Male adnexal tumor of probable Wolffian origin: a new entity in males similar to female adnexal tumor of probable Wolffian origin.

Female adnexal tumor of probable Wolffian origin is a rare tumor listed in the 2016 WHO classification of the female reproductive tract. It does not have a WHO-recognized counterpart in the male urogenital tract. However, some cases of male adnexal tumors have been described in the literature. We present the case of a 41-year-old male who presented with a 2-cm nodule in the testicle. LDH, HCG, and AFP blood levels were normal. Gross examination showed an intratesticular, whitish, microcystic, firm, and encapsulated nodule of 2 cm. Microscopically, the tumor was well circumscribed, solid, and microcystic. In the solid areas, cells were fusiform or polygonal with an eosinophilic pale cytoplasm and a regular oval nucleus. Cysts were surrounded by a fibromuscular stroma and lined by a single layer of cylindrical epithelium, with apical cilia. On immunohistochemistry, tumor cells expressed AE1/AE3 and vimentin and were negative for calretinin, epithelial membrane antigen (EMA), and inhibin. All the differential diagnoses at this localization being ruled out, the tumor was compared to a female adnexal tumor of probable Wolffian origin. Both tumors had approximately the same morphological and immunohistochemical profile. Naming our tumor MATPWO is therefore justified, but it remains of a probable origin because further studies need to be performed in order to certify this hypothesis.

Female adnexal tumors of probable Wolffian origin: morphological, immunohistochemical, and molecular analysis of 15 cases.

Female adnexal tumors of probable Wolffian origin are rare and present a diagnostic challenge due to their morphological and immunohistochemical overlap with more common ovarian and broad ligament entities. We evaluated the morphological, immunohistochemical, and molecular features of 15 tumors of probable Wolffian origin. Patients ranged from 32 to 69 (mean 47) years and tumors from 1.8 to 30 (mean 10) cm. All except one arose in para-adnexal soft tissues. Follow-up was available for six patients, five of whom were alive and well, while the sixth, who had extra-adnexal disease at diagnosis, died from unrelated causes. The following patterns were noted: tubular (all tumors), solid 11/15 (73%), sieve-like 7/15 (47%), and reticular 1/15 (7%). A myxoid background was present in 3/15 (20%) of tumors and eosinophilic luminal secretions in 11/15 (73%). Most tumors (12/15, 80%) had low-grade nuclear atypia, while three showed foci with scattered high-grade atypia. Mitotic index ranged from 0 to 17 (mean 4) per ten high-power fields. Tumors were positive for pankeratin and negative for TTF-1. EMA, GATA3, and PAX8 were positive in 2/10 (20%; focal), 3/15 (20%; focal), and 1/15 (7%; focal) of tumors, respectively. CD10, SF-1, calretinin, inhibin, ER, PR, cytokeratin 7, and WT1 were variably expressed. Pathogenic mutations were rare and included STK11 (n = 3), APC (n = 1), and MBD4 (n = 1). Copy number variations were detected in the three tumors with STK11 mutations and a myxoid background. These data demonstrate that female adnexal tumors of probable Wolffian origin are morphologically and immunohistochemically diverse, but infrequently harbor pathogenic mutations. However, their lack of mutations in contrast to their mimickers may be a valuable tool in diagnostically difficult cases.

Targeted Genomic Profiling of Female Adnexal Tumors of Probable Wolffian Origin (FATWO).

Female adnexal tumor of probable Wolffian origin (FATWO) is a rare gynecologic neoplasm of low-malignant potential presumed to be derived from mesonephric remnants in the upper female genital tract. Similarly, mesonephric remnants in the lower female genital tract are thought to be the origin for mesonephric carcinoma. Although the molecular alterations in mesonephric carcinoma have been recently reported, the pathogenesis of and molecular alterations in FATWO are not well understood. The aims of this study were to examine the molecular alterations in FATWO and to establish whether these neoplasms are molecularly similar to mesonephric carcinoma. Eight FATWOs underwent massively parallel sequencing to detect single nucleotide variations, copy number variations, and structural variants by surveying exonic DNA sequences of 300 cancer genes and 113 introns across 35 genes. Good quality DNA was isolated from 7 of 8 cases. Novel KMT2D variants (1 frameshift, 3 missense) were identified in 4 of 7 cases (57%), but were variants of uncertain biologic significance. STK11 mutations (both frameshift) were identified in 2 of 7 cases (29%); one of these was in a patient with a known history of Peutz-Jeghers syndrome. A mutation in the chromatin remodeling gene ARID1B was identified in 1 of 7 cases (14%). No cases harbored KRAS, NRAS, TP53, PIK3CA, PTEN, or DICER1 mutations. There were relatively low numbers of copy number variations, and no recurrent copy number variations were identified. One case demonstrated moderate copy gain of CCND1. No structural variants were identified. In summary, FATWO is characterized molecularly by the absence of KRAS/NRAS mutations (characteristic of mesonephric carcinoma), absence of DICER1 mutations (characteristic of Sertoli-Leydig cell tumor) and frequent KMT2D mutations of unknown biologic significance. FATWOs exhibit a limited number of molecular aberrations that are significantly different from those reported in tumors in the differential diagnosis, and our results question the relationship of mesonephric carcinoma with FATWO. Disease-defining molecular alterations for FATWO have yet to be discovered.

Female Adnexal Tumors of Probable Wolffian Origin (FATWO): A Case Series With Next-Generation Sequencing Mutation Analysis.

Female adnexal tumors of probable Wolffian origin are rare gynecologic tumors with <90 cases reported in the current scientific literature. Their clinical features have been described extensively; less is known about the pathophysiological mechanisms and the molecular alterations underlying their development and growth. We performed a complete histopathologic examination and a systematic mutation analysis using a next-generation sequencing approach on 3 female adnexal tumors of probable Wolffian origin from the archives of our institution to detect possible genetic alterations and to explore their role in the development of these rare tumors. The 3 cases contained missense mutations in different genes belonging to distinct molecular pathways: CTNNB1 and MET mutations for the first case, PIK3CA for the second one, and BRAF and CDKN2A for the third one. Two variants with an unknown functional effect on the protein were found in KDR and TP53 genes. In conclusion, genetic heterogeneity was found in our series. No constant involvement of the most common pathways involved in tumorigenesis was found; nevertheless, further studies are necessary to confirm the results of this pilot study.

A reappraisal of the diagnostic and therapeutic management of uncommon histologies of primary ocular adnexal lymphoma.

Lymphoma is the most common malignancy arising in the ocular adnexa, which includes conjunctiva, lachrymal gland, lachrymal sac, eyelids, orbit soft tissue, and extraocular muscles. Ocular adnexal lymphoma (OAL) accounts for 1%-2% of non-Hodgkin lymphoma and 5%-15% of extranodal lymphoma. Histology, stage, and primary localizations are the most important variables influencing the natural history and therapeutic outcome of these malignancies. Among the various lymphoma variants that could arise in the ocular adnexa, marginal zone B-cell lymphoma (OA-MZL) is the most common one. Other types of lymphoma arise much more rarely in these anatomical sites; follicular lymphoma is the second most frequent histology, followed by diffuse large B-cell lymphoma and mantle cell lymphoma. Additional lymphoma entities, like T-cell/natural killer cell lymphomas and Burkitt lymphoma, only occasionally involve orbital structures. Because they are so rare, related literature mostly consists of anecdotal cases included within series focused on OA-MZL and sporadic case reports. This bias hampers a global approach to clinical and molecular properties of these types of lymphoma, with a low level of evidence supporting therapeutic options. This review covers the prevalence, clinical presentation, behavior, and histological and molecular features of uncommon forms of primary OAL and provides practical recommendations for therapeutic management.

Selenium supplementation reduced oxidative DNA damage in adnexectomized BRCA1 mutations carriers.

Some experimental evidence suggests that BRCA1 plays a role in repair of oxidative DNA damage. Selenium has anticancer properties that are linked with protection against oxidative stress. To assess whether supplementation of BRCA1 mutation carriers with selenium have a beneficial effect concerning oxidative stress/DNA damage in the present double-blinded placebo control study, we determined 8-oxodG level in cellular DNA and urinary excretion of 8-oxodG and 8-oxoGua in the mutation carriers. We found that 8-oxodG level in leukocytes DNA is significantly higher in BRCA1 mutation carriers. In the distinct subpopulation of BRCA1 mutation carriers without symptoms of cancer who underwent adnexectomy and were supplemented with selenium, the level of 8-oxodG in DNA decreased significantly in comparison with the subgroup without supplementation. Simultaneously in the same group, an increase of urinary 8-oxoGua, the product of base excision repair (hOGG1 glycosylase), was observed. Therefore, it is likely that the selenium supplementation of the patients is responsible for the increase of BER enzymes activities, which in turn may result in reduction of oxidative DNA damage. Importantly, in a double-blinded placebo control prospective study, it was shown that in the same patient groups, reduction in cancer incidents was observed. Altogether, these results suggest that BRCA1 deficiency contributes to 8-oxodG accumulation in cellular DNA, which in turn may be a factor responsible for cancer development in women with mutations, and that the risk to developed breast cancer in BRCA1 mutation carriers may be reduced in selenium-supplemented patients who underwent adnexectomy.

Early diagnosis and predictors of malignancy of adnexal masses.

PURPOSE OF REVIEW: Ovarian cancer is an important cause of death among women with a malignant gynecological tumor. Cure rates for the disease at an early stage are around 80-90%, but survival is only 50% as the majority of women already show advanced disease upon diagnosis. The combination of gynecological examination, ultrasonography, and systemic tumor marker assay is considered to be a good strategy for the early diagnosis of ovarian neoplasia. RECENT FINDINGS: Today, new technologies such as ultrasonography and tumor marker assay have increased the diagnosis rate for adnexal masses. These non-invasive methods, however, frequently do not distinguish benign conditions from malignant ones, which results in unnecessary surgery. Transvaginal ultrasonography is useful for diagnosing adnexal masses, but benign and malignant adnexal masses can present similar morphological characteristics. Combination with color Doppler ultrasonography and/or tumor markers may improve the accuracy of the method. Gene-expression array, proteomics and mathematical models form new approaches, but proper prospective studies are needed to validate them. SUMMARY: The techniques of pelvic examination, ultrasonography, color Doppler ultrasonography, and tumor markers can be indicated for the diagnosis of ovarian cancer. The differentiation between benign and malignant ovarian tumor is, however, a clinical challenge. Until better diagnostic methods become available, patients and their physicians can use these techniques to decide on management.

Ovarian torsion: to pex or not to pex? Case report and review of the literature.

STUDY OBJECTIVE: We report the case of a 7-year-old girl who underwent laparoscopic ovariopexy for a suspected ovarian torsion after a previous oophorectomy. We consider the role of elective ovariopexy of the contralateral ovary in the case of adnexal torsion. DESIGN: Case study and review of the literature. RESULT: There was evidence to suggest a very recent adnexal torsion and an unusually long ovarian pedicle, with a possible familial linkage. The patient underwent laparoscopic ovariopexy for the remaining normal ovary, which was found to be loosely twisted at operation. After detorsion, ovariopexy was performed laparoscopically, by suturing the ovary to the back of uterus. There are no other descriptions in the literature of a familial linkage with ovarian torsion. CONCLUSION: The case presented reminds doctors of the strong possibility of ovarian torsion in young girls presenting with pelvic pain. Laparoscopic ovariopexy for the contralateral ovary should be considered in all women with evidence of torsion, including children and adolescents, as is standard for testicular torsion.

Local expression of cytokine genes in uterine adnexa and endometrium of women with pyoinflammatory adnexal diseases.

Changes in the local expression of IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-15, IL-18, TNF-alpha, IFN-gamma- and TGF-beta(2) genes in the uterine adnexa and endometrium were studied in women with pyoinflammatory adnexal diseases. Examination of tissue specimens from the uterine adnexa involved in inflammation revealed a direct correlation in the levels of mRNA production between IL-6 and IL-10 (r=0.93, p<0.1), IL-6 and IL-4 (r=0.96, p<0.01), IL-10 and IL-4 (r=0.91, p<0.01), IL-12 and IFN-gamma (r=0.98, p<0.01). Expression of IL-4 gene increased 5.1-fold (p=0.001), IL-6 2-fold (p=0.007), IL-8 90.2-fold (p=0.009), IL-10 2.9-fold (p=0.008), IL-12 2.3-fold (p=0.3), and TGF-beta(2) gene 10.3-fold (p=0.1). In the endometrium of women with pyoinflammatory adnexal diseases only IL-10 gene expression increased (15.6-fold, p=0.007).

Expression of differentiation and proliferation related proteins in epithelium of prophylactically removed ovaries from women with a hereditary female adnexal cancer predisposition.

AIMS: To investigate the occurrence of preinvasive neoplastic lesions in ovarian surface epithelium and ovarian inclusion cyst epithelium of women with a hereditary predisposition to the development of female adnexal (ovarian and fallopian tube) carcinoma and to assess the expression of differentiation and proliferation related proteins within putative sites of origin of serous ovarian carcinoma, the ovarian surface epithelium and ovarian inclusion cyst epithelium. METHODS: Twenty-one ovaries, prophylactically removed from 11 women predisposed to the development of female adnexal cancer (cases) were compared with 22 ovaries from 11 women without such predisposition (controls). Archival histological specimens were screened for hyperplastic and dysplastic epithelial lesions. In both the ovarian surface and inclusion cyst epithelia, the percentage of cells was determined that stained positively for Ki67, p21, p27, p53, cyclin A, cyclin D1, bcl-2 and the presence of HER-2/neu, oestrogen (ER-alpha) and progesterone receptors (PR). RESULTS: No preinvasive neoplastic lesions were detected. However, hyperplastic areas were found in three cases and in four controls (NS). ER-alpha (P = 0.013), PR (P < 0.001), bcl-2 (P = 0.008), p21 (P = 0.046) and p27 (P = 0.008) were expressed in a significantly higher percentage of cells in inclusion cyst epithelium than in ovarian surface epithelium (both groups). The latter showed higher bcl-2 expression in cases (P = 0.05) compared with controls. The inclusion cyst epithelium of cases showed higher expression of bcl-2 (P = 0.006) and PR (P = 0.039) compared with controls. Proliferation was low in both cases and controls as reflected by low Ki67 expression. Over-expression of p53, cyclin D1 and HER-2/neu was not detected. CONCLUSIONS: Premalignant changes are not a common feature of ovaries removed prophylactically from women predisposed to the development of female adnexal carcinoma. Increased expression of p21, p27, and ER-alpha is seen in inclusion cyst compared with ovarian surface epithelium of women with and without an inherited risk of adnexal carcinoma. This is most probably caused by the different intraovarian hormonal milieu of inclusion cyst epithelium. However, the increased expression of bcl-2 and PR in the inclusion cyst epithelium of patients with a hereditary predisposition may reflect early disruption of hormonal balance and growth control.

DNA ploidy of ovarian and adnexal cyst fluid. A useful adjunct to cytology.

It is increasingly common for cytology laboratories to receive ovarian, adnexal and pelvic cyst fluids obtained via sonographically directed aspiration and laparoscopic techniques, especially from women who are desirous of preserving fertility or who are undergoing in vitro fertilization (IVF). Accurate characterization of such cysts is a worthwhile goal, given the superior prognosis for ovarian carcinomas that are diagnosed at an early stage. In an effort to improve upon the false-negative diagnosis rate associated with cytology, we evaluated DNA ploidy as a possible adjunctive criterion. We examined 55 benign, 3 borderline and 6 malignant aspirates received by our cytopathology laboratory; 35 were aspirated directly from the patient from clinically and ultrasonographically benign cysts, and 29 were aspirated from surgically removed benign (20) and malignant (9) cysts. Adjunctive DNA ploidy and cell cycle analysis was performed using the Cell Analysis Systems CAS-200 on Feulgen-stained cytologic smears of the 64 cyst fluids. Adequate material for DNA analysis was obtained from 33/35 in situ aspirated cysts and from 19/29 surgical specimen cysts. Forty-seven of 52 cytologically benign cysts were diploid. Of the 5 nondiploid benign cysts, 3 were follicle cysts (2 from hormonally stimulated IVF patients and 1 from a postpartum patient), and 1 was a benign cystic teratoma. Their nondiploid DNA pattern or tetraploidy may be due to a high proliferative index. The fifth nondiploid benign aspirate was from a resected benign epithelium-lined cyst; its DNA histogram contained a conspicuous tetraploid population. All 9 malignant cysts were cytologically malignant. Of the 3 borderline cysts, 1 was nondiploid, and 2 were diploid. All 6 fully malignant cysts were nondiploid; 2 of them were tetraploid. Based on our results, we conclude that DNA ploidy analysis of cells derived from ovarian and adnexal cyst aspirates is feasible (in 95% of cases) and relatively specific (90%) and has a relatively high negative predictive value (92%). The results are not sufficiently predictive of the histology of the lesion to warrant therapeutic intervention based on ploidy alone (sensitivity of nondiploid results, 78%; positive predictive value of nondiploid results, 58%). Nondiploidy should suggest consideration, but is not conclusive, of a malignancy diagnosis. There may even be prognostic implications to the ploidy pattern, particularly in borderline tumors, in which nondiploidy portends a poor prognosis.

Female adnexal tumor of wolffian origin.

We describe a female adnexal tumor of probable wolffian origin with stage 2B disease. The presence of peritoneal implants suggests a more aggressive clinical course than is usually expected. We present the findings of light microscopic and ultrastructural evaluation as well as those of immunohistochemical and DNA ploidy analysis, which, to our knowledge, have not been previously described for this type of tumor.