateral TIN/CIS was found in 5%. The median ages of patients with TIN/CIS and those without were 31.8 and 34.9 years respectively (p = 0.02). The discordance rate among biopsy pairs was of 33%. Two-site biopsies provide a 17% gain in diagnostic sensitivity. Local radiotherapy with 20 Gy is the safest treatment of TIN/CIS failing in 2%. Chemotherapy has significantly lower efficacy. Contralateral testicular biopsies in GCT patients are well accepted among German urologists. The prevalence of contralateral TIN/CIS found in this series is in accordance with previous reports. Double biopsies should be the diagnostic standard because of their diagnostic superiority. Local radiotherapy with 20 Gy is the safest way of eradicating TIN/CIS. Failures occur in only 2%, usually many years after irradiation. Cisplatin-based chemotherapy is dose dependent and less effective.

The value of the biopsy of the contralateral testis in patients with testicular germ cell cancer: the recent German experience.

PURPOSE: Testicular intraepithelial neoplasia (TIN; so-called carcinoma in situ of the testis), the precursor of testicular germ cell neoplasms can be detected by testicular biopsy many years before the clinical manifestation of the tumour. This study looked at the prevalence of contralateral TIN in patients with testicular germ cell cancer. The purpose was to evaluate this new approach of early detection of testicular cancer and to evaluate the current management strategies. PATIENTS, METHODS: 1954 consecutive patients with unilateral testicular germ cell tumour underwent contralateral biopsy. All specimens were examined immunohistologically with staining for placental alkaline phosphatase. Patients with TIN were usually submitted to low-dose radiotherapy of the testis. A rebiopsy was performed after 3 months. Endocrinological evaluations were done before, during and after treatment. RESULTS: TIN was observed in 4.9% (95% confidence intervals 3.95%-5.91%). Testicular atrophy constitutes a 4.3 fold increased risk of having contralateral TIN. 64% of the cases with TIN were found in clinically normal testes. Patients with TIN were significantly younger than those without (p < 0.017). No case with TIN was found in patients older than 50 years. Three patients developed a second testicular tumour during follow-up despite a negative biopsy. After radiotherapy, all of 23 patients had complete disappearance of TIN in the rebiopsy. After chemotherapy, 3 of 10 patients had persistent TIN histologically. After radiotherapy, 12 of 41 patients required testosterone replacement. CONCLUSION: The prevalence of contralateral TIN accords well with the known prevalence of bilateral testicular tumours. Testicular atrophy is a strong indicator for the presence of TIN but about 60% of TIN-cases occur without atrophy. Local radiotherapy to the testis with 18-20 Gy is efficaceous in eradicating TIN, but it causes significant damage to almost one quarter of these patients. Chemotherapy is an unsafe treatment for TIN. This study shows the feasibility of early detection of testicular cancer in a high-risk population by means of searching for TIN. Although the management of the condition still needs refinement, the TIN-concept offers an avenue for the early detection of testicular cancer and early conservative management.

Low-dose radiation therapy for testicular intraepithelial neoplasia.

Four patients with unilateral testicular germ-cell tumor and biopsy-proven contralateral testicular intraepithelial neoplasia (TIN; so-called carcinoma in situ) received localized low-dose radiation therapy (18-20 Gy) of the testis with TIN. Repeated biopsies disclosed the disappearance of TIN and germ cells. No recurrence of TIN or germ cells was observed after a follow-up of 18-42 months. All patients reported a normal sex life without need of androgen supplementation. Serum follicle-stimulating hormone increased significantly immediately after radiation treatment and started to decline after 24 months. Serum luteinizing hormone increased slightly but not significantly. A decline after 24 months was observed in only one of three patients. Serum testosterone decreased significantly in all patients after 1 year but never became subnormal. Low-dose radiation treatment is efficacious in eradicating testicular intraepithelial neoplasia without destroying Leydig cells or stromal cells of the testis. Thus, a patient otherwise destined to develop a second testicular tumor can be spared orchiectomy and life-long hormonal replacement.

False-negative biopsy for testicular intraepithelial neoplasia.

A routine biopsy of the contralateral testis obtained during orchiectomy for embryonal carcinoma in a 26-year-old patient was negative for testicular intraepithelial neoplasia (TIN; carcinoma in situ of the testis). However, a rebiopsy that was taken because of unexplained elevation of alpha-fetoprotein 15 months later proved to be positive for TIN. Six previously reported cases of false-negative testicular biopsies obtained during a search for TIN are reviewed. In the light of several thousands of biopsies performed world-wide to date, the number of false-negative biopsies is probably very low. Although TIN is obviously not randomly dispersed throughout the testis in all patients, a routine biopsy of the contralateral testicle in patients with testis cancer remains a valuable tool for early detection of bilateral testicular tumors.-cal distribution of TIN in testes removed for this lesion. Their results suggested that after puberty TIN is usually randomly dispersed throughout the testicle. Support for this concept was recently given by Mumperow et al. (1992). These authors examined tumor-bearing testes and they did not find differences in the presence of TIN in biopsies taken from a location close to the tumor and taken from a location distant from the tumor. Thus, one single biopsy is regard to be representative for the entire testis and one biopsy taken after puberty is also assumed to be reliable for predicting whether the testis will ever develop cancer (Berthelsen and Skakkebaek 1981 a). Conversely, if the biopsy is negative for TIN, a future tumor manifestation in the testicle examined is not expected according to this theory (Skakkebaek et al. 1987). Taken together, the concept of TIN would constitute an ideal avenue for the early detection of testis cancer in high-risk populations with the biopsy being a safe means of discriminating between individuals who will or who will not develop testis cancer.

Nesidioblastosis of the pancreas in an adult with persistent hyperinsulinemic hypoglycemia.

The rare finding of pancreatic nesidioblastosis in an adult is described. A 43-year-old woman presented with a two-year history of hypoglycemic hyperinsulinism. Extensive diagnostic procedures revealed no insulinoma. Subtotal (75%) pancreatectomy relieved her symptoms; she has normal insulin levels 2.5 years after surgery. The pancreatic specimen revealed only discrete islet cell abnormalities, namely B-cells budding off ductular epithelium, islets in apposition to ducts, slight islet cell hypertrophy, and islet enlargement. Immunohistochemistry showed normal total endocrine cell content as well as normal proportions of islet cell subpopulations. Review of 20 cases in the literature and the authors' experience led to subtotal (75-90%) pancreatectomy as the treatment of choice. The authors conclude that the pediatric disease of nesidioblastosis may rarely occur in adults and that the paucity of histologic findings makes the exclusion of an insulinoma mandatory.

Immunohistological determination of proliferative activity in seminomas.

The proliferative activity and growth pattern of 20 seminomas were determined immunohistologically with the monoclonal antibody Ki-67. A growth fraction of tumour cells between 50 and 80% was found in seminomas with an almost even distribution of proliferating cells in all sections, regardless of tumour size. There was a slight tendency towards a greater growth fraction in tumours at an advanced histopathological stage. No positive correlation could be found between growth fraction and tumour size or lymphocytic infiltration. The results confirm the well known sensitivity of seminomas to radiation and chemotherapy and show that the determination of proliferative activity should be included in the histopathological routine diagnosis of malignant tumours with regard to systemic treatment and prognosis.

Characterisation of adenoid cystic carcinoma of the breast by immunohistology.

An adenoid cystic carcinoma of the breast in a 78 year old woman was analysed immunohistologically for the production of type IV collagen, the expression of vimentin, epithelial membrane antigen (EMA) and steroid receptors, and the proliferative activity of the tumour cells. The data were compared with those obtained in eight adenoid cystic carcinomas of salivary glands and in ductal carcinomas of the breast with a cribriform growth pattern. The patients' ages were as follows: 45-80 years (mean 63.2) for the salivary gland carcinomas; 37-69 years (mean 50.6) for the ductal breast carcinomas. In contrast to the cribriform spaces of ductal carcinomas, the pseudocysts in adenoid cystic carcinomas were lined by type IV collagen. The opposite pattern was observed for EMA. Like the myoepithelium of normal breast, the myoepithelium-like cells of adenoid cystic carcinoma stained positive for vimentin while the ductular epithelium-like ones did not. All adenoid cystic carcinomas, including that of the breast, were negative for the oestrogen and progesterone receptors, unlike the ductal carcinomas. Proliferative activity of the adenoid cystic carcinoma of the breast was relatively low. These data broaden the range of antibodies suitable for differential diagnosis of both tumour types. They may explain the differences in prognosis, and they explain why hormonal treatment or radiotherapy of adenoid cystic carcinoma of the breast are often ineffectual.

Testicular sex cord stromal tumour with granulosa cell differentiation: detection of steroid hormone receptors as a possible basis for tumour development and therapeutic management.

A testicular sex cord stromal tumour with granulosa cell differentiation, typical of granulosa cell tumours of the adult type, was investigated immunohistologically on snap frozen and paraffin wax embedded material. The predominance of vimentin and the additional expression of cytokeratin subtypes 8 and 18, as well as the negative staining for epithelial membrane antigen, accorded with results previously reported, for ovarian granulosa cell tumours; the lack of expression of desmoplakin, however, was a distinctive feature. Together with negative staining for leucocyte common antigen, the antigen pattern facilitates the differential diagnosis between granulosa cell tumour and undifferentiated carcinoma or gonadal lymphoma, although its suitability for differentiating within the group of gonadal stromal tumours seems to be limited. The small growth fraction, shown by the monoclonal antibody Ki-67, is typical of the clinical behaviour of granulosa cell tumours. The expression of oestrogen and progesterone receptors, also recently found in testicular Leydig cell tumours, may provoke new approaches to the management of testicular granulosa cell tumours, as well as a new hypothesis on the development of these tumours.

[The angiographic and morphologic features of angiomyolipoma of the kidney (author's transl)]. / Das Angiomyolipom der Niere aus angiographischer und morphologischer Sicht.

The angiographic and morphologic findings of angiomyolipomas of the kidney are described in three patients. These benign tumours contain three types of vessel in addition to fat and smooth muscle. One vessel type is thick-walled with fibrosis of its walls and no internal elastic lamina. The second type consists of sinuses with considerable variations in calibre. The third type resembles capillaries and is found in the muscular parts of the tumour. Because of the abnormal structure of their walls, these vessels are easily damaged and may cause massive bleeding.

Knowledge-based system ADNEXPERT to assist the sonographic diagnosis of adnexal tumors.

ADNEXPERT is a knowledge-based system for the computer-assisted ultrasound diagnosis of adnexal tumors. In a case-based approach, ADNEXPERT used histopathologic and sonographic data from 2,290 adnexal tumors. After an ultrasound examination, the gynecologist interacts with the system. A maximum of 15 questions are posed; all but one question (age) relate to the sonographic findings. The help system gives online access to an ultrasound image library. Once the dialogue is complete, ADNEXPERT assesses the adnexal tumor pathology and makes a histological classification. A certainty factor (CF) model is used for knowledge representation. The CFs of the knowledge base are computed from the case database. During system evaluation, the accuracy of ADNEXPERT was tested by 69 new adnexal tumor cases, for which verified histopathological diagnoses were available. ADNEXPERT accurately assessed pathology in 49 cases (71%); in 10 cases (14%) correct indications to pathology were given; no diagnostic hints were attained in 2 cases (3%); and 8 cases (12%) were falsely diagnosed. Based on the positive results of the evaluation, ADNEXPERT will be tested under clinical conditions.

Diagnosis and therapeutic management of so-called complicated renal cysts: a report of 4 cases.

We report 4 cases of so-called "complicated cyst of the kidney". The inconclusiveness of the imaging techniques--i.e. ultrasound, ct scan and arteriography--is discussed. The need to explore the affected kidney is emphasized. We advocate a conservative approach to surgery, with the aim of preserving the kidney provided the lesion can be totally removed.

[Management of testicular intraepithelial neoplasia (TIN)--a review based on the principles of evidence-based medicine]. / Therapie der testikulären intraepithelialen Neoplasie (TIN)--eine Ubersicht auf Grundlage der evidenzbasierten Medizin (EBM).

Testicular intraepithelial neoplasia (TIN; also called carcinoma in situ of the testis) is the uniform precursor of testicular germ cell tumors. There is general agreement on the biological significance of TIN, however, the treatment is still a matter of dispute. The present review summarizes the treatment options currently available. In general, the management of TIN has to be adapted to the particular clinical situation of the patient. Eradication of TIN usually implies the loss of fertility. Therefore, fertility aspects should be considered before any kind of treatment is employed. Usually, patients with TIN have only small residual potential of fertility. Nonetheless, individual patients may qualify for sperm banking or cryopreservation of testicular tissue for future sperm extraction (TESE) and assisted fertilization. The most common clinical situation is the case of contralateral TIN in the presence of unilateral testicular cancer. Low dose radiotherapy to the testis with 18 Gy is the standard management option in these patients. The same procedure may be applied to solitary testicles after partial orchiectomy for germ cell tumors. During follow-up, testosterone levels should be evaluated every six months. If chemotherapy is required due to metastatic disease of the primary tumor management of TIN should be deferred. After chemotherapy 30% of TIN cases will persist and approximately 42% will recur in the later course. Repeat biopsy should be done six months after completion of chemotherapy or later. Only in cases with persistent TIN additional radiotherapy should be administered. If one testicle is afflicted with TIN while the other testis is in healthy condition (conceivable in infertility cases or patients with primary extragonadal germ cell tumors), then the TIN-bearing testis should be excised. Radiotherapy is not feasible in these cases because of shielding problems with the healthy testis.

Testicular microlithiasis: case report and discussion of management under special consideration of testicular germ cell tumours.

We report a case of testicular microlithiasis in a 24-year-old man who was referred to us for evaluation of unclear ultrasonographic appearance of his testes while being examined for bilateral varicocele and epididymal cysts. Since testicular microlithiasis has been found to be associated with testicular germ cell tumours we suggest a diagnostic work-up with testis biopsy to rule out testicular intraepithelial neoplasia (so-called carcinoma in situ) in otherwise normal appearing testis.

[Carcinoma in situ of the testis: clinical significance, diagnosis and therapy]. / Das Carcinoma in situ des Hodens: klinische Bedeutung, Diagnostik und Therapie.

The term "carcinoma in situ (CIS) of the testis" is used to mean the presence of atypical neoplastic spermatogonia exhibiting distinct morphological and immunohistological characteristics that differentiate them from normal germ cells. The lesion is considered to be the uniform precursor cell of all germ cell tumors, and it can usually be detected many years before manifestation of the tumor by surgical biopsy and subsequent immunohistological staining for placental alkaline phosphatase (PIAP). This paper gives a review of the theoretical and clinical features of CIS. The description is based on data in the literature and on the authors' experience with two recently detected cases of CIS in the contralateral testis of patients with germ cell tumors. In view of the observation of intraepithelial spread inside the seminiferous tubules, the term "testicular intraepithelial neoplasia" (TIN) is suggested instead of carcinoma in situ.