Two cases of adenodermatofibroma.

Dermatofibromas (DF) are common skin lesions composed of a dermal proliferation of fibroblasts and histiocytes. Among the variants of DFs, adenodermatofibroma are characterized by a dense proliferation of fibroblasts and histiocytes admixed with entrapped dilated glandular structures. We report two additional cases of adenodermatofibromas, review the literature, theorize on the histopathogenesis of this variant, and suggest that there are different patterns among adenodermatofibromas, from primarily cystic to primarily glandular.

Pulmonary Adenofibromas: A Clinicopathologic Correlation of 13 Cases.

Thirteen cases of primary pulmonary adenofibromas are presented. The patients are 8 women and 5 men between the ages of 41 and 73 years (average: 57 y). The patients presented with nonspecific symptomatology or their tumor was identified during routine chest films. A wedge resection was performed in all cases with lymph node sampling. Grossly, the tumors varied in size from 1 to 2.5 cm in greatest dimension. The entire tumor was histologically evaluated in all cases. All the tumors shared similar histologic features namely leaf-like/phyllodes-like growth patterns with varying areas of sclerosis, focal inflammation, and entrapped epithelium. A wide panel of immunohistochemical studies was performed including epithelial, neural, muscle, and vascular markers, all of which showed negative staining. The tumors were positive only for vimentin in the stroma and keratin in the entrapped epithelium. Further evaluation in 6 cases using in situ hybridization for the solitary fibrous tumor was performed and was negative. Clinical follow-up in all the patients showed no evidence of recurrence or metastatic disease, during a period of 12 to 36 months. The current cases highlight the unusual occurrence of pulmonary adenofibromas and the importance of separating these tumors from other tumors that may have the potential to recur or metastasize. The use of proper immunohistochemical stains/molecular analysis aids in the proper classification of these tumors.

Semaphorin 4C Promotes Macrophage Recruitment and Angiogenesis in Breast Cancer.

Semaphorins are a large family of evolutionarily conserved morphogenetic molecules that are associated with repelling axonal guidance. Intriguingly, recent researches indicate that semaphorins are involved in cancer progression. Semaphorin 4C (SEMA4C) has long been considered a neuronal migration gene, but we detected that it is also highly expressed in many malignant human cancers. During an investigation of subcutaneous tumor models, we found that SEMA4C expression promoted tumor growth and progression. We discovered that SEMA4C was involved in maintaining tumor cell self-renewal, likely by regulating the p53 pathway. Inhibiting the expression of endogenous SEMA4C in tumor cells impaired growth and induced senescence and cell-cycle arrest in the G2-phase. In addition, we found that SEMA4C induced the production of angiogenin and colony-stimulating factor-1 (CSF-1) in tumor cells by activating the NF-κB pathway in a plexinB2-dependent manner. In conclusion, SEMA4C expression in breast cancer cells promotes cancer cell proliferation, macrophage recruitment, and angiogenesis. Thus, inhibition of SEMA4C activity may be a novel therapeutic strategy for human breast cancer. IMPLICATIONS: In breast cancer, therapeutic targeting of the SEMA4C pathway may prevent tumor growth, angiogenesis, metastasis, and progression.

Recurrent NAB2-STAT6 gene fusions and oestrogen receptor-α expression in pulmonary adenofibromas.

AIMS: Pulmonary adenofibromas are rare benign fibroepithelial tumours of the lung with unknown histogenesis and an indolent clinical behaviour. Their stroma resembles that of solitary fibrous tumours, whereas the glands are composed of respiratory epithelium organized in a phyllodes-like architecture. Differentiation of pulmonary adenofibromas from other more aggressive intrathoracic tumours is clinically relevant. However, their biology is unknown. Here, we sought to characterize pulmonary adenofibromas at a clinicopathological level and to define whether they could be underpinned by a highly recurrent somatic genetic alteration akin to tumours with similar morphology. METHODS AND RESULTS: Seven pulmonary adenofibromas were subjected to immunohistochemical analysis for thyroid transcription factor 1 (TTF1), napsin A, cytokeratin 7, E-cadherin, CD99, CD34, CD31, STAT6, oestrogen receptor (ER), progesterone receptor, androgen receptor, bcl-2, and vimentin, as well as electron microscopy and capillary sequencing on microdissected samples to evaluate the presence of NAB2-STAT6 fusion genes and MED12 exon 2 mutations in their discrete components. A control group comprising pulmonary solitary fibrous tumours, pulmonary hamartomas and breast fibroadenomas was also analysed. We confirmed that the stromal elements of pulmonary adenofibromas pertain to the fibroblastic lineage, and show ER overexpression in 71% of cases, whereas the epithelium consists of TTF1-positive, E-cadherin positive bronchiolar elements. A highly recurrent NAB2-STAT6 fusion variant (exon 4-exon 2) was detected in the stroma but not in the epithelium. No MED12 mutations were identified. CONCLUSIONS: Here, we demonstrate that pulmonary adenofibromas are neoplastic lesions harbouring the molecular hallmark of solitary fibrous tumours.

ARID1A expression in ovarian clear cell carcinoma with an adenofibromatous component.

AIMS: The carcinogenesis of ovarian clear cell carcinoma (CCC) has been hypothesized to comprise two different pathways: an adenofibroma-carcinoma sequence and an endometriosis-carcinoma sequence. However, the difference in the genetic basis of these two pathways remains unclear. Recent studies have suggested that an ARID1A mutation and the loss of the corresponding protein, BAF250a, are frequent events in CCC. Herein, we investigated the difference in the loss of BAF250a expression in adenofibroma-related CCC and endometriosis-related CCC. METHODS AND RESULTS: In total, 93 cases of surgically treated CCC were evaluated. The presence of adenofibroma and endometriosis associated with carcinoma was determined by reviewing haematoxylin and eosin-stained slides for each case. BAF250a expression in carcinoma was examined immunohistochemically. The loss of BAF250a expression was detected in carcinomas in 50 of 93 (54%) cases, including five of 18 (28%) with adenofibroma alone, 30 of 45 (67%) with endometriosis alone, eight of 18 (44%) with both conditions and seven of 12 (58%) with neither condition. The loss of BAF250a expression was significantly less frequent in CCC cases with adenofibroma than in cases with endometriosis (P = 0.01, Fisher's exact test). CONCLUSIONS: The action of ARID1A in carcinogenesis differs between adenofibroma-related CCC and endometriosis-related CCC.

[Recurrent Müllerian adenofibroma of uterus: a clinicopathologic study of 7 cases].

OBJECTIVE: To study the clinicopathologic features and differential diagnosis of recurrent Müllerian adenofibroma (MAF) of the uterus. METHODS: Clinicopathologic information of 7 cases of recurrent MAF of uterus was retrieved from January 1992 to April 2006 and compared with 12 cases of MAF without recurrence and 14 cases of low-grade Müllerian adenosarcoma (MAS). EnVision immunohistochemistry of estrogen receptor (ER), progesterone receptor (PR), smooth muscle actin (SMA), CD10, Ki-67 and p53 were performed in all cases. RESULTS: All cases of recurrent MAF of the uterus were polypoid, lobulated, and broad based mass arising from the corpus or cervix. Microscopically, the tumor consisted of benign epithelial and mesenchymal components with low mitotic activity ( ≤ 1/10 HPF). The clinical and pathologic features of 3 recurrent tumors were similar to their primary tumors, while 4 cases of recurrent tumor presented with focally higher cellularity and mitotic activity, meeting the diagnostic criteria of adenosarcoma. The stromal expression patterns of ER, PR, SMA and p53 in recurrent MAF were similar to those of clinically benign MAF and low-grade MAS. Negative or focally positive stromal cell expression of CD10 was seen infrequently in recurrent MAF (1/7) and clinically benign MAF (1/12). In contrast, a moderate to strong CD10 staining was frequently seen in MAS (9/14, P < 0.05). The difference of Ki-67-labeling index between MAF and MAS did not reach a statistical significance (P > 0.05). Ki-67-labeling index increased in areas of periglandular stromal cuffing as compared with interglandular areas in all MAS cases, but it was not observed in either recurrent MAF or clinically benign MAF cases. CONCLUSIONS: Recurrent MAF may be associated with aggressive behavior. It is difficult to distinguish MAF from low-grade MAS. CD10 and Ki-67 staining pattern in stromal cells may be helpful for the differential diagnosis.

A case of unclassified multicystic biliary tumor with biliary adenofibroma features.

A 40-year-old Japanese man was admitted to our hospital for evaluation of upper abdominal pain. Abdominal computed tomography (CT) revealed a well-circumscribed multicystic mass measuring approximately 7 × 6 cm. The mass contained a solid lesion measuring 3 × 2 cm. Biopsy of a swollen cervical lymph node led to a diagnosis of diffuse large B-cell lymphoma. After initial chemotherapy for lymphoma, the multicystic mass was surgically resected. The tumor was composed of a multicystic lesion and a solid lesion. Histopathologic examination of the multicystic lesion revealed that the locules were lined by biliary epithelium, demonstrating various degrees of cytological atypia. The stroma was fibrous, and the tumor showed marked apocrine snouts. Part of the tumor showed papillary growth with strong cytological atypia. The solid lesion showed tubulocystic proliferation of tumor cells, with prominent apocrine snouts, embedded in dense and partially hyalinized fibrous stroma. The morphology of the solid part was quite similar to that of reported biliary adenofibroma. Despite lengthy discussion, an appropriate pathological diagnosis could not be found among the current classifications of biliary tumor. The tumor was finally diagnosed as unclassified multicystic biliary tumor with adenofibroma features.

Aberrant expression of the mammalian target of rapamycin, hypoxia-inducible factor-1α, and glucose transporter 1 in the development of ovarian clear-cell adenocarcinoma.

Ovarian clear-cell adenocarcinoma (CCA) is known to be a type of cancer in humans with a high frequency of expression of the mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1 (HIF-1), and glucose transporter 1 (Glut1). In this study, we aimed to determine how these alterations contribute to tumor development of CCAs. Immunohistochemical expressions of phosphorylated-mTOR (p-mTOR), HIF-1α, and Glut1 were analyzed in 36 CCAs and 60 coexistent putative precursor lesions: 19 nonatypical and 16 atypical endometriotic lesions, and 11 benign and 14 borderline clear-cell adenofibroma (CCAF) components. Twenty-one cases with solitary endometriosis were also examined. The frequencies of immunopositivity for p-mTOR (in cytoplasm or nucleus), HIF-1α (in nucleus), and Glut1 increased in accordance with higher cytological atypia in the putative precursors: 58%, 5%, and 16% in the nonatypical endometriosis; 63%, 37%, and 50% in the atypical endometriosis; 77%, 95%, and 95% in the endometriosis-associated CCAs; 27%, 0%, and 0% in the benign-CCAF components; 64%, 79%, and 43% in the borderline CCAF components; and 71%, 100%, and 93% in the CCAF-associated CCAs, respectively. p-mTOR, HIF-1α (in the nucleus), and Glut1 were positive in 10%, 5%, and 19% of the solitary endometriosis, respectively. In the putative precursor lesions coexisting with CCA, a strong correlation in the expression between p-mTOR and HIF-1α and between HIF-1α and Glut1 was identified. Expressions of p-mTOR, HIF-1α, and Glut1 have already been evident in the putative precursor lesions of CCA, and these alterations cumulatively occur in the development of ovarian CCA.

ACTN4 gene amplification and actinin-4 protein overexpression drive tumour development and histological progression in a high-grade subset of ovarian clear-cell adenocarcinomas.

AIMS: Actinin-4, encoded by the ACTN4 gene located on chromosome 19q13.2, enhances cell motility by bundling the actin cytoskeleton. We assessed how ACTN4/actinin-4 alterations contribute to the tumorigenesis of ovarian clear-cell adenocarcinomas (CCAs). METHODS AND RESULTS: Fluorescence in-situ hybridization analysis demonstrated that ACTN4 amplification (≥4 ACTN4 copies in ≥40% of cells) occurred in 27 (33%) of 81 CCAs and genomic gains of ACTN4 were associated strongly with immunohistochemical actinin-4 overexpression, poorly differentiated tumour histology and shorter patient survival (all P < 0.05). From the 27 ACTN4-amplified CCAs, 23 tumours with adjacent putative precursor lesions were selected and examined for ACTN4/actinin-4 alterations with respect to their intratumoral heterogeneity. In this selected cohort, none of the precursors lacking cytological atypia exhibited gains of ACTN4 or actinin-4 overexpression; 50% of the atypical endometrioses and 75% of the borderline CCAFs showed low-level gains of ACTN4 and actinin-4 overexpression, respectively. In 12 of 23 ACTN4-amplified CCAs, intratumoral heterogeneity for ACTN4 alterations was documented in carcinomatous components; the better differentiated carcinoma components exhibited fewer alterations than those with poorly differentiated histology. CONCLUSION: Accumulative genomic gains of ACTN4, causing actinin-4 protein overexpression, drive the development and progression of ovarian CCAs with high-grade histology.

Accumulative copy number increase of MET drives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas.

Our previous study demonstrated that, among ovarian carcinomas, amplification of the MET gene and overexpression of MET specifically and commonly occur in clear-cell adenocarcinoma histology. This study was conducted to address how these alterations contribute to development and progression of this highly chemoresistant form of ovarian cancer. We histologically reviewed 21 previously described MET amplification-positive clear-cell adenocarcinoma cases, and selected 11 tumors with synchronous endometriosis and 2 tumors with adjacent clear-cell adenofibroma (CCAF) components. Using double in situ hybridization and immunohistochemistry, copy number alterations of the MET gene and levels of MET protein expression were analyzed in these putative precursor lesions and the corresponding invasive carcinoma components in this selected cohort. All of the non-atypical precursor lesions analyzed (ie, non-atypical endometrioses and the benign CCAFs) were negative for MET gain. However, low-level (≥3 MET copies in ≥10% and ≥4 MET copies in 10-40% of tumor cells) gain of MET was detected in 4 (40%) of the 10 atypical endometrioses and 1 of the 2 borderline CCAFs. Moreover, high-level (≥4 MET copies in ≥40% of tumor cells) gain of MET were detected in five (50%) of the atypical endometrioses. In 4 (31%) of the 13 cases enrolled, intratumoral heterogeneity for MET gain was documented in invasive carcinoma components, wherein all the relatively differentiated carcinoma components showed low-level gain of MET and all the corresponding poorly differentiated carcinomas showed high-level gain. The overall incidence of MET overexpression gradually increased from the precursors of non-atypical form (0%), through those of atypical form (67%) and the relatively differentiated carcinoma components (92%), to the poorly differentiated carcinoma components (100%). These results suggest that accumulative MET gene copy number alterations causing MET overexpression are associated with higher tumor grade and might drive the development and progression of the MET amplification-positive ovarian clear-cell adenocarcinoma.

A composite renal tumor: metanephric adenofibroma, Wilms tumor, and renal cell carcinoma: a missing link?

A coexistence of different renal tumors has rarely been reported. The most commonly described association is of Wilms tumor and renal cell carcinoma. Metanephric adenofibroma has also been associated with Wilms tumor or papillary renal cell carcinoma. Another reported association is metanephric adenoma and papillary renal cell carcinoma with sarcomatoid dedifferentiation. Herein we describe a complex renal tumor containing areas of metanephric adenofibroma, Wilms tumor, and undifferentiated renal cell carcinoma in a previously healthy 18-year-old boy. The tumor showed histologic and immunohistochemical features of these 3 different tumors, offering additional support to the view that these 3 tumors are related.

Papillary cystadenofibroma of epididymis: a case report.

We present the first reported case of papillary cystadenofibroma of the epididymis. The tumor occurred in a 46-year-old man. The mass was 3.7 cm and included a hemorrhagic fluid-filled cyst. Microscopically, stromal-filled papillae were lined by low cuboidal to columnar epithelium. Epithelial cells were reactive for cytokeratin 7, cytokeratins AE1/3, and focally in the apical cytoplasm for CD10. Focal CD10 reactivity was also noted in the stroma. The lesion was negative for alpha-fetoprotein. These findings ruled out other lesions, including metastatic renal cell carcinoma.

Ovarian serous cystadenofibroma with signet ring-stromal cells: report of 2 cases.

We report 2 ovarian serous cystadenofibromas with signet ring cells within the stromal component. The signet ring-stromal cells were widespread in 1 case and focal in the other. Immunohistochemically, they were negative with cytokeratin and other epithelial markers and positive with mesenchymal markers. The occurrence of signet ring-stromal cells in ovarian serous cystadenofibromas is an unusual pseudoneoplastic phenomenon, which has not been reported previously, although signet ring cells may occur within a variety of ovarian stromal neoplasms, including fibromas, sclerosing stromal tumors, and signet ring-stromal tumors. In reporting these cases, we review ovarian stromal neoplasms and other lesions with signet ring cells.

A pathologist's road map to benign, precancerous, and malignant intraepithelial proliferations in the fallopian tube.

The fallopian tube has recently emerged as an important site of origin for not only early serous cancer in women with inherited mutations in BRCA1/BRCA2 but as a source of many pelvic serous carcinomas. With this increased attention has come the inevitable need to sort out what epithelial abnormalities are clinically important and how they should be reported by the practicing pathologist. This review addresses 4 categories of tubal epithelial change: (1) metaplasias; (2) nonmalignant atypias; (3) potential precursors, including secretory cell outgrowths and p53 signatures; and (4) tubal intraepithelial carcinomas. A modified protocol for sectioning the fallopian tube (SEE-FIM) is discussed and each of the above topics is covered in the context of its differential diagnosis and recommendations for reporting are included. Finally, the rationale for close inspection of the tube, both in presumed benign and malignant disease, is discussed, with reference to an ongoing multi-institutional web-based project (Pelvic-ovarian Cancer Interception project).

Aberrant expression of p27(Kip1)-interacting cell-cycle regulatory proteins in ovarian clear cell carcinomas and their precursors with special consideration of two distinct multistage clear cell carcinogenetic pathways.

We have previously reported that alterations of p27(Kip1)-interacting cell-cycle proteins frequently occur during the development of endometriosis-associated ovarian clear cell adenocarcinoma (CCA; Yamamoto et al., Histopathology in press, 20). However, CCA also occurs in association with clear cell adenofibroma (CCAF). In this study, the expressions of p27(Kip1)-interacting proteins, i.e., p27(Kip1), Skp2, Cks1, cyclin A, cyclin E, and the Ki-67 labeling index (LI), were analyzed in 25 CCAFs (11 benign and 14 borderline) and 15 CCAF-associated CCAs, and compared with the expression status of each protein in the 23 previously studied endometriosis-associated CCAs. Although aberrant expression of all p27(Kip1)-interacting proteins was more frequent in the CCAF-associated CCAs than in the benign CCAFs, statistical significance was found only for Cks1 overexpression. The frequencies of p27(Kip1) downregulation and overexpression of Skp2 and cyclin A were significantly lower in CCAF-associated than in endometriosis-associated CCAs (P < 0.05, respectively). The frequencies of p27(Kip1) downregulation and Skp2 overexpression in borderline CCAFs were significantly lower than those in atypical endometriosis components in endometriosis-associated CCAs (P < 0.05, respectively). Mean Ki-67 LI increased significantly through benign (4.9%) to borderline (11.1%) CCAF and to CCAF-associated CCA (30.6%), but the latter two values were significantly lower than those in atypical endometriosis (21.4%) and endometriosis-associated CCA (46.9%; P < 0.05, respectively). These data suggest that accumulated alterations of p27(Kip1)-interacting proteins may accelerate the development of CCAs regardless of their carcinogenetic pathways, but that tumor cells in the CCAF-associated pathway appear to show slower cell-cycle progression than those in the endometriosis-associated pathway, possibly accounting for the distinct clinicopathological features of the two CCA subtypes.

Mullerian adenosarcoma: a clinicopathologic and immunohistochemical study of 55 cases challenging the existence of adenofibroma.

Mullerian adenosarcomas are rare mixed tumors of low malignant potential that occur mainly in the uterus and also in extrauterine locations. Microscopically, they may be difficult to distinguish from adenofibromas. In this clinicopathologic study of 55 adenosarcomas, the mean patient age was 50 years (range: 13 to 83 y). Thirty-seven tumors were of the uterine corpus, 11 of the cervix, 4 of the ovary, and 1 each of the fallopian tube, vagina, and Douglas peritoneum. Abdominal pain and vaginal bleeding were the usual complaints. Treatment was known in 50 patients: 10 had polypectomy, 1 cone biopsy, and 39 hysterectomy, which was accompanied by bilateral salpingo-oophorectomy in 24 and lymphadenectomy in 4. Five patients had radiotherapy and 2 of them had chemotherapy. Stage was known in 41 cases. Of 30 tumors of the uterine corpus, 17 were stage IA, 11 stage IB, 1 stage IC, and 1 stage IIIC. Four cervical tumors were stage IB. Three of the 4 ovarian tumors were stage IA and the other was stage IIIC. The tumor of the fallopian tube was stage IC, and the tumors of the vagina and recto-uterine pouch were confined to their site of origin. Most uterine tumors were polypoid masses ranging from 1 to 20 cm (mean: 6.5 cm). Microscopically, sarcomatous overgrowth was found in 18 cases (33%), heterologous elements in 13 (24%), and sex cordlike differentiation in 7 (13%). Fourteen of 30 uterine tumors (47%) had myometrial invasion that was minimal in 5, involved one-third of the myometrial thickness in 7, and more than 50% in 2. Of 4 cervical tumors, 2 were endocervical polyps, 1 invaded one-third of the cervical wall, and the other invaded its full thickness. Follow-up information (2 mo to 18 y; average: 7.5 y) was available in 29 patients. Six developed metastases and 5 of them died of tumor. Four had adenosarcomas with sarcomatous overgrowth; however, the other 2 patients had typical low-grade adenosarcomas of the uterine corpus and cervix, respectively, exhibiting only mild nuclear atypia of the stromal component and