Search

Lysyl oxidase–like 2 (Loxl2) interacts with and stabilizes Snai1 transcription factor, promoting epithelial-mesenchymal transition. Either Loxl2 or Snai1 knock-down blocks tumor growth and induces differentiation, but the specific role of each factor in tumor progression is still unknown. Comparison of the gene expression profiles of the squamous cell carcinoma cell line HaCa4 after knocking-down Loxl2 or Snai1 revealed that a subset of epidermal differentiation genes was specifically up-regulated in Loxl2-silenced cells. In agreement, although both Loxl2- and Snai1-knockdown cells showed reduced in vivo invasion, only Loxl2-silenced cells exhibited a skin-like epidermal differentiation program. In addition, we show that expression of Loxl2 and Snai1 correlates with malignant progression in a two-stage mouse skin carcinogenesis model. Furthermore, we found that increased expression of both LOXL2 and SNAI1 correlates with local recurrence in a cohort of 256 human laryngeal squamous cell carcinomas. We describe for the first time that high levels of LOXL2 are associated with decreased overall and disease-free survival in laryngeal squamous cell carcinomas, lung squamous cell carcinoma, and lymph node–negative (N0) breast adenocarcinomas. Altogether, our results show that LOXL2 can be used as a new poor prognosis indicator in human squamous cell carcinomas promoting malignant transformation by both SNAI1-dependent and SNAI1-independent pathways. [Cancer Res 2008;68(12):4541–50]

Supplementary Figure 2 from Lysyl Oxidase–Like 2 as a New Poor Prognosis Marker of Squamous Cell Carcinomas

Supplementary Figure 1 from Lysyl Oxidase–Like 2 as a New Poor Prognosis Marker of Squamous Cell Carcinomas

Supplementary Table 3 from Lysyl Oxidase–Like 2 as a New Poor Prognosis Marker of Squamous Cell Carcinomas

Supplementary Figure 3 from Lysyl Oxidase–Like 2 as a New Poor Prognosis Marker of Squamous Cell Carcinomas

Supplementary Table 1 from Lysyl Oxidase–Like 2 as a New Poor Prognosis Marker of Squamous Cell Carcinomas

Supplementary Table 2 from Lysyl Oxidase–Like 2 as a New Poor Prognosis Marker of Squamous Cell Carcinomas

Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy. A distinctive characteristic of KS is oligozoospermia. Despite multiple studies that have described the natural history of the degenerative process of germ cells in patients with KS, the molecular mechanisms that initiate this process are not well characterized. MicroRNA (miRNA)-mediated post-transcriptional control mechanisms have been increasingly recognized as important regulators of spermatogenesis; however, only a few studies have evaluated the role of miRNAs in the gonadal failure of these patients. Here, we describe a differential expression profile for the miRNAs in testicular tissue samples taken from KS patients. We analysed testicular tissue samples from 4 KS patients and 5 control patients (obstructive azoospermia) through next-generation sequencing, which can provide information about the mechanisms involved in the degeneration of germ cells. A distinctive differential expression profile was identified for 166 miRNAs in the KS patients: 66 were upregulated, and 100 were downregulated. An interactome analysis was performed for 7 of the upregulated and the 20 downregulated miRNAs. The results showed that the target genes are involved in the development, proliferation, and differentiation processes of spermatogenesis, which may explain their role in the development of infertility. This is the first report of a miRNA expression profile generated from testicular tissue samples of KS patients.

The volume of ubiquitous chemicals with estrogenic properties is on the rise and some reports relate the increase in hormonal diseases to these compounds. A morphological and immunohistochemical analysis has been performed on 42 bilateral orchiectomy specimens from adult individuals who underwent gender reassignment surgery after receiving crossed-sex hormone therapy to give insight into vascular, inflammatory and epididymal changes following long-term treatment with estrogens and antiandrogens and raise awareness of the consequences of hormone therapy. The present study confirms previously reported findings in testicular parenchyma and epididymis, such as identification of three histological patterns according to lesion severity and cell dedifferentiation, and reports for the first time vascular and inflammatory lesions (atherosclerosis and vasculitis), both on testicle and epididymis. Cross-sex hormone therapy should be provided in specialized units in order to systematize treatments and ensure adequate follow-up.

There are two primitive tumors of the rete testis: adenomas with a benign behavior and adenocarcinomas with a malignant outcome. According to their architectural pattern, adenomas can be solid (sertoliform cystadenoma), papillary (papillary cystadenoma), cystic (cystadenoma), or with a fibromatous stromal component (adenofibromas). In addition to the most common variety, adenocarcinomas of the rete testis include clear cell adenocarcinomas. Two cases have been chosen as representative of this group: a sertoliform cystadenoma and an adenocarcinoma; they both make it possible to comment on the differential diagnosis not only between them but also with other tumors, as it is the case of adenocarcinoma, both primary tumors of the testis and metastases.

Lipomas represent the most frequent benign neoplasm of the spermatic cord followed by leiomyomas and hemangiomas. The most frequent malignant tumors in young people are rhabdomyosarcomas, while in older adults they are liposarcomas.

Following 2016 WHO classification, tumors that meet these three characteristics are included in this group: they are not associated with GCNIS, they do not present 12p chromosome amplification, usually in the form of 12p isocromosome, and they do not settle on testes with testicular dysgenesis. Three entities are included: spermatocytic tumor (type III germ cell tumor), teratoma, prepubertal-type (type I germ cell tumor of the testis), and yolk sac tumor, prepubertal-type (type I germ cell tumor of the testis). The spermatocytic tumor probably originates in premeiotic germ cells (cells in transition between spermatogonias and spermatocytes). Cytogenetically, it is characterized by gains of chromosome 9. It is an exclusive tumor of the testicle and appears in ages older than the tumors derived from GCNIS (mean of age is 52–59 years). In most cases, their behavior is benign. Two cases are included: the first one we could consider characteristic with some peculiarities, and the second one, although it is not admitted as a variant of the spermatocytic tumor, has some interesting and unusual data.

Germinal cell neoplasia in situ (GCNIS) is characterized by the presence of cells morphologically and immunohistochemically similar to gonocytes located inside the seminiferous tubules between the basement membrane and the Sertoli cells. They have spherical nuclei with irregularities in the kariotheca, one or two nucleoli and chromatin granulations. The cytoplasm is broad and clear. Immunohistochemically, these cells express PLAP, OCT3/4, and D2-40, among other markers. In the beginning, they develop in the testicle in a patchy way, and later on they can affect most of the parenchyma. They are a very frequent finding in the peripheral parenchyma of seminomas and their presence is constant in that of non-seminomatous tumors and in 3–5% of the testes contralateral to the tumor. Many of the testicles show other findings of the entity known as testicular dysgenesis. GCNIS is disseminated intratubularly with a pagetoid growth, displacing germ cells, Sertoli cells, and even the epithelial cells of the rete testis into the lumen. In their growth inside the tubules, they can completely take them up while preserving the same cytological and immunohistochemical characteristics (intratubular seminoma), or adopting new ones with cells with higher pleomorphism that do not express PLAP and acquire new markers such as CD30 and cytokeratins (embryonic carcinoma).

Under this umbrella term, there are very diverse entities that only share their absolutely no relationship with germ cell tumors nor with those of the gonadal stroma. Even within the diversity of the entities, it is possible to clearly differentiate four groups of tumors: ovarian epithelial-type tumors, juvenile xanthogranuloma, vascular tumors, and other tumors. Examples of tumors reminiscent of the tumors of the epithelial-like ovarian surface include an example of each of the following entities: serous cystadenoma, serous borderline tumor, serous cystadenocarcinoma, and endometrioid adenocarcinoma. In the subgroup of juvenile xanthogranuloma, an example of this tumor is included in the pediatric age and another one in the adult with its peculiar differential diagnoses. The subgroup of vascular tumors is represented by three cases: the first one a capillary hemangioma, the second one a hemangioma in the pubertal age with macroorchidism, and the third one a curious case of diffuse hemangiomatosis of the testicle. The fourth subgroup consists of examples of each of the following entities: testicular adrenal rest tumor, intratesticular inflammatory myofibroblastic tumor, low-grade myxofibrosarcoma of the testis, myxoid neurofibroma of the tunica albuginea, and intratesticular mesothelial cyst.

This category includes tumors that present complete or incomplete differentiation towards Leydig cells, Sertoli cells, granulosa cells, and theca cells. In the prepubertal age, they are the most frequent (25%) of all testicular tumors, but much less frequent in adults (2–5%). These data are probably related to the high incidence of germ cell tumors in adulthood. The most frequent ones are Leydig cell tumors, followed in decreasing order of frequency by Sertoli cell tumors, granulosa cell tumors, unclassified sex cord-stromal tumors, and theca tumors. Cases have been chosen taking into account that they represented all ages, different forms of clinical presentation, and different biological behavior. Eight cases of Leydig cell tumor are included, among which there are functioning cases (precocious puberty, gynecomastia, infertility), non-functioning with infrequent morphological findings (bone and adipose metaplasia, microcystic and myxoid patterns, associated with Leydig cell nodular hyperplasia) and with malignant behavior. Eight cases of Sertoli cell tumors (adenoma, NOS, sclerosing, large Sertoli cells with calcifications, intratubular large cell hyalinizing Sertoli cell neoplasia). Three granulosa cell tumors, two juvenile-type with different patterns (follicular and solid) and one adult-type granulosa cell tumor, a fibrothecoma, a myoid gonadal stromal tumor, and three mixed and unclassified sex cord stromal tumors.

Several tumors that have little to do with each other are grouped under this heading, except for the preferred location in the epididymis and tunica vaginalis. Two examples of adenomatoid tumor are included: one of the epididymis, another one an intratesticular tumor; two cystadenomas of the epididymis, one papillary, another one solid; one primary adenocarcinoma of the epididymis; one tumor of adrenal remnants in the epididymis; one malignant mesothelioma of the tunica vaginalis and a cystic lymphangioma of the epididymis. In most of them the architectural pattern is diagnostic, but in others, as the solid pattern epididymis cystadenoma, primary adenocarcinoma of the epididymis and mesothelioma of the tunica vaginalis, the help of immunohistochemistry may be necessary.

Most tumors containing both germ cell and sex cord-stromal elements are characterized by combining in a harmonic way, in nests or cords, two cell types, germ cells (some similar to gonocytes) and cells of the sexual cords (similar to immature granulosa cells). This is the case of gonadoblastomas. The three cases of gonadoblastomas chosen are representative of the different gonads in which it can develop, one on a streak gonad of a patient with Frasier syndrome (gonadal dysgenesis 46, XY and nephropathy), another on a dysgenetic testis with AMH (dysgenetic male pseudohermaphroditism) deficit, and the third one in a gonad associated with seminoma of a patient with 46,XY gonadal dysgenesis. Throughout the three cases we expose: (a) the different patterns that may be present in the gonadoblastomas (nodular, dissecting) and the relationship with the undifferentiated gonadal tissue (UGT); (b) the evolution of this neoplasia either towards regression by calcification, or progression to a germ cell tumor; and (c) the differential diagnosis with other entities with which the gonadoblastoma has certain morphological similarity. This is the case of Sertoli cell nodules with infiltration by GCNIS or gonadoblastoid testicular dysplasia.

Normal testicular physiology requires appropriate function of endocrine glands and other tissues. Testicular lesions have been described in disorders involving the hypothalamus-hypophysis, thyroid glands, adrenal glands, pancreas, liver, kidney, and gastrointestinal tract. Testicular abnormalities can also associate with chronic anemia, obesity, and neoplasia. Although many of the disorders that affect the abovementioned glands and tissues are congenital, acquired lesions may result in hypogonadism in children and adolescents.

Testicular tumors in the prepubertal age are relatively rare, representing only 9.4% of the total testicular and paratesticular specimens from a 20-year review performed at a large pediatric hospital [ 1 ]. They account for 1% to 2% of all solid tumors in the pediatric age group, with an annual incidence between 0.5/100000 and 2/100000 boys according to Coppes et al [ 2 ] and data from the Prepubertal Testicular Tumor Registry [ 3 ]. Similar to other neoplasms afflicting children, a bimodal age distribution is observed. The first peak is between birth and 3 years of age, and a second one occurs at the onset of puberty, extending to the fourth decade. Reports on their frequency vary because some investigators include the adolescent period, while others do not [ 4 ]. The vast majority of testicular tumors are germ cell neoplasms, accounting for 95% across all ages [ 5 ]. In children, germ cell tumors also predominate, representing 71% of all testicular neoplasms. These include yolk sac tumors (49%), teratomas (13%), seminomas and mixed germ cell tumors (9%), and sex-cord stromal tumors (29%). Malignant potential is significantly lower (less than 70%) in the pediatric age group compared to adults (90%) [ 6 ]. According to Pohl et al, 74% of prepubertal testicular tumors are benign [ 7 ].

Among the most frequent specimens at the pediatric surgical pathology bench, orchiectomy performed after testicular torsion deserves significant attention. Multiple implications, including fertility, legal complications, possibility of occult lesion, and others, need to be considered. Furthermore, torsion of testicular and other appendices represents common urological emergencies frequently encountered in surgical pathology. Here we present a review of testicular torsion and infarction, including theories about their pathogenesis and the appropriate handling by the diagnostic pathologist.

Inborn errors of metabolism have wide and profound effects in many or all organs, and especially so in those with endocrine functions. The testes are greatly affected by systemic metabolic disorders, leading to specific histological findings that generally reveal the nature of the underlying disorder. Here we describe the main testicular changes seen in the setting of metabolic disease.

Cryptorchidism is one of the most frequent problems encountered in pediatric urology. Its causes, associated lesions, and prognosis in terms of fertility have been a source of interest and discrepancies for pediatric pathologists and urological surgeons.