Adenomatoid Tumor: A Review of Pathology With Focus on Unusual Presentations and Sites, Histogenesis, Differential Diagnosis, and Molecular and Clinical Aspects With a Historic Overview of Its Description.

Adenomatoid tumors have been described almost a century ago, and their nature has been the subject of debate for decades. They are tumors of mesothelial origin usually involving the uterus, the Fallopian tubes, and the paratesticular region. Adenomatoid tumors of the adrenal gland, the liver, the extragenital peritoneum, the pleura, and the mediastinum have been rarely reported. They are usually small incidental findings, but large, multicystic and papillary tumors, as well as multiple tumors have been described. Their pathogenesis is related to immunosuppression and to TRAF7 mutations. Despite being benign tumors, there are several macroscopic or clinical aspects that could raise diagnostic difficulties. The aim of this review was to describe the microscopic and macroscopic aspects of adenomatoid tumor with a special focus on its differential diagnosis and pathogenesis and the possible link of adenomatoid tumor with other mesothelial lesions, such as the well-differentiated papillary mesothelioma and the benign multicystic mesothelioma, also known as multilocular peritoneal cysts.

Curcumin: a phytochemical modulator of estrogens and androgens in tumors of the reproductive system.

Curcumin (Cur) is an active derivative extracted from turmeric which exerts a wide range of interactions with biomolecules through complex signaling pathways. Cur has been extensively shown to possess potential antitumor properties. In addition, there is growing body of evidence suggesting that Cur may exert potential anti-estrogen and anti-androgen activity. In vitro and in vivo studies suggest that anticancer properties of Cur against tumors affecting the reproductive system in females and males may be underlied by the Cur-mediated inhibition of androgen and estrogen signaling pathways. In this review we examine various studies assessing the crosstalk between Cur and both androgen and estrogen hormonal activity. Also, we discuss the potential chemopreventive and antitumor role of Cur in the most prevalent cancers affecting the reproductive system in females and males.

Genotype-phenotype correlation, gonadal malignancy risk, gender preference, and testosterone/dihydrotestosterone ratio in steroid 5-alpha-reductase type 2 deficiency: a multicenter study from Turkey.

BACKGROUND: Studies regarding genetic and clinical characteristics, gender preference, and gonadal malignancy rates for steroid 5-alpha-reductase type 2 deficiency (5α-RD2) are limited and they were conducted on small number of patients. OBJECTIVE: To present genotype-phenotype correlation, gonadal malignancy risk, gender preference, and diagnostic sensitivity of serum testosterone/dihydrotestosterone (T/DHT) ratio in patients with 5α-RD2. MATERIALS AND METHODS: Patients with variations in the SRD5A2 gene were included in the study. Demographic characteristics, phenotype, gender assignment, hormonal tests, molecular genetic data, and presence of gonadal malignancy were evaluated. RESULTS: A total of 85 patients were included in the study. Abnormality of the external genitalia was the most dominant phenotype (92.9%). Gender assignment was male in 58.8% and female in 29.4% of the patients, while it was uncertain for 11.8%. Fourteen patients underwent bilateral gonadectomy, and no gonadal malignancy was detected. The most frequent pathogenic variants were p.Ala65Pro (30.6%), p.Leu55Gln (16.5%), and p.Gly196Ser (15.3%). The p.Ala65Pro and p.Leu55Gln showed more undervirilization than the p.Gly196Ser. The diagnostic sensitivity of stimulated T/DHT ratio was higher than baseline serum T/DHT ratio, even in pubertal patients. The cut-off values yielding the best sensitivity for stimulated T/DHT ratio were ≥ 8.5 for minipuberty, ≥ 10 for prepuberty, and ≥ 17 for puberty. CONCLUSION: There is no significant genotype-phenotype correlation in 5α-RD2. Gonadal malignancy risk seems to be low. If genetic analysis is not available at the time of diagnosis, stimulated T/DHT ratio can be useful, especially if different cut-off values are utilized in accordance with the pubertal status.

Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation.

Adenomatoid tumors are the most common neoplasm of the epididymis, and histologically similar adenomatoid tumors also commonly arise in the uterus and fallopian tube. To investigate the molecular pathogenesis of these tumors, we performed genomic profiling on a cohort of 31 adenomatoid tumors of the male and female genital tracts. We identified that all tumors harbored somatic missense mutations in the TRAF7 gene, which encodes an E3 ubiquitin ligase belonging to the family of tumor necrosis factor receptor-associated factors (TRAFs). These mutations all clustered into one of five recurrent hotspots within the WD40 repeat domains at the C-terminus of the protein. Functional studies in vitro revealed that expression of mutant but not wild-type TRAF7 led to increased phosphorylation of nuclear factor-kappa B (NF-kB) and increased expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation. Immunohistochemistry demonstrated robust L1CAM expression in adenomatoid tumors that was absent in normal mesothelial cells, malignant peritoneal mesotheliomas and multilocular peritoneal inclusion cysts. Together, these studies demonstrate that adenomatoid tumors of the male and female genital tract are genetically defined by TRAF7 mutation that drives aberrant NF-kB pathway activation.

Osteoclast-rich, proximal-type epithelioid sarcoma: clinicopathologic features of 3 unusual cases expanding the histomorphological spectrum.

Epithelioid sarcoma (ES) displays a wide clinicopathologic spectrum. On histopathology, osteoclast-like giant cells have been rarely described in these tumors. A 45-year-old gentleman presented with a perineal swelling of 6-month duration. Radiologic imaging disclosed a large, highly vascular tumor mass in his perineal region that was diagnosed elsewhere as pigmented villonodular synovitis. A 58-year-old lady presented with a recurrent tumor in her right inguinolabial region for which she underwent multiple tumor resections in the past. A 33-year-old lady presented with a right inguinal swelling of 1-month duration that was diagnosed elsewhere as a non-Hodgkin lymphoma on fine needle aspiration cytology. Histopathologic examination of tumors in all the 3 cases revealed epithelioid to "rhabdoid-like" cells arranged in a diffuse pattern interspersed with many osteoclast-like giant cells. The first tumor also revealed focal pseudoangiosarcomatous areas and heterotopic bone formation. By immunohistochemistry, tumor cells in all 3 cases were positive for AE1/AE3, epithelial membrane antigen, and CD34 and were completely negative for INI1/SMARCB1. CD68 immunostaining in 2 tumors highlighted osteoclast-like giant cells. Osteoclast-rich, proximal-type ES are unusual tumors, indicative of an expanding spectrum of ESs. Awareness of this histopathologic pattern and diagnostic confirmation with necessary immunohistochemical stains is crucial to avoid misinterpretation, as these tumors are clinically aggressive and are treated with wide local excision and optional adjuvant radiation therapy.

Recent advances in understanding the etiology and pathogenesis of pediatric germ cell tumors.

Pediatric germ cell tumors (GCTs) are rare neoplasms arising predominantly in the gonads and sacrococcygeal, mediastinal, and intracranial localizations. In this article, we review current knowledge of pathogenesis of pediatric GCTs, which differs from adult/adolescent GCTs. One distinctive feature is the absence of a progenitor stage, such as carcinoma in situ or gonadoblastoma, which are seen in adult/adolescent GCTs, except spermatocytic seminoma. The primordial germ cell (PGC) is the suggested origin of all GCTs, with variations in histology reflecting differentiation stage. Expression of pluripotency transcription factors OCT-3/4, NANOG, and AP-2γ in germinomas/seminomas/dysgerminomas is consistent with retaining a germ cell phenotype. Teratomas, in contrast, develop through a pathway of aberrant somatic differentiation of immature germ cells, and the yolk sac tumors and choriocarcinomas result from abnormal extraembryonic differentiation. In pediatric GCTs, origin is suggested at an earlier developmental stage because of predisposing genetic factors, although responsible genes remain largely unknown. Some extragonadal GCTs have been linked to overexpression of the KIT/KITLG system, allowing for survival of aberrantly migrated ectopic PGCs. Infant gonadal/sacrococcygeal GCTs may be caused by apoptosis-related pathways, consistent with an association with polymorphisms in BAK1. Although recent advances have identified candidate pathways, further effort is needed to answer central questions of pathogenesis of these fascinating tumors.

[Relaxin 2--a pregnancy hormone involved in the process of carcinogenesis]. / Relaksyna--hormon ciazowy zaangazowany w proces nowotworzenia.

Relaxin 2 is a polypeptide hormone structurally related to insulin and insulin-like growth factors (IGFs). However it does not interact with insulin receptors and has a decidedly different biological properties. Relaxin 2 activates LGR 7 and LGR 8 relaxin receptors, that belong to the leucine-rich repeat-containing (LRR), G protein-coupled receptors. The characteristic functions of relaxin are associated with female reproductive system, especially during pregnancy. However recent studies have shown that polypeptides with relaxin-like factor family (RLF) are involved in cell proliferation and differentiation, as well as invasion and angiogenesis of female and male reproductive cancers. This review provides information on the structure and function of relaxin and its receptors. Furthermore, we present evidence of the involvement of these elements in the process of cancerogenesis.

[Molecular basis of oncogenesis induced by human papilloma viruses].

Human papilloma viruses (HPV) of high carcinogenesis risk play important role in development of cancer of oropharyngeal and anogenital areas. Possible malignant transformation of cells, infected by HPV, is due to the expression of three proteins, E6, E7 and E5. These proteins mostly influence on mechanisms that regulate cellular cycle, proliferation and apoptosis inducing and maintaining oncogenesis. This review briefly presents data on malignant tumors induced by HPV as well as biology of these viruses and their vital cycle. Special accent is made on description of current trends in molecular basis of oncogenesis, induced by HPV, which understanding is necessary for elaboration of new methods of treatment for HPV-infection such as therapeutic vaccines.

[Clinicopathologic features of calcifying fibrous tumor with reappraisal of its histogenesis].

OBJECTIVE: To study the clinicopathologic features and histogenesis of calcifying fibrous tumor (CFT). METHODS: The clinical manifestations, histopathologic characteristics and immunophenotype were analyzed in 11 cases of CFT. RESULTS: The male-to-female ratio was 5:6, with a mean age of 38 years and age range of 25 to 52 years. The sites of involvement included abdominopelvic cavity (n=6), soft tissue (n=4) and scrotum (n=1). Most patients presented with a gradually enlarging and painless mass. Nearly half of the cases were associated with other diseases or history of inflammation, trauma or surgical intervention. One third of the tumors represented incidental findings and showed no recurrence after resection. Imaging revealed a solitary solid soft tissue mass or multiple nodules with clear borders and associated high-density calcifications. Macroscopically, the tumors were well-circumscribed but non-encapsulated. They ranged from 0.5 to 20.0 cm in diameter and were tan-greyish, round to oval, lobulated or irregular and solid with rubbery consistency. The cut surface was whitish to tan-yellowish, gritty and showed scattered spotty yellowish discoloration corresponding to the foci of dystrophic calcifications. Histologically, CFT was composed of hyalinized fibrous tissue and thickened vessel walls with interspersed bland spindly fibroblastic cells, scattered psammomatous calcifications, dystrophic calcification and lymphoplasmacytic infiltration. In addition, focal cloak-like polymorph infiltration at the tumor periphery and entrapment of adipocytes and nerves were demonstrated in some cases. Foci resembling solitary fibrous tumor, fibromatosis, keloid or inflammatory myofibroblastic tumor were observed. Immunohistochemical study showed that the tumor cells were diffusely positive for vimentin and focally positive for CD34, factor VIII-related antigen and beta-catenin. The admixed plasma cells were notably IgG positive, with more than 50% being IgG4 positive. CONCLUSIONS: CFT has characteristic histopathologic manifestations and shows morphologic and immunohistochemical overlaps with known IgG4-related sclerosing diseases. It is possible that CFT may represent another example of IgG4-related diseases. It often runs a benign clinical course, with rare recurrence after surgical resection. Previous inflammation and trauma may be the precipitating factors of CFT.

Extracellular vesicles in urological malignancies.

Extracellular vesicles (EVs) are small lipid bound structures released from cells containing bioactive cargoes. Both the type of cargo and amount loaded varies compared to that of the parent cell. The characterisation of EVs in cancers of the male urogenital tract has identified several cargoes with promising diagnostic and disease monitoring potential. EVs released by cancers of the male urogenital tract promote cell-to-cell communication, migration, cancer progression and manipulate the immune system promoting metastasis by evading the immune response. Their use as diagnostic biomarkers represents a new area of screening and disease detection, potentially reducing the need for invasive biopsies. Many validated EV cargoes have been found to have superior sensitivity and specificity than current diagnostic tools currently in use. The use of EVs to improve disease monitoring and develop novel therapeutics will enable clinicians to individualise patient management in the exciting era of personalised medicine.

Extramammary paget disease of scrotum with oncocytic changes.

We report an unusual case of primary scrotal extramammary Paget disease that infiltrated reticular dermis and lymph vessels, with metastasis in inguinal lymph node. The 67-year-old patient died at 14 months due to systemic metastases. The tumor, which was located in epidermis and infiltrated the dermis, comprised cells with wide, granular, and eosinophilic cytoplasm and intense positivity for antimitochondrial antibody. This seems to be the first report of oncocytic changes in extramammary Paget disease.

Adenomatoid tumors of the female and male genital tracts: a clinicopathological and immunohistochemical study of 44 cases.

Adenomatoid tumors of the female and male genital tracts are well characterized as mesothelial in origin, but a detailed histological and immunohistochemical analysis comparing both traditional and newer mesothelial markers across gender and site has not been formally conducted. A variety of morphologic features previously described as characteristic of adenomatoid tumors were evaluated in 44 adenomatoid tumors from the male and female genital tracts. Immunohistochemical analysis with pankeratin (AE1/CAM5.2), WT-1, calretinin, CK5/6, D2-40, and caldesmon was also performed. The extent and intensity of staining were scored semiquantitatively on one representative section per case and mean value for each parameter was calculated. All (n=44) the adenomatoid tumors from both the female and male genital tracts demonstrated a distinctive thread-like bridging strand pattern. Lymphoid aggregates were seen in all 12 adenomatoid tumors of male patients, but in only 4 of 32 (13%) tumors in female patients (P<0.0001). The remaining morphologic features were variably present with no clear sex predilection. Pankeratin, calretinin, and D2-40 reactivity were identified in all female (n=32) and male (n=12) genital tract adenomatoid tumors. Adenomatoid tumors expressed WT-1 in 11/12 (92%) male patients and in 31/32 (97%) female patients. In male patients, reactivity for CK5/6 and caldesmon was found in 1/12 (8%) and 0/12 (0%) adenomatoid tumors (respectively), whereas reactivity in female patients was found in 5/32 (16%) and 1/32 (3%); respectively. Female tumors differ from their male counterparts by the frequent absence of lymphoid aggregates and the presence of a circumscribed margin when occurring in the fallopian tube. Of the putative mesothelial markers evaluated, calretinin, D2-40, and WT-1 show a similar immunoprofile and have a higher sensitivity than CK5/6 and caldesmon in genital tract adenomatoid tumors. However, the presence of additional, often strong expression of WT-1 in normal tissues of the female genital tract limits the utility of WT-1 in this setting.

Lymphoid neoplasms of the urinary tract and male genital organs: a clinicopathological study of 40 cases.

Lymphoid neoplasms of the urinary tract and male genital organs are relatively rare, comprising less than 5% of all primary extranodal lymphomas; only a handful of small case series and isolated case reports have been published describing their predominant sites and subtypes. We identified 40 patients with lymphoid neoplasms of the urinary tract and male genital organs. Hematoxylin and eosin slides and immunohistochemical stains were reviewed, and follow-up data were also obtained. Twenty-six of 40 cases (65%) were primary genitourinary lymphomas. Mean age at diagnosis was 56 years (range 4-86 years). Among renal, bladder, and ureter lymphomas, a male predominance was noted (1.6:1). The subtypes of the lymphoid neoplasms observed were diffuse large B-cell lymphoma (17 cases, 43%); Burkitt lymphoma, extranodal marginal zone lymphoma, SLL/CLL, and follicular lymphoma (4 cases, or 10% each); B-cell ALL (2 cases, 5%); B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, mantle cell lymphoma, plasmacytoma, polymorphic post-transplant lymphoproliferative disorder, and peripheral T-cell lymphoma NOS (1 case, or 2.5% each). In most cases, the genitourinary tract was the site of initial presentation. Genitourinary tract lymphomas most commonly occurred in the kidney. B-cell non-Hodgkin's lymphomas predominated, with diffuse large B-cell lymphoma being the most common subtype in the entire group. Extranodal marginal zone lymphoma was seen only in the kidney, rather than the bladder, where it is typically thought to be more common. Although this study confirms the predominance of diffuse large B-cell lymphoma in extranodal sites, the findings also highlight the variety of lymphomas that may occur in the genitourinary tract. This diversity of subtypes affirms the importance of fully characterizing lymphomas by immunohistochemistry and other modalities, which are indispensable for accurate diagnosis.

High expression of Ki-67 and cyclin D1 in invasive extramammary Paget's disease.

BACKGROUND: Invasive extramammary Paget's disease (EMPD) is commonly associated with a poor prognosis. Although early detection of micro invasion can improve the prognosis, diagnosis is not always straightforward in some EMPD cases. Several clinical studies have proposed mechanisms underlying the increased invasiveness of EMPD; however, molecular markers indicative of the invasiveness have yet to be well characterized. OBJECTIVE: The purpose of this study was to identify a reliable immunohistochemical marker for predicting the risk of invasion and metastasis in EMPD cases. METHODS: A total of 32 specimens from 23 primary EMPD cases were analyzed by immunohistochemical staining. In formalin-fixed, paraffin-embedded tissue sections, immunolabeling of tumor cells were scored by stain intensity on a four-tiered scale. Using antibodies against several tumor proliferation markers, such as Her2, p53, Ki-67, cyclin D1 and Bcl-2, we determined the correlation between the expression of these molecular markers and the types of EMPD lesions (in situ, invasive or metastatic). RESULTS: In contrast to Her2, p53 and Bcl-2, which are similarly expressed among different types of lesions, Ki-67 and cyclin D1 are expressed at significantly higher levels in invasive lesions than in situ lesions (P<0.01 and P<0.05, respectively). Furthermore, the mean of the sum of Ki-67 and cyclin D1 expression scores was significantly higher in invasive lesions, compared to the scores obtained for in situ lesions. In addition, the difference was more significant (P

[Burkitt's lymphoma of the spermatic cord: a case report and review of the literature].

OBJECTIVE: To investigate the clinicopathological characteristics of primary Burkitt's lymphoma (BL) in the spermatic cord. METHODS: A case of BL of the spermatic cord was studied by histopathology and immunohistochemical techniques. The clinical data and the related literature were reviewed. RESULTS: The patient was a 4-year-old boy, who was accidentally found with a bump in the scrotum. Surgery showed it to be a tumor located in the left spermatic cord and 5 cm x 3 cm x 2 cm in size, gray and fish-like on cross-sectional imaging. Histologically, it was characterized by monotonous infiltration of medium-sized cells with round nuclei, coarse chromatin, 2-5 basophilic nucleoli, and an appreciable rim of basophilic cytoplasm, in a typically starry-sky pattern imparted by interspersed tangible-body macrophages. Immunohistochemically, the tumor cells were diffused, positive for CD20 and CD79, some for CD10 and about 95% with the nuclear expression of Ki-67, but negative for CD3, CD43, bcl-2 and TdT as well as for EBER in situ hybridization. CONCLUSION: Primary spermatic cord BL is extremely rare, highly aggressive and with poor prognosis. Diagnosis of the tumor relies on its pathological characteristics and immunohistochemical staining. It is essential to differentiate BL from other types of lymphomas and malignant small-cell tumors of the non-lymphatic system.

Rare paratesticular aggressive angiomyxoma with negative oestrogen and progesterone receptors in a male patient.

Aggressive angiomyxoma (AAM) is a rare mesenchymal myxoid tumour localised to the pelvis and/or perineum in adult females in reproductive age group. AAM is very rare in males, with <50 cases described in literature, and involves scrotum, spermatic cord and perineum. It is slow growing, with a marked tendency for local recurrence after excision, but without metastatic potential. We present a rare case of a paratesticular AAM in a man aged 53 years. Tumour cells were immunoreactive for desmin, smooth muscle actin (SMA), vimentin, CD34 and were negative for S100. Unlike AAMs in females which express oestrogen receptor (ER) and/or progesterone receptor (PR) in >90% cases, the tumour cells in our case were negative for ER and PR, suggesting that the hypothesis that these markers play a role in tumour development and pathogenesis, does not apply in males. Androgen receptor positivity was noted in 2%-5% tumour cells.