The role of insulin-like growth factor in Acrochordon Etiopathology.

BACKGROUND: There are reports that acrochordon (skin tag), the most common fibroepithelial tumor of the skin, may be associated with metabolic syndrome components, particularly insulin metabolism disorders. However, to the best of our knowledge, there is no study examining its association with insulin resistance and tissue levels of insulin-like growth factor 1 receptor (IGF-1R) and insulin-like growth factor 2 receptor (IGF-2R). METHODS: Thirty patients with at least one acrochordon in their body who had no known history of diabetes mellitus and a control group comprised 30 individuals who had no acrochordon or no known history of diabetes mellitus were included. The tissue expression of IGF-1R and IGF-2R were investigated via immunohistochemical assessment in both groups. RESULTS: In the group with acrochordon, IGF-1R and IGF-2R expression was found to be significantly higher compared to the control group (p < 0,01). Using logistic regression analysis, an increase in serum insulin, serum IGF-1 and HOMA-IR levels was found to be associated with the expression levels of IGF-1R and IGF-2R. CONCLUSION: These findings support the view that insulin metabolism disorders should be evaluated in patients with acrochordon. Our study indicates that IGF receptors may have an effect on acrochordon pathogenesis and that acrochordon etiology and related conditions can be clarified by detection of parameters that influence receptor levels.

Cystic fibroepithelioma of Pinkus: two new cases and cystic changes in classical fibroepithelioma of Pinkus.

We report two new cases of cystic fibroepithelioma of Pinkus together with immunohistochemical features and analyze the presence of cystic changes in a series of 16 classical fibroepitheliomas of Pinkus. Our findings show that the formation of cystic spaces is most probably caused by ischemic degeneration of stromal fenestrations, rather than by central tumor cell necrosis. This finding is supported by lack of CD34 positive blood vessels in edematous and hyalinized stromal fenestrations undergoing transformation into cystic spaces, as opposed to the uninvolved stromal fenestrations. Therefore, it is probably more accurate to refer to this process as pseudocystic stromal degeneration rather than true cyst formation. Also, two out of 16 classical Pinkus fibroepitheliomas exhibited focal pseudocystic changes in 50% and 10% of the tumor, respectively, demonstrating that this degenerative process can be found, rarely and focally, in classical cases as well.

Biomarkers distinguishing mammary fibroepithelial neoplasms: a tissue microarray study.

AIM: To determine whether any markers in biopsy specimens were useful for distinguishing (1) fibroadenoma (FA) from benign phyllodes tumors (PTs); and (2) from benign borderline PTs of the breast. MATERIALS AND METHODS: Specimens of 80 breast tumors (20 FA, 38 benign, 12 borderline, and 10 malignant PTs) diagnosed at Tri-Service General Hospital from 1986 to 2006 and 10 normal breast tissue were investigated immunohistochemically for the expression of 11 biomarkers including p53, Ki-67, topoisomerase IIα, p16, retinoblastoma protein (pRb), fascin-1, estrogen receptor-ß, CD117, osteopontin, hypoxia-inducible factor-1α, and cyclooxygenase-2. The binary logistic regression method was used to generate functions that discriminate between benign and borderline PT and also between FA and benign PT. RESULTS: On the basis of the most active area of stained stromal cells, the staining intensity, and the immunoscore, the expression of Ki-67, topoisomerase IIα, p16, and pRb was significantly higher in borderline or malignant PTs than in benign PTs. Ki-67 could discriminate benign from borderline PTs singly with a high sensitivity (91.7%), specificity (100%), and accuracy (98%). In addition, expression of Ki-67, p16, and pRb was significantly higher in benign PT than in FA. Binary logistic regression identified p16 and pRb as the only marker combination capable of distinguishing FA from benign PTs with sensitivity (94.7%), specificity (75%), and accuracy (87.9%). CONCLUSION: Ki-67 may be a useful marker for discriminating benign from borderline PTs, and p16 and pRb may be a useful combination of markers for distinguishing FA from benign PTs in core biopsy specimen.

Fibroepithelial tumors of the breast: pathologic and immunohistochemical features and molecular mechanisms.

CONTEXT: The 2 main prototypes of fibroepithelial tumors of the breast include fibroadenoma and phyllodes tumor (PT). Although both tumors share some overlapping histologic features, there are significant differences in their clinical behavior and management. Phyllodes tumors have been further divided into clinically relevant subtypes, and there is more than one classification scheme for PT currently in use, suggesting a lack of consistency within different practices. Accurate differentiation between fibroadenoma and PT, as well as the grading of PT, may sometimes be challenging on preoperative core needle biopsy. Some immunohistochemical markers have been suggested to aid in the pathologic classification of these lesions. OBJECTIVE: To discuss the salient histopathologic features of fibroepithelial tumors and review the molecular pathways proposed for the initiation, progression, and metastasis of PTs. Also, to provide an update on immunohistochemical markers that may be useful in their differential diagnosis and outline the practice and experience at our institution from a pathologic perspective. DATA SOURCES: Sources included published articles from peer-reviewed journals in PubMed (US National Library of Medicine). CONCLUSIONS: Fibroepithelial tumor of the breast is a heterogenous group of lesions ranging from fibroadenoma at the benign end of the spectrum to malignant PT. There are overlapping histologic features among various subtypes, and transformation and progression to a more malignant phenotype may also occur. Given the significant clinical differences within various subtypes, accurate pathologic classification is important for appropriate management. Although some immunohistochemical markers may be useful in this differential diagnosis, histomorphology still remains the gold standard.

A subset of malignant phyllodes tumors harbors alterations in the Rb/p16 pathway.

Breast phyllodes tumors are fibroepithelial neoplasms with variable risk of aggressive local recurrence and distant metastasis, and the molecular pathogenesis is unclear. Here, we systematically study p16 and Rb expression in 34 phyllodes tumors in relation to proliferation. Tissue microarrays were constructed from 10 benign, 10 borderline, and 14 malignant phyllodes (5 cores/tumor) and from 10 fibroadenomas (2 cores/tumor). Tissue microarrays were labeled by immunohistochemistry for p16, Rb, and Ki-67 and by in situ hybridization for high-risk human papillomavirus. Cytoplasmic and nuclear p16 were scored by percentage labeling (0%-100%, diffuse >95%) and intensity. Nuclear Rb was scored by percentage labeling (0%-100%, diffuse >75%) and intensity. p16 and Rb labeling were repeated on whole sections of cases with Rb loss on the tissue microarray. Twenty-nine percent (4/14) malignant phyllodes showed diffuse strong p16 labeling with Rb loss in malignant cells (diffuse p16+/Rb-), whereas 21% (3/14) malignant phyllodes showed the reverse pattern of p16 loss with diffuse strong Rb (p16-/diffuse Rb+). Results were consistent between tissue microarrays and whole sections. No borderline phyllodes, benign phyllodes, or fibroadenoma showed diffuse p16+/Rb- or p16-/diffuse Rb+ phenotypes. No cases contained high-risk human papillomavirus. Average Ki-67 proliferation indices were 15% in malignant phyllodes, 1.7% in borderline phyllodes, 0.5% in benign phyllodes, and 0% in fibroadenoma. Ki-67 was highest in malignant phyllodes with diffuse p16+/Rb- labeling. In summary, 50% malignant phyllodes display evidence of Rb/p16 pathway alterations, likely reflecting p16 or Rb inactivation. These and other mechanisms may contribute to the increased proliferation in malignant phyllodes relative to other fibroepithelial neoplasms.

Neural crest transcription factor Sox10 is preferentially expressed in triple-negative and metaplastic breast carcinomas.

The transcription factor Sox10 mediates the differentiation of neural crest-derived cells, and Sox10 labeling by immunohistochemistry (IHC) is used clinically primarily to support the diagnosis of melanoma. Sox10 expression by IHC has been previously documented in benign breast myoepithelial cells but not in breast carcinomas. Here, we report the first systematic study of Sox10 expression in invasive ductal carcinomas subclassified by IHC-defined molecular subtype (100 cases), as well as in 24 cases of ductal carcinoma in situ and 44 mammary fibroepithelial neoplasms. Tissue microarrays containing 168 primary breast tumors were subjected to IHC for Sox10. The extent of nuclear Sox10 labeling was scored by percentage labeling as follows: 0 (0%), 1+ (1%-25%), 2+ (25%-50%), 3+ (50%-75%), and 4+ (>75%). Overall, 40 (40%) of 100 invasive breast carcinomas demonstrated Sox10 immunoreactivity, which was seen primarily in the basal-like, unclassified triple-negative, and metaplastic carcinomas. Sox10 labeling was seen in 66% (38/58) of the basal-like, unclassified triple-negative, and metaplastic carcinomas as compared with 5% (2/42) of the luminal A, luminal B, and Her-2 carcinomas (P < .00001). Sox10 labeling was seen in 1 (4%) of 24 cases of ductal carcinoma in situ, which was negative for estrogen receptor/progesterone receptor. No labeling was seen in the stromal component of phyllodes tumors or fibroadenomas. These findings show that breast carcinoma must be considered in the differential diagnosis of melanoma for an S100-positive, Sox10-positive metastatic malignant neoplasm. Sox10 expression in the basal-like, unclassified triple-negative, and metaplastic carcinomas types supports the concept that these neoplasms show myoepithelial differentiation.

Fibroepithelial polyps of the vagina in bitches: a histological and immunohistochemical study.

The histological and immunohistochemical features of 13 cases of suspected vaginal fibroepithelial polyps are reported. The characteristic microscopical features of these lesions were an abundant oedematous or fibrous stroma containing spindle-shaped and stellate cells and the presence of variable inflammation and haemorrhage. There was often a superficial layer of compressed tissue, but the stroma in the peripheral areas of the masses was generally more loosely arranged than in central areas. The connective tissue cells expressed vimentin and desmin, but did not express smooth muscle actin or calponin. Individual cases had additional changes including granulomatous inflammation, epithelial dysplasia suggestive of papillomavirus infection and a lesion resembling phyllodes tumour in women.

Lymphedematous fibroepithelial polyps of the penis associated with long-term condom catheter use: case report and review of the literature.

Lymphedematous fibroepithelial polyps of the penis are lesions that have only recently been described and are frequently associated with condom catheter use. We report an additional case of lymphedematous fibroepithelial polyps of the penis in association with long-term condom catheter use in a 36-year-old man. Local excision showed large polypoid nodules with compact orthohyperkeratosis and mild acanthosis. The stroma was hypercellular with spindled to stellate fibroblasts and occasional multinucleated cells. Proliferation of small linear to slightly arcuate vessels with some superficial dilatation was a prominent feature. Focal expression of smooth muscle actin and desmin was present in the stroma. Lymphedematous fibroepithelial polyps of the penis are rare lesions with only 11 cases previously reported. We present here an additional example of this entity to highlight the differential diagnosis, the association with condom catheter use and to raise awareness for this unusual diagnosis.

Fibroepithelioma of Pinkus with pleomorphic epithelial giant cells.

Fibroepithelioma of Pinkus is a rare, indolent variant of basal cell carcinoma (BCC). The presence of pleomorphic giant cells in such a tumor is extremely rare and to our knowledge, only one such case has been previously reported in the literature. We report another case occurring as a pedunculated, gluteal lesion in an 82-year-old man. The nodule was lightly pigmented, polypoid, and measured 1.0 cm in greatest dimension. Immunohistochemical staining confirmed that the giant cells were of epithelial origin and that the proliferative rate of these cells was low.

Expression of androgen receptor by fibroepithelioma of Pinkus: evidence supporting classification as a basal cell carcinoma variant?

The classification of fibroepithelioma of Pinkus as basal cell carcinoma or trichoblastoma remains controversial. Immunohistochemical stains for androgen receptor may be useful in differentiating basal cell carcinoma from trichoepithelioma or trichoblastoma. We studied androgen receptor expression in 13 fibroepitheliomas of Pinkus, 11 basal cell carcinomas, 12 trichoepitheliomas, and 3 trichoblastomas. Androgen receptor expression was present in 77% (10/13) of fibroepitheliomas of Pinkus, 73% (8/11) of basal cell carcinomas, 17% (2/12) of trichoepitheliomas, and 0% (0/3) of trichoblastomas. Androgen receptor expression was significantly higher in fibroepitheliomas of Pinkus compared with trichoepitheliomas and trichoblastomas (P = .0007), but not basal cell carcinoma (P = 1.00). Tumor-associated Merkel cells, a feature of benign follicular tumors, was identified by cytokeratin 20 stains. Merkel cells were identified in 85% (11/13) of fibroepitheliomas of Pinkus, 27% (3/11) of basal cell carcinoma cases, and 73% (11/15) of benign follicular tumors. Cytokeratin 20 expression was significantly higher in fibroepithelioma of Pinkus and benign follicular tumors compared with basal cell carcinomas (P = 0.0111 and P = 0.025, respectively). No significant difference was found between fibroepitheliomas of Pinkus and trichoepitheliomas and trichoblastomas (P = 1.00). Similar to basal cell carcinomas, fibroepitheliomas of Pinkus express androgen receptors, potentially supporting classification as a basal cell carcinoma. Conversely, fibroepithelioma of Pinkus demonstrates retention of Merkel cells, a feature of benign follicular tumors. Immunophenotypic evidence for the classification of fibroepithelioma of Pinkus remains inconclusive. In small, partial biopsy specimens, coexpression of androgen receptor and cytokeratin 20 may aid in the diagnosis of fibroepithelioma of Pinkus.

Pinkus tumor may originate from intraepidermal eccrine ducts and proliferate in the dermis.

To clarify the histopathogenesis of Pinkus tumor (fibroepithelial basal cell carcinoma, FEBCC), we have studied cytokeratin (CK) expression in FEBCC using ten different anti-keratin antibodies against CK 1, 7, 8, 10, 14, 15, 16, 17, 18 and 19. Tumor nests consisted of two epithelial components: duct-like structures and basaloid cells of anastomosing strands. In duct-like structure, CK 1, 10, 14, 16, 17 and 19 were detected. CK expression of duct-like structure showed the hyperproliferative state of eccrine intraepidermal ducts. In basaloid cells of anastomosing strands, CK 14 and 17 were detectable. These results suggested that duct-like structure originates from the intraepidermal duct and proliferates to spread in the dermis.

Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast.

INTRODUCTION: Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance of HIF-1alpha and its downstream targets in phyllodes tumors and fibroadenomas of the breast. METHODS: The expression of HIF-1alpha, CAIX, VEGF and p53 was investigated by immunohistochemistry in a group of 37 primary phyllodes tumors and 30 fibroadenomas with known clinical follow-up. The tumor microvasculature was visualized by immunohistochemistry for CD31. Proliferation was assessed by Ki67 immunostaining and mitotic counts. Being biphasic tumors, immunoquantification was performed in the stroma and epithelium. RESULTS: Only two fibroadenomas displayed low-level stromal HIF-1alpha reactivity in the absence of CAIX expression. Stromal HIF-1alpha expression was positively correlated with phyllodes tumor grade (P = 0.001), with proliferation as measured by Ki67 expression (P < 0.001) and number of mitoses (P < 0.001), with p53 accumulation (P = 0.003), and with global (P = 0.015) and hot-spot (P = 0.031) microvessel counts, but not with CAIX expression. Interestingly, concerted CAIX and HIF-1alpha expression was frequently found in morphologically normal epithelium of phyllodes tumors. The distance from the epithelium to the nearest microvessels was higher in phyllodes tumors as compared with in fibroadenomas. Microvessel counts as such did not differ between fibroadenomas and phyllodes tumors, however. High expression of VEGF was regularly found in both tumors, with only a positive relation between stromal VEGF and grade in phyllodes tumors (P = 0.016). Stromal HIF-1alpha overexpression in phyllodes tumors was predictive of disease-free survival (P = 0.032). CONCLUSION: These results indicate that HIF-1alpha expression is associated with diminished disease-free survival and may play an important role in stromal progression of breast phyllodes tumors. In view of the absence of stromal CAIX expression in phyllodes tumors, stromal upregulation of HIF-1alpha most probably arises from hypoxia-independent pathways, with p53 inactivation as one possible cause. In contrast, coexpression of HIF-1alpha and CAIX in the epithelium in phyllodes tumors points to epithelial hypoxia, most probably caused by relatively distant blood vessels. On the other hand, HIF-1alpha and CAIX seem to be of minor relevance in breast fibroadenomas.

Fibroepithelioma of pinkus is a fenestrated trichoblastoma.

Pinkus described "pre-malignant fibroepithelioma" as a proliferation that gave rise to many tiny basal cell carcinomas within each lesion. Later authors have generally considered it to be an unusual variant of basal cell carcinoma (BCC). The delineation of trichoblastoma as the general term for the benign counterpart of BCC raises the possibility that the fibroepithelioma of Pinkus (FEP) would be better classified under that rubric. To address this subject, we examined the records of 114 patients with FEP for body site, age and sex distribution, and sections from 75 lesions. All FEP examined show a blunt interface with the underlying dermis (where one could be seen), differentiation toward follicular bulbs and papillae, and large areas of cellular stroma. FEP has a slight female preponderance in contrast to BCC, which is more common in males. Unlike the common types of BCC, FEP has an overwhelming predilection for the trunk and extremities, and only 5% of tumors are set in a dermis with significant amounts of solar elastosis. Next, FEP, BCC, and FEP with BCC-like areas were stained with MIB-1 (to assess proliferation), p53 (an oncogene product), and CK20 (a Merkel cell marker) antisera. FEP shows a low level of staining for p53 and MIB-1, in contrast to conventional BCCs that over-express these markers. FEP also shows retention of Merkel cells, a characteristic of benign neoplasms with follicular germinative differentiation but not in general of BCC. The BCC-like areas in some FEP tumors reflect these staining tendencies with less striking differences. Given the contrast between FEP and BCC with respect to site of occurrence, relationship to sun damage, histopathologic features, and immunohistochemical studies, it appears that FEP more closely resembles trichoblastoma than BCC.

CD34+ stromal cells and hyalinized vascular changes in the anal fibroepithelial polyps.

AIMS: To elucidate the pathogenesis of the anal fibroepithelial polyp, we examined surgically resected lesions histopathologically. METHODS AND RESULTS: Twenty-seven surgically resected anal fibroepithelial polyps were investigated histologically with an additional immunohistochemical examination using anti-CD34. For a control study, the surgical specimens of the anal canal showing non-polypoid lesions, obtained from haemorrhoidectomy (18 specimens) and rectectomy (five specimens) due to rectal cancer without anal canal involvement, were also analysed. We demonstrated characteristic spindle or stellate cells immunohistochemically positive for CD34 in the anal fibroepithelial polyps (24/27, 89%). The number of CD34+ cells was statistically related to the size of anal fibroepithelial polyps, although CD34+ stromal cells were recognized in the non-polypoid anal submucosa and haemorrhoids. We also found hyalinized vascular changes in the base of six anal fibroepithelial polyps examined. These features were not detected in the non-polypoid anal canal. CONCLUSIONS: An increase in CD34+ stromal cells may play a role in the enlargement of anal fibroepithelial polyps. CD34+ stromal cells are suggested to be distinctive mesenchymal cells with a capability for tissue repair and overgrowth. The vascular impairment could be secondary change associated with localized tissue damage by abnormal traction.

Recurrent atypical myxoid fibroepithelial polyp associated with vulvar Crohn's disease.

Fibroepithelial polyps of the lower female genital tract are common lesions that can rarely exhibit atypical features including increased and atypical mitoses, bizarre nuclei, and hypercellularity, a combination of findings that may suggest malignancy. Five recurrent cases have been published to date, two of which were in pregnant females; the other three followed incomplete excisions. Our case is that of a 25-year-old female with Crohn's disease who developed multiple recurrences of polypoid and domed lesions of the labium minus following surgical excision. Histologic findings in the initial and recurrent lesions were consistent with atypical myxoid fibroepithelial polyps with underlying vulvar Crohn's disease. The lesions subsequently improved with standard Crohn's treatment including 5-amino-salicylic acid (Pentasa) and prednisone. The present case represents the only example of this entity associated with Crohn's disease, and it is the only reported recurrent case not associated with pregnancy, tamoxifen administration, or positive excision margins. The clinical, microscopic, and immunohistochemical findings of this case suggest that atypical fibroepithelial polyps of the lower female genital tract, cutaneous pleomorphic fibroma, and lesions such as fibroepithelial polyps of the anus may represent variants of the same atypical reparative process.