Cost-Effectiveness Analysis of a HMGA2 Prognostic Test for Acute Myeloid Leukemia in a Canadian Setting.

BACKGROUND: Current strategies for risk stratification of patients with acute myeloid leukemia assign approximately 40% of patients to the intermediate-risk group, where uncertainty about optimal therapy still persists. OBJECTIVE: The objective of this study was to assess the cost effectiveness of a HMGA2 prognostic test based on HMGA2+/HMGA2- expression, which improves genetic risk stratification in acute myeloid leukemia, and compare this test with the current standard of care in Canada. METHODS: A cost-effectiveness model was developed from the Canadian National Healthcare Service and societal perspective using data from the Quebec Leukemia Cell Bank, published literature, and physician surveys. The model includes a lifetime horizon assessing the HMGA2 test vs. standard of care. RESULTS: The HMGA2 test outperformed the standard of care at all time horizons culminating with estimated improvements of 1.92 and 3.12 months in leukemia-free survival and overall survival, respectively. Costs associated with the HMGA2 test were consistently lower, except diagnostic costs, routine medical costs, and costs related to infections and false positives. From a societal perspective, total lifetime costs were $161,358 CAD and $151,908 CAD with the standard of care and the HMGA2 test, respectively. The incremental quality-adjusted life-year gain was 0.138, which led to dominance over the standard of care. Deterministic sensitivity analyses confirmed the results of the base-case scenario. Probabilistic sensitivity analyses revealed that for a willingness-to-pay threshold of $100,000 CAD, the probability of cost effectiveness was 87.19%. CONCLUSIONS: The HMGA2 test is estimated to improve leukemia-free survival and overall survival outcomes, and yield costs savings from a healthcare system and societal perspective.

HMGA2 Contributes to Distant Metastasis and Poor Prognosis by Promoting Angiogenesis in Oral Squamous Cell Carcinoma.

The highly malignant phenotype of oral squamous cell carcinoma (OSCC), including the presence of nodal and distant metastasis, reduces patient survival. High-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor that is involved in advanced malignant phenotypes and poor prognosis in several human cancers. However, its biological role in OSCC remains to be elucidated. The purpose of this study was to determine the clinical significance and role of HMGA2 in the malignant potential of OSCC. We first investigated the expression pattern of HMGA2 and its clinical relevance in 110 OSCC specimens using immunohistochemical staining. In addition, we examined the effects HMGA2 on the regulation of vascular endothelial growth factor (VEGF)-A, VEGF-C, and fibroblast growth factor (FGF)-2, which are related to angiogenesis, in vitro. High expression of HMGA2 was significantly correlated with distant metastasis and poor prognosis. Further, HMGA2 depletion in OSCC cells reduced the expression of angiogenesis genes. In OSCC tissues with high HMGA2 expression, angiogenesis genes were increased and a high proportion of blood vessels was observed. These findings suggest that HMGA2 plays a significant role in the regulation of angiogenesis and might be a potential biomarker to predict distant metastasis and prognosis in OSCC.

Hmga2 regulation of tooth formation and association with Sox2 and Nanog expression.

Tooth formation is accomplished under strict genetic programs. Although patients with chromosome 12q14 aberration shows tooth phenotype including the size and eruption timing with bone growth anomaly, its etiology is uncertain. Here, we examined expression of Hmga2, which is encoded at chromosome 12q14, in mouse tooth germs and analyzed the involvement in lower first molar (M1) and mandibular bone development. Hmga2 expression was immunohistochemically detected at enamel organ and the surrounding mesenchyme of the M1 germs. The expression was dynamically changed with gestation and rapidly decreased in postnatal mice. In Hmga2-/- mice, the M1 germs and crowns were diminished in size, and formation and eruption of molars were delayed with mandibular bone growth retardation. Hmga2 cDNA or siRNA transfection showed that Hmga2 transcriptionally up-regulates expression of stem cell factors, Sox2 and Nanog. They were co-localized with Hmga2 in the germs, but differentially distributed at enamel organ and mesenchyme in Hmga2-/- mice. These results demonstrate that Hmga2 expressed in tooth germs regulates the growth, sizing and eruption and stem cell factor expression in different compartment of the germ and associates with mandibular bone growth. Although future studies are needed, the present study demonstrates HMGA2 regulation of tooth genesis with skeletal development.

H19 Facilitates Tongue Squamous Cell Carcinoma Migration and Invasion via Sponging miR-let-7.

The long noncoding RNA (lncRNA) H19 has been described to participate in the metastasis of various tumors. Nevertheless, whether H19 promotes or impedes tongue squamous cell carcinoma (TSCC) cell migration and invasion remains controversial. Here we found that the expression of H19 was elevated in TSCC tissues compared with adjacent normal tissues. Moreover, we demonstrated that the expression of H19 was higher in metastasized tumors compared with unmetastasized tumors. Consistently, TSCC cells express higher levels of H19 than human squamous cells. Subsequently, depletion of H19 impaired the migration and invasion abilities of TSCC cells. Mechanistically, we demonstrated that H19 functions as a competing endogenous RNA (ceRNA) to sponge miRNA let-7a, leading to an increase in a let-7a target, the key regulator of tumor metastasis HMGA2, which is enriched in TSCC tissues and cell lines. Intriguingly, inhibition of let-7a significantly rescued the short hairpin H19 (shH19)-induced decrease in TSCC migration and invasion. These findings revealed that the H19/let-7a/HMGA2/EMT axis plays a critical role in the regulation of TSCC migration and invasion, which may provide a new therapeutic target for TSCC.

Expression of PTEN, Androgen Receptor, HER2/neu, Cytokeratin 5/6, Estrogen Receptor-Beta, HMGA2, and PLAG1 in Salivary Duct Carcinoma.

Salivary duct carcinoma (SDC) is an aggressive neoplasm that resembles high-grade invasive ductal carcinoma of the breast. It can develop de novo or from the malignant transformation of pleomorphic adenoma (PA). We performed immunohistochemical stains for phosphatase and tensin homologue [PTEN androgen receptor (AR)], HER2/neu, cytokeratin 5/6, estrogen receptor-beta, high-mobility group AT-hook 2 (HMGA2), and pleomorphic adenoma gene 1 (PLAG1) on tissue microarray samples of 75 SDCs and 31 adenocarcinomas, not otherwise specified (NOS). Our data showed the following in SDC samples: loss of PTEN was found in 17 of 60 (28.3%); AR was expressed in 43 of 62 (69.4%); HER2/neu was overexpressed in 25 of 58 (43.1%); cytokeratin 5/6 was expressed in 14 of 54 (25.9%); estrogen receptor-beta was expressed in 37 of 56 (66.1%); HMGA2 was expressed in 29 of 63 (46.0%); and PLAG1 was expressed in 0 of 62 (0%). In addition, there was no statistically significant difference in the age at onset between patients with HMGA2-positive SDCs (range 32-85 years; mean: 64.3 years; median: 64.5 years) and those with HMGA2-negative SDCs (range 41-79 years; mean: 62.5 years; median: 64.5 years). There was also no statistically significant difference in overall survival between patients with HMGA2-positive and HMGA2-negative SDCs (follow-up period range 3-201 months; mean: 49.8 months; median: 30 months). Among 10 patients with a definite PA component (SDC ex-PA), 6 were positive and 4 were negative for HMGA2. Our data were consistent with previous findings that AR and estrogen receptor-beta are expressed in most SDCs, whereas HER2/neu overexpression and loss of PTEN are expressed in a subset of SDCs. In our cohort of patients, HMGA2 was expressed in approximately half of SDCs. HMGA2 and PTEN are promising therapeutic targets for salivary gland tumors.

CCN6 regulates IGF2BP2 and HMGA2 signaling in metaplastic carcinomas of the breast.

PURPOSE: Metaplastic breast carcinomas are an aggressive subtype of triple-negative breast cancer (TNBC) in which part or all of the adenocarcinoma transforms into a non-glandular component (e.g., spindled, squamous, or heterologous). We discovered that mammary-specific Ccn6/Wisp3 knockout mice develop mammary carcinomas with spindle and squamous differentiation that share upregulation of the oncofetal proteins IGF2BP2 (IMP2) and HMGA2 with human metaplastic carcinomas. Here, we investigated the functional relationship between CCN6, IGF2BP2, and HMGA2 proteins in vitro and in vivo, and their expression in human tissue samples. METHODS: MMTV-cre;Ccn6fl/fl tumors and spindle TNBC cell lines were treated with recombinant CCN6 protein or vehicle. IGF2BP2 was downregulated using shRNAs in HME cells with stable CCN6 shRNA knockdown, and subjected to invasion and adhesion assays. Thirty-one human metaplastic carcinomas were arrayed in a tissue microarray (TMA) and immunostained for CCN6, IGF2BP2, and HMGA2. RESULTS: CCN6 regulates IGF2BP2 and HMGA2 protein expression in MMTV-cre;Ccn6fl/fl tumors, in MDA-MB-231 and - 468, and in HME cells. CCN6 recombinant protein reduced IGF2BP2 and HMGA2 protein expression, and decreased growth of MMTV-cre;Ccn6fl/fl tumors in vivo. IGF2BP2 shRNA knockdown was sufficient to reverse the invasive abilities conferred by CCN6 knockdown in HME cells. Analyses of the TCGA Breast Cancer Cohort (n = 1238) showed that IGF2BP2 and HMGA2 are significantly upregulated in metaplastic carcinoma compared to other breast cancer subtypes. In clinical samples, low CCN6 is frequent in tumors with high IGF2BP2/HMGA2 with spindle and squamous differentiation. CONCLUSIONS: These data shed light into the pathogenesis of metaplastic carcinoma and demonstrate a novel CCN6/IGF2BP2/HMGA2 oncogenic pathway with biomarker and therapeutic implications.

Pancreatic Lipomatous Hamartoma: A Hitherto Unrecognized Variant.

Pancreatic masses consisting of lipomatous components clinically include lipoma, liposarcoma, lipomatous pseudohypertrophy of the pancreas, fat-containing neoplasms such as perivascular epithelioid cell tumor, and malignant neoplasm with lipoid degeneration. We present pancreatic lipomatous hamartoma, which has not been reported hitherto. A solid pancreatic mass was detected from a computed tomographic scan check-up in each of 3 cases of Japanese men. Macroscopically, well-demarcated solid lipomatous masses were detected at the uncus, body, and tail of the pancreas, respectively. Microscopically, the masses predominantly consisted of mature adipocytes with no atypia, but contained characteristics components of pancreatic hamartoma, such as small ducts, a well-preserved acinar structure, and/or fibrous stroma. On the basis of the unique features, lack of islets and absence of periductal elastic fibers, these tumors are a distinct variant of pancreatic hamartoma. Furthermore, high-mobility group AT-hook 2 expression in the fibro-adipocytes of this tumor indicated that these cells are an integral component of the pancreatic lipomatous hamartoma. Consequently, the unique tumors described herein are pancreatic lipomatous hamartoma, which must be discriminated from other lipomatous lesions of the pancreas.

Expression of Matrix Metalloproteinase-9, Pituitary Tumor Transforming Gene, High Mobility Group A 2, and Ki-67 in Adrenocorticotropic Hormone-Secreting Pituitary Tumors and Their Association with Tumor Recurrence.

OBJECTIVE: Matrix metalloproteinase-9 (MMP-9), pituitary tumor transforming gene (PTTG), and high mobility group A 2 (HMGA2) play important roles in the tumorigenesis of adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors, but their associations with tumor recurrence after transsphenoidal adenomectomy remain unclear. The aim of the study was to investigate the immunohistochemical expression profiles of MMP-9, PTTG, HMGA2, and Ki-67 in recurrent and nonrecurrent ACTH-secreting pituitary tumors and to identify their associations with tumor behavior and recurrence status. METHODS: A retrospective study was performed including 55 patients with sporadic Cushing's disease with long-term remission after transsphenoidal adenomectomy. Fifty-five ACTH-secreting pituitary tumor specimens and 2 normal pituitary glands were collected. After an intensive follow-up (33-59 months, mean 41.8 months), patients were divided into 2 groups based on their recurrence status: the nonrecurrent group (n = 28) and the recurrent group (n = 27). The expression of MMP-9, PTTG, HMGA2, and Ki-67 in each sample was examined and quantified by immunohistochemistry. The association between MMP-9, PTTG, HMGA2, and Ki-67 expression and clinicopathologic characteristics and tumor recurrence were evaluated. RESULTS: There was a significantly increased expression of MMP-9 in the recurrent group compared with the nonrecurrent group (P = 0.022), and this was strongly associated with the recurrence-free interval (P = 0.007, correlation coefficient. = -0.354). PTTG, HMGA2, and Ki-67 expression were not significantly different between the recurrent group and the nonrecurrent group. No expression of MMP-9, PTTG, HMGA2, or Ki-67 was detected in the 2normal pituitary glands. CONCLUSIONS: ACTH-secreting pituitary tumors with greater levels of MMP-9 were associated with a greater recurrence rate and a shorter recurrence-free interval. MMP-9 could be a valuable tool for predicting recurrence of ACTH-secreting pituitary tumors.

Expression of hsa-let-7b-5p, hsa-let-7f-5p, and hsa-miR-222-3p and their putative targets HMGA2 and CDKN1B in typical and atypical carcinoid tumors of the lung.

Typical and atypical carcinoid tumors belong to the neuroendocrine lung tumors. They have low recurrence and proliferation rate, lymph node, and distant metastases. Nevertheless, these tumors have shown a more aggressive behavior. In the last years, microRNAs were screened as new tumor markers for their potential diagnostic and therapeutic relevance. The expression of hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-222-3p, and their targets HMGA2 (high-mobility group A2) and CDKN1B (cyclin-dependent kynase inhibitor 1B, p27kip1) was evaluated in this rare small group of patients. We analyzed the clinical data of all typical and atypical carcinoid tumors of patients who underwent surgical operation at Marburg University Hospital (n = 18) from 2000. Quantitative reverse transcription polymerase chain reaction was performed in formalin-fixed paraffin-embedded tumor tissue versus four tumor-free lung tissue samples. HMGA2 was stable or downregulated; only one patient showed a significant overexpression. CDKN1B showed a significant overexpression or a stable level; it was downregulated in two samples only. Hsa-miR-222-3p resulted almost stable or overexpressed except for two samples (significantly downregulated). Hsa-let-7f-5p was stable or overexpressed in the majority of analyzed samples, whereas hsa-let-7b-5p was significantly downregulated. HMGA2 and CDKN1B are differently expressed between atypical and typical carcinoid tumors, thus representing valid biomarkers for the classification of the two tumor groups. Hsa-let-7f-5p and HMGA2 are inversely correlated. Hsa-miR-222-3p does not correlate with its predicted target CDKN1B.

CXCR4/Let-7a Axis Regulates Metastasis and Chemoresistance of Pancreatic Cancer Cells Through Targeting HMGA2.

BACKGROUND/AIMS: Pancreatic cancer cells (PCC) is one of the most risky cancers and gemcitabine (GEM) is the standard first-line drug for treating PCC. The PCC will develop drug resistance to GEM after a period of treatment. However, the detailed molecular mechanism of pathogenesis and drug resistance remains unresolved. METHODS: we employed qRT-PCR and western blot to examine the expression level of CXCR4, let-7a and HMGA2. In addition, we used MTT assay to detect cell proliferation and transwell assay to measure migration and invasiveness. The expression level of epithelial marker E-cadherin and mesenthymal marker N-cadherin was detected by western blot. The apoptosis was determined using annexin V-FITC/PI apoptosis detection kit by flow cytometry. RESULTS: we first proved that CXCR4 negatively regulated let-7a in PCC. Next, let-7a was confirmed to play crucial role in tumorigenesis, metastasis and drug resistance of pancreatic cancer cells Bxpc-3 and Panc-1 in vitro and in vivo. Finally, we identified HMGA2 as important downsteam target of let-7a in PCC and overexpression of HMGA2 restores cell proliferation, metastasis and chemosensitivity of GEM inhibited by let-7a. Conlusion: Taken together, we show an important signaling pathway involved in pathogenesis and drug resistance of PCC, thereby providing deeper insight into molecular mechanism by which CXCR4/let-7a regulates tumorigenesis and drug resistance of PCC. These findings will help us develop new strategies for diagnosis and treatment of PCC.

HMGA2 upregulation mediates Cd-induced migration and invasion in A549 cells and in lung tissues of mice.

Cadmium (Cd) is a toxic metal widely found in a number of environmental matrices, and it induces serious adverse effects in various organs and tissues. In this study, the role of high mobility group A2 (HMGA2) in promoting migration and invasion in Cd-treated A549 cells and lung tissues of mice was investigated. Our findings showed that exposure to Cd (2 µM) for 48 h or subcutaneous injection of Cd daily for 6 weeks significantly enhanced the expression of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-2 (MMP-2), phosphorylated focal adhesion kinase (p-FAK), and HMGA2 in A549 cells or lung tissues of mice. In A549 cells, HMGA2 knockdown significantly decreased expression of MMP-9, MMP-2 and p-FAK and inhibited the migration and invasion compared to that of only Cd-treated cultures. Overexpression of HMGA2 in HEK-293T cells increased expression of MMP-9, MMP-2 and p-FAK and enhanced the migration and invasion compared with the empty vector transfection group. In conclusion, upregulation of HMGA2 plays an important role in Cd-enhanced migration and invasion. Suppressing HMGA2 expression might have potential values in prevention of Cd-resulted toxicities.

Myolipoma of Soft Tissue: Clinicopathologic Analysis of 34 Cases.

Myolipoma of soft tissue, which was first described by Meis and Enzinger (1991), is a rare benign neoplasm characterized by the admixture of mature adipocytes and well-differentiated smooth muscle cells. Recently, cytogenetic alteration of the HMGA2 gene has been reported in 2 myolipomas. We present the clinicopathologic features of 34 cases of myolipoma of soft tissue, study immunoreactivity for HMGA2, and review the previous literature. In our series, there were 32 women and 2 men, with age at presentation ranging from 35 to 94 years (median, 55 y). The most frequently affected site was retroperitoneum (47%), followed by pelvis (15%), abdominal wall (12%), and intra-abdominal sites (9%). Follow-up information was available for 17 patients (50%), ranging from 1 to 202 months (mean, 41 mo). None has developed local recurrence or metastasis. Grossly, tumors were well circumscribed, and the cut surface showed an admixture of yellowish adipose tissue and tan-whitish nodules. The size ranged from 2.4 to 60 cm (median 10.5 cm). Histologically, the tumors were composed of an intimate admixture of mature fat cells and bland spindle-shaped cells with brightly eosinophilic cytoplasm, arranged in fascicles. Some cases showed the following unusual features focally: hypercellular fascicular pattern (N=2), degenerative nuclear atypia (N=1), round cell morphology (N=1), hemosiderin deposition (N=1), metaplastic cartilage (N=1), metaplastic bone (N=1), and eosinophil infiltrates (N=1). Immunohistochemically, spindle cells showed strong and diffuse positivity for desmin (26/26 cases), SMA (20/21), and ER (13/15). Nuclear positivity for HMGA2 was identified in 15 of 25 cases (60%). MDM2 and CDK4 were usually negative (14/15, 8/9, respectively). In summary, myolipoma of soft tissue is a distinctive benign tumor composed of mature fat cells and smooth muscle cells and arises most commonly in deep-seated locations of middle-aged women. In our study, 60% of cases showed nuclear staining for HMGA2 by immunohistochemistry, which supports the possibility that these tumors harbor aberration of the HMGA2 gene, as seen in lipomas and leiomyomas elsewhere.

HMGA2 is associated with the aggressiveness of tongue squamous cell carcinoma.

OBJECTIVE: To analyze the effects of HMGA2 on proliferation, invasion, and metastasis in tongue squamous cell carcinoma (TSCC). METHODS: HMGA2 knockdown was performed in SCC15 cell lines, and functional assay was applied to observe the effects on cell migration and invasion. Real-time PCR, Western blotting, and immunohistochemistry (IHC) were also used to measure the expression of HMGA2 and EMT markers. RESULTS: HMGA2 expression was decreased after lentivirus infection. Functional assay showed that silence of HMGA2 can inhibit the proliferation of SCC15 cells and arrest the cells in G1/S phase. Moreover, knockdown of HMGA2 enhanced apoptosis of SCC15 cells. Wound-healing assay and transwell assay indicated that knockdown of HMGA2 significantly inhibited migration and invasion ability of SCC15 cells. Expression detection suggested that HMGA2 may be involved in the metastasis of SCC15 cells by activating Twist family expression and inducing epithelial-mesenchymal transition (EMT) process. IHC analysis showed that HMGA2 and vimentin were up-regulated in TSCC tissues, while E-cadherin was down-regulated. Clinicopathological analysis indicated that expression of HMGA2, E-cadherin, and Vimentin were associated with recurrence of patients with TSCC. CONCLUSION: Our findings demonstrated that HMGA2 may promote malignant transformation of TSCC through EMT process and may be an independent prognosis biomarker for TSCC.

Myogenin, AP2ß, NOS-1, and HMGA2 are surrogate markers of fusion status in rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the children's oncology group.

Pediatric rhabdomyosarcoma (RMS) is traditionally classified on the basis of the histologic appearance into alveolar (ARMS) and embryonal (ERMS) subtypes. The majority of ARMS contain a PAX3-FOXO1 or PAX7-FOXO1 gene fusion, but about 20% do not. Intergroup Rhabdomyosarcoma Study stage-matched and group-matched ARMS typically behaves more aggressively than ERMS, but recent studies have shown that it is, in fact, the fusion status that drives the outcome for RMS. Gene expression microarray data indicate that several genes discriminate between fusion-positive and fusion-negative RMS with high specificity. Using tissue microarrays containing a series of both ARMS and ERMS, we identified a panel of 4 immunohistochemical markers-myogenin, AP2ß, NOS-1, and HMGA2-which can be used as surrogate markers of fusion status in RMS. These antibodies provide an alternative to molecular methods for identification of fusion-positive RMS, particularly in cases in which there is scant or poor-quality material. In addition, these antibodies may be useful in fusion-negative ARMS as an indicator that a variant gene fusion may be present.

MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma.

Recent identification of somatic MED12 mutations in most uterine leiomyomas brings a new venue for the study of the tumorigenesis of leiomyomas. We are particularly interested in the correlation of MED12 and HMGA2 gene products in leiomyomas and leiomyosarcomas with and without MED12 mutations. To address these issues, in this study we examined MED12 mutations in a large cohort of usual type leiomyomas (178 cases) and uterine leiomyosarcomas (32 cases). We found that 74.7% (133/178) of leiomyomas had MED12 mutations, which was consistent with several independent studies. In contrast, only 9.7% (3/32) of leiomyosarcomas harbored MED12 mutations. Expression analysis by western blot and immunohistochemistry revealed that those leiomyomas with complex MED12 mutations had significantly lower protein products than the matched myometrium. Interestingly, most leiomyosarcomas without MED12 mutations also had very low levels of MED12 expression in comparison to the matched myometrium. These findings suggest a potential functional role of MED12 in both benign and malignant uterine smooth muscle tumors. When we further examined HMGA2 expression in all leiomyomas and leiomyosarcomas, we found that HMGA2 overexpression was exclusively present in those leiomyomas with no MED12 mutation, accounting for 10.1% (18/178) of total leiomyomas and 40% (18/45) of non-MED12 mutant leiomyomas. Twenty-five percent (8/32) of leiomyosarcomas had HMGA2 overexpression, and no MED12 mutations were found in HMGA2 positive leiomyosarcoma. These findings strongly suggest that MED12 mutations and HMGA2 overexpression are independent genetic events that occur in leiomyomas, and they may act differently in the tumorigenesis of uterine leiomyomas.

The expression of HMGA2 varies strongly among colon carcinomas.

BACKGROUND: The expression of high mobility group protein AT-hook2 (HMGA2) indicates a worse prognosis in many epithelial malignancies, such as colon cancer. The present study addresses methodological aspects, as well as the genetic background, of the HMGA2 expression in colon cancer. MATERIALS AND METHODS: Samples of 38 colon carcinomas were studied for the expression of HMGA2 by quantitative Real-Time PCR (qRT-PCR). In selected cases, immunohistochemistry (IHC) was also performed. RESULTS: The overexpression of HMGA2, compared to adjacent mucosa, is not consistent among colon carcinomas: Only a minority of carcinomas strongly overexpressed HMGA2, but in no more than 50% of the tumors did the expression exceed the average value in mucosa samples. qRT-PCR clearly reveals a continuum between cases with high and low expression. CONCLUSION: For HMGA2-based risk assessment, continuous rather than discontinuous models seem to be most appropriate. However, in daily practice, IHC seems to be a suitable method to stratify for high-risk patients.

Aggressive angiomyxoma of the vaginal wall at the initial stage: a case report.

Aggressive angiomyxoma (AA) is a rare mesenchimal tumor usually located in the pelvic and perineal region. Less than 30 cases of aggressive angiomyxoma with vaginal location have been reported in the literature up to this date. The authors report the case of a 50-year-old female patient diagnosed with vaginal AA whose characteristics at its initial stage were macroscopically indistinguishable from those of a polypoid lesion. Therefore this case suggests that this type of tumor should be considered as part of the differential diagnosis of vaginal polypoid lesions.

Aggressive angiomyxoma [corrected] of the female genital tract and pelvis--clinicopathologic features with immunohistochemical analysis.

Aggressive angiomyxoma (AA) is a benign, slow-growing tumor that characteristically occurs in women of reproductive age. Local recurrence is cited in 30% to 40% of cases. Wide local excision is the treatment of choice. However, recent reports suggest a role for hormone manipulation in the management of these tumors. The morphology and immunophenotype of AA overlap with that of other, mainly benign vulvovaginal mesenchymal tumors. Diagnosis rests primarily on hematoxylin and eosin staining features, and distinction is important in determining appropriate treatment and follow-up. Rearrangement of HMGA2 has been shown in AA, and reports suggest that HMGA2 immunohistochemistry may have a role in the routine diagnosis of AA, its distinction from mimics, and in the evaluation of margins. Furthermore, CDK4 immunopositivity has been described in AA. We describe a series of 9 cases of AA with typical histology and long-term follow-up, and evaluate the role of HMGA2, CDK4, estrogen, and progesterone immunohistochemistry. One of 9 women (11%) experienced recurrence, with the second at 17 years, which is the longest recorded in the English literature. HMGA2 immunohistochemistry was positive in 37.5% of cases, consistent with the reported frequency of HMGA2 gene rearrangement, and negative in all benign mimics. CDK4 immunoreactivity was weak, diagnostically not helpful, and of uncertain significance. Immunohistochemistry for estrogen and progesterone were positive in 87.5% of AAs, and were widely positive in control groups.

Reactive fibroblastic and myofibroblastic proliferation of the vulva (Cyclist's Nodule): A hitherto poorly described vulval lesion occurring in cyclists.

Perineal nodules occurring in male cyclists are reported in the literature, although the histologic features are not extensively documented. There has been little description of similar lesions in the female population. We describe 4 cases in which a vulval nodule or swelling developed in competitive female cyclists aged 15 to 45 years. The lesions were unilateral and occurred on the right or left labium majus (2 cases each). The histologic features were similar in all cases and consisted of a haphazard admixture of adipose tissue, variably cellular hyalinized tissue containing bland spindle-shaped fibroblasts, blood vessels, and nerve fibers. In some areas, thick cords of fibrous tissue imparted a keloid-like appearance. Other histologic features included plump mesenchymal cells with round or ovoid nuclei and abundant eosinophilic cytoplasm resulting in an epithelioid, plasmacytoid, or ganglion-like appearance (2 cases), a lymphocytic infiltrate around blood vessels (3 cases), foci of fat necrosis (1 case), and collections of elastic fibers (2 cases). One case recurred, the histologic features of the recurrent lesion being identical to the original. The overall morphologic appearances, especially in the cases with plump mesenchymal cells, bore some resemblance to proliferative fasciitis. Immunohistochemically, the cells were estrogen receptor positive and the plump mesenchymal cells were smooth muscle actin positive, in keeping with myofibroblasts. Desmin, S100, CD34, and HMGA2 were negative. Pathologists should be aware of this pseudoneoplastic lesion occurring on the vulva, which arises in a specific clinical setting and has the potential to be misdiagnosed as a variety of other mesenchymal lesions. We term this lesion as reactive fibroblastic and myofibroblastic proliferation of the vulva or "cyclist's nodule."

Isolation and characterization of portal branch ligation-stimulated Hmga2-positive bipotent hepatic progenitor cells.

Hepatic stem/progenitor cells are one of several cell sources that show promise for restoration of liver mass and function. Although hepatic progenitor cells (HPCs), including oval cells, are induced by administration of certain hepatotoxins in experimental animals, such a strategy would be inappropriate in a clinical setting. Here, we investigated the possibility of isolating HPCs in a portal branch-ligated liver model without administration of any chemical agents. A non-parenchymal cell fraction was prepared from the portal branch-ligated or non-ligated lobe, and seeded onto plates coated with laminin. Most of the cells died, but a small number were able to proliferate. These proliferating cells were cloned as portal branch ligation-stimulated hepatic cells (PBLHCs) by the limiting dilution method. The PBLHCs expressed cytokeratin19, albumin, and Hmga2. The PBLHCs exhibited metabolic functions such as detoxification of ammonium ions and synthesis of urea on Matrigel-coated plates in the presence of oncostatin M. In Matrigel mixed with type I collagen, the PBLHCs became rearranged into cystic and tubular structures. Immunohistochemical staining demonstrated the presence of Hmga2-positive cells around the interlobular bile ducts in the portal branch-ligated liver lobes. In conclusion, successful isolation of bipotent hepatic progenitor cell clones, PBLHCs, from the portal branch-ligated liver lobes of mice provides the possibility of future clinical application of portal vein ligation to induce hepatic progenitor cells.