A rare diagnosis： testicular dysgenesis with carcinoma in situ detected in a patient with ultrasonic microlithiasis

A rare case is presented where a dysgenetic testis with microinvasive carcinoma in situ （CIS, also known as intratubular germ cell neoplasm of unclassified type [IGCNU] and testicular intraepithelial neoplasia [TIN]） with microinvasion to rete testis and the interstitial tissue was found in a 32-year-old man presenting with mild scrotal pain and ultrasonic testicular microlithiasis. Knowledge of the association of ultrasound and CIS is important to diagnose patients at the stage prior to development of an overt germ cell tumor. The patient had three of four disorders considered symptoms of the testicular dysgenesis syndrome （TDS）： a dysgenetic left testicle with CIS, a mild left-sided cryptorchidism （high positioned scrotal hypotrophic testis） and a slightly reduced semen quality. Therefore, it should be kept in mind that a patient with one TDS symptom may harbour the other, even CIS or testicular cancer. Accordingly, patients with one TDS symptom ought to be examined for the presence of the others, and if more that one is present, extra concern is warranted.     

睾丸源性生殖障碍综合征研究进展

睾丸源性生殖障碍综合征(TDS)是近10年来男性不育领域研究的热点。环境内分泌干扰因子作用于睾丸Leydig细胞和/或Sertoli细胞致使睾丸发育异常,从而导致TDS症状的出现是被广泛接受的发病机制。分子生物学研究提示类胰岛素样因子3(INSL-3)、雄激素受体(AR)、P27kip蛋白、WT-1基因及副中肾管抑制物(M IS)等可能与TDS的发病有关,本文对TDS的病因、机制及研究进展等进行了综述。     

Testicular carcinoma in situ in subfertile Danish men

Carcinoma in situ (CIS) testis is the precursor stage for the majority of testicular germ cell tumours (TGCT). Infertility is one of the conditions known to predispose to TGCT, but based on scarce existing data, the prevalence of CIS in this risk group was estimated at only approximately 1%. To establish more objective data, we investigated retrospectively the prevalence of CIS based on testicular biopsies performed in a well-defined group of subfertile males. We included 453 patients who had testicular biopsies performed for infertility reasons during 1995-2005 at the Copenhagen University Hospital (Rigshospitalet). Biopsies were evaluated by two experienced observers independently. CIS was detected in 10 individuals, of whom three had bilateral CIS, corresponding to a prevalence of 2.2% (95% CI 1.1-4.0%). This is greater than the estimated risk of 0.45% for the age- and birth cohort-matched general Danish population. All patients with CIS testis had severe oligozoospermia (相似文献   

Current approaches for detection of carcinoma in situ testis

Testicular germ cell tumours have a favourable prognosis if detected early, but are potentially lethal in a subset of patients. Multi-modality treatment is often necessary, thus the preferable time of diagnosis is at the pre-invasive, but unfortunately often asymptomatic precursor stage of carcinoma in situ (CIS). This review describes current possible approaches for the detection of CIS. At present, an open testicular biopsy is the only definitive way of establishing the presence of CIS. The tissue section should be of an adequate size, be properly fixed, and evaluation be supported by at least one solid immunohistochemical marker, for example PLAP, OCT-3/4 or AP-2gamma. Determination of who should be offered testicular biopsies is based on clinical and ultrasonic examination along with the evaluation of risk factors. A surgical biopsy is an invasive procedure with potential complications, although rare. Therefore, a noninvasive and equally reliable method is needed. Testicular ultrasound is risk-free, painless and at present the only noninvasive method of aid for andrologists when CIS is suspected. The presence of testicular microlithiasis is, in some cases, indicative of pre-malignant changes, especially in males with additional risk factors. Promising results have recently been obtained with a novel noninvasive detection method based on immunocytological AP-2gamma-staining of CIS cells in semen. This method could be a supporting method in andrology centres where careful follow-up is possible. In conclusion, one difficulty is to determine in which males CIS should be suspected; secondly, there does not as yet exist an optimal noninvasive method of diagnosis that is more acceptable than an open surgical biopsy.     

Lipoprotein lipase and endothelial lipase in human testis and in germ cell neoplasms

The aim of this study was to investigate endothelial lipase (EL, LIPG) and lipoprotein lipase (LPL) mRNA and protein expression in normal human testis and testicular germ cell tumours (GCT). Both EL and LPL were expressed in normal seminiferous tubules and in the interstitial compartment. EL mRNA and protein were found in all germ cells as well as in Sertoli and Leydig cells. EL mRNA was abundant in pre-invasive carcinoma in situ (CIS) cells and GCTs, and EL protein was present in the cytoplasm of these cells. LPL mRNA was also relatively abundant in germ cells, Sertoli cells, CIS cells and GCTs. The LPL protein, however, was restricted to the cell membranes of pachytene spermatocytes and spermatids in normal tubules, absent from CIS cells and scarcely represented in tumours. The distribution of LPL protein in non-seminomas resembled the distribution of OCT3/4, a marker of embryonal carcinoma. The results suggest that both EL and LPL participate in the supply of nutrients and steroidogenesis in the testes, and that especially EL may be important for the supply of cholesterol for testosterone production in the Leydig cells. The partial cellular separation of the expression of the two lipases in normal testis suggests the existence of distinct biological roles, perhaps developmentally regulated, as indicated by the LPL expression in GCTs with embryonic features. A high expression of EL and abundance of lipid in tubules with CIS may have a diagnostic value.     

Evaluation of testicular biopsies for carcinoma in situ: immunohistochemistry is mandatory

Carcinoma in situ (CIS) is the common precursor of all type II testicular germ cell tumors (TGCTs), i.e. seminomas and non-seminomas, which can be diagnosed using a surgical biopsy. The objective of this study was to investigate the additional value of immunohistochemistry for the diagnosis of CIS in assessing testicular biopsies taken in the context of infertility. A series of 21 infertile patients were retrieved from the Dutch pathological database (PALGA), being diagnosed with an invasive TGCT, while a matched previously obtained testicular biopsy was diagnosed as non-malignant. From 20 patients, both the invasive tumors as well as the biopsies were revised using morphology and immunohistochemistry for OCT3/4, placental-like alkaline phosphatase and c-KIT, all known established markers for CIS. The presence of CIS or invasive malignancies was scored. There are no interventions. Morphological criteria alone allowed an experienced pathologist in TGCTs to diagnose CIS in five and an invasive tumor in two cases (total n  = 7, 35%). Application of immunohistochemistry resulted in the identification of an additional four cases of CIS (total n  = 11, 55%, additional value of 20%). The initial correct diagnosis of CIS could have prevented a second gonadectomy in four patients (20%). This study, for the first time, really shows that time of progression from CIS to seminoma is longer than to non-seminoma. Our study demonstrates that immunohistochemistry should be performed for the diagnosis of CIS of the testis on single biopsies obtained because of infertility, resulting in an extra diagnostic yield of at least 20%. Application of this protocol will allow early diagnosis, and therefore prevent any adverse anti-cancer treatment sequelae including gonadectomy, and requiring life long androgen supplementation in some patients.     

Prevalence of carcinoma in situ in testicular biopsies of infertile Iranian men

Almost all testicular germ cell tumours are proved to originate from carcinoma in situ cells. Infertility is one of the factors that increase the risk of carcinoma in situ. The reported prevalence for carcinoma in situ from different parts of the world is 0–3.7% in infertile men. This retrospective study was performed to determine the prevalence of carcinoma in situ in Iranian infertile men. We reviewed the testicular biopsies of 1153 infertile men at the pathology department of Avicenna Infertility Center. One hundred and fifty‐one cases were suspicious of having carcinoma in situ. Immunohistochemical marker for placental alkaline phosphatase was employed to confirm the diagnosis of carcinoma in situ. Positive results were detected in 7 (0.6%) of 1153 cases (95% CI 0.24%–1.24%), 6 (0.94%) of which (95% CI 0.34%–2.04%) were under the age of 35 years (636 patients were in this age group). This study is the first study in Iran determining the prevalence of carcinoma in situ among the infertile Iranian men; the result is in the range of reports from other countries.     

Management of carcinoma-in-situ of the testis

Carcinoma-in-situ (CIS) of the testis progresses to invasive cancer within 5 years in 50% of cases, and therefore requires therapeutic intervention. CIS is probably eradicated by intensive cancer chemotherapy but this is too toxic for the management of non-invasive disease. Eight patients with unilateral testicular cancer and contralateral CIS received localized irradiation (20 Gy in ten fractions of 2 Gy) to the remaining testis: after 3 months the CIS cells had disappeared and 'Sertoli-cell-only' tubules were found. LH and FSH levels were elevated but testosterone levels remained fairly constant. Localized irradiation should be considered as the treatment of CIS in the contralateral testis of testicular tumour patients unless chemotherapy is indicated for the primary tumour. Unilateral orchidectomy is recommended for unilateral CIS associated with infertility or testicular maldescent. Localized testicular irradiation should now be considered for bilateral disease. Patients with the androgen insensitivity syndrome should normally be treated with bilateral orchidectomy, but irradiation may be useful in selected cases.     

The risk profiles of three clinical types of carcinoma in situ of the bladder

Study Type – Therapy (individual cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Although it has been reported that patients with primary carcinoma in situ of the bladder (CIS) have a better prognosis than patients with concomitant or secondary CIS, the risk profiles of these three clinical types of CIS have not yet been fully clarified. The current study was performed to give further insight into the risk profiles of these three clinical types of CIS. In clinical practice it would be helpful to be able to discriminate ‘high‐risk’ from ‘low‐risk’ CIS before the start of intravesical therapy and as such to tailor the treatment and follow‐up to this risk‐profile.

OBJECTIVE

? To further clarify the risk profiles of three clinical types of carcinoma in situ (CIS) of the bladder.

MATERIALS AND METHODS

? Population‐based data from the Comprehensive Cancer Centre Middle Netherlands, as part of the nationwide Netherlands Cancer Registry, were used for patients presenting with CIS in the period from 1987 to 2009. ? Patients with muscle‐invasive bladder cancer on primary diagnosis were excluded. The patients were divided into three groups according to their ‘clinical type’, being primary, concomitant or secondary CIS.

RESULTS

? Overall, 90 patients with CIS were identified with a mean age of 63.4 years, predominantly men (91.1%). Primary CIS (P‐CIS) was found in 43 patients (47.8%), concomitant CIS (C‐CIS) in 21 patients (23.3%) and secondary CIS (S‐CIS) in 26 patients (28.9%). Mean follow up was 81.3 months (range 8–222 months). Recurrence of disease was observed in 68.9% of patients, with significantly more recurrences in the S‐CIS group (88.5%). ? Progression to muscle‐invasive disease was seen in 17 patients (18.9%): eight patients (18.7%) with P‐CIS, four (19.0%) with C‐CIS and five (19.2%) with S‐CIS. Overall, 29 patients underwent a cystectomy, equally distributed over the three groups. The duration of bladder preservation was worse in the C‐CIS group but did not differ significantly between the groups. ? Overall survival at 5 years was 79.6% for the total group, with poorer results for the C‐CIS group, although the difference was not significant.

CONCLUSIONS

? Carcinoma in situ is clearly an entity that requires meticulous treatment and thorough follow up because of its high recurrence rate (68.9%) and high rate of progression to muscle‐invasive bladder cancer (18.9%). ? The C‐CIS group appears to have a poorer prognosis with a shorter duration of bladder preservation and a worse overall survival.     

Testicular germ cell cancer despite previous local radiotherapy to the testis

BACKGROUND: Testicular intraepithelial neoplasia (TIN, also carcinoma in situ of the testis) is the uniform precursor of testicular germ cell cancer. Local radiotherapy to the testis with dosages of 18-20 Gy has been found to safely eradicate TIN and germ cells, too. Thus, the general assumption is that the development of invasive germ cell tumours can be prevented by this radiotherapy. PATIENTS AND METHODS: Herein, we report two patients with one-sided testicular tumour and biopsy-proven contralateral TIN. Both of them developed germ cell neoplasms in the remaining testis although local radiotherapy with 20 Gy had been applied to the testis. RESULTS: One patient developed pure seminoma 7 years after completion of radiotherapy, the other developed a combined tumour consisting of embryonal carcinoma and seminoma after 5 years. Treatment consisted of orchiectomy in each of the cases. Histologically, both had TIN in the testicular tissue surrounding the new growths. CONCLUSIONS: Pathogenetically, a small fraction of radioresistent TIN cells overcoming irradiation and progressing to full-blown germ cell cancer in the later course may be the histogenetic clue to explain these unexpected events. Other explanations, though less probable, could be technical radiotherapeutic failure due to targeting problems and a pre-existing radioresistent germ cell tumour in the irradiated testicle.     

Testicular metastasis from squamous cell carcinoma of the lung

We present a case of squamous cell carcinoma of the testis that metastasized from lung cancer. The patient, who had received left pneumonectomy 2 years earlier for squamous cell carcinoma (SCC) of the lung, developed pulmonary metastasis, which was treated with chemotherapy. Although the recurrence regressed after treatment, the testicular tumor progressed gradually. Left radical orchiectomy was performed. Pathological examination revealed metastatic SCC. Testicular metastasis from lung cancer is a very rare disease.     

Ductal carcinoma in situ in a 27-year-old woman with McCune-Albright syndrome

McCune-Albright syndrome (MAS) is a sporadic disorder characterized by the triad of irregularly edged hyperpigmented macules (café au lait spots); a slowly progressive bone disorder, polyostotic fibrous dysplasia, usually involving the base of the skull and the long bones; and luteinizing hormone-releasing hormone (LHRH)-independent precocious puberty. This case is the first report of a 27-year-old woman with ductal carcinoma in situ (DCIS) and Paget's disease of the nipple associated with MAS. The discussion focuses on two endocrine manifestations of this syndrome including precocious puberty and excess growth hormone secretion. In our patient, both her early puberty and pituitary adenoma, in association with MAS, resulted in excess production and secretion of estrogen and growth hormone. Both of these hormones function to stimulate breast growth and development. We hypothesize they are responsible for this patient's DCIS and Paget's disease of the nipple so early in life.     

Testicular microlithiasis and carcinoma in situ overview and proposed clinical guideline

Testicular microlithiasis (TM) has been associated with testicular germ cell tumours (TGCTs) in adolescents and adults and with its precursor carcinoma in situ (CIS). A clear definition of TM and the need for further diagnostics and follow-up is lacking. We reviewed the literature of TM and its association with TGCT/CIS and current follow-up advises and propose a management approach based on associated risk factors for TGCT. In the literature, a wide variance of TM incidence is reported in different patient populations. A consensus concerning the malignant potential of TM has not been reached. In addition, a clear definition on TM is lacking. Although a correlation between TM and TGCT or CIS is found, precise management and follow-up schedules are absent. We suggest that all hyperechogenic foci smaller than 3 mm without shadowing should be named TM irrespective of their number. In addition, we suggest a management scheme for physicians encountering TM in daily practice. Our algorithm suggests taking a testicular biopsy in a selected patient population with at least one additional risk factor for TGCT. A long-term active follow-up schedule, including ultrasonography and physical examinations, is not indicated in the remaining patients with TM.     

睾丸混合性非精原细胞性生殖细胞癌1例并文献复习

目的:睾丸混合性非精原细胞性生殖细胞癌的文献报道极少,本文旨在探讨睾丸混合性非精原细胞性生殖细胞癌的临床症状、病理特点及诊疗方法。方法:分析1例睾丸混合性非精原细胞性生殖细胞癌的临床资料,并运用组织学、细胞化学和免疫组化技术对该例睾丸混合性非精原细胞性生殖细胞癌进行光镜观察和免疫标记并结合文献就该类肿瘤的临床特征进行探讨。结果:患者以睾丸无痛性肿大3年就诊,病理组织学表现为肿瘤排列结构多样,有乳头状结构、裂隙或腺样结构,细胞大,呈多角形或柱状,核不规则呈泡状,一个或多个核仁,核膜清楚,胞质嗜碱或嗜酸,间质少量淋巴细胞浸润。免疫组化显示:白细胞分化抗原(CD117)(-)、细胞角蛋白(CK8-18)(++)、CD30(++)、CK(+++)、波形纤维蛋白(Vimentin)(-)、胎盘型碱性磷酸酶(PLAP)(±)、抑癌基因产物(P53)(+)、甲胎蛋白(AFP)(+)和上皮膜抗原(EMA)(++)。病理诊断为睾丸畸胎胚胎癌,行手术根治术,按混合性非精原细胞性生殖细胞癌行术后辅助化疗。随访时间l年,健康生存。结论:睾丸混合性非精原细胞性生殖细胞癌是一种罕见的恶性肿瘤,多数临床症状不明显。诊断主要依靠体格检查、B超、CT、血清肿瘤标记物测定等,确诊需要病理学检查,手术切除是其首选的治疗方法。     

Risk counseling and management in patients with lobular carcinoma in situ

BACKGROUND: The understanding of lobular carcinoma in situ (LCIS) has evolved since it was first described. LCIS once was thought to be a premalignant condition, but now it is considered a marker for increased risk for developing invasive breast cancer. We evaluated patient perception of risk, counseling, and subsequent management. METHODS: A community cancer registry of 3,605 cases of breast cancer was reviewed. Fifty-five (1.5%) patients with LCIS as their sole diagnosis were identified and these patients were sent a questionnaire. RESULTS: Forty of 55 patients completed the questionnaire for a 73% response rate. The patients' perception of lifetime risk for invasive cancer was variable. Surgeons performed the majority of counseling. Fourteen patients (35%) were placed on a selective estrogen-receptor modulator. Eleven patients (28%) had bilateral mastectomy. Three patients had unilateral mastectomy. Screening recommendations included an annual mammography (64%), a professional examination (64%), and a monthly self-breast examination (75%). CONCLUSION: A patient's perception of risk for invasive breast cancer after a diagnosis of LCIS is widely variable. Patients will adhere to suggested screening recommendations. Surgeons are performing the majority of counseling and must stay abreast on current recommendations.     

From embryonic stem cells to testicular germ cell cancer-- should we be concerned?

Since the discovery of testicular carcinoma in situ (CIS) -- the precursor cell for the vast majority of germ cell tumours -- it has been proposed that CIS cells could be derived from transformed primordial germ cells or gonocytes. Here, we review recent discoveries not only substantiating that initial hypothesis but also indicating that CIS cells have a striking phenotypic similarity to embryonic stem cells (ESC). Many cancers have been proposed to originate from tissue-specific stem cells [so-called 'cancer stem cells' (CSC)] and we argue that CIS may be a very good example of a CSC, but with exceptional features due to the retention of embryonic pluripotency. In addition, considering the fact that pre-invasive CIS cells are transformed from early fetal cells, possibly due to environmentally induced alterations of the niche, we discuss potential risks linked to the uncontrolled therapeutic use of ESC.     

Triad of columnar cell alteration, lobular carcinoma in situ, and tubular carcinoma of the breast

Columnar cell alteration in the breast encompasses a spectrum of pathologic changes ranging from simple columnar cell change to more complex columnar cell hyperplasia with and without atypia to in situ carcinoma, often with a micropapillary architecture. For reasons that remain unclear, the columnar cell lesions are associated with tubular carcinomas and lobular carcinoma in situ. Therefore it is important to be familiar with the spectrum of changes and the associated lesions, especially in breast core biopsies for further management.