New genetic mutations in a Chinese child with Ehlers-Danlos syndrome-like spondyloepimetaphyseal dysplasia: A case report.

Background: Ehlers-Danlos syndrome (EDS) spinal deformity type 2 has clinical features similar to those of spondyloepimetaphyseal dysplasia with joint laxity, type 1 (SEMDJL1). They have similar clinical manifestations and a similar genetic basis, both of which can be caused by mutations in the B3GALT6 gene. Hence, genetic screening and careful clinical examination are key to the differential diagnosis of these two diseases. Case presentation: A 4-month-old boy was admitted to our hospital in order to find the causes of developmental delay. The clinical examination revealed that the child was delayed, with an excessive range of motion of joints, patent foramen ovale, and was accompanied by skin aging; the child was suspected to have EDS. However, unlike EDS, the child had normal muscle tension, and at the same time had a spinal deformity, mild kyphosis, widened right hip joint space, as well as a special face, joint laxity, and slender fingers, which were typical characteristics of SEMDJL1. A gene analysis showed two suspicious mutations in the B3GALT6 gene: c.808G > A(p.(G270S)) and c.942G > C(p.(W314C)), which were verified to be compound heterozygous mutations by analyzing genes in his parents. This mutation was not included in the HGMD, ClinVar, and other mutation databases, and thus was a newly discovered mutation. Conclusion: Using the clinical and genetic analyses, this study reported a Chinese case with EDS-like SEMDJL1 for the first time. Two pathogenic mutations were discovered in the B3GALT6 gene: c.808G > A(p.(G270S)) and c.942G > C(p.(W314C)).

Evaluation of the long-term effect of foldable capsular vitreous bodies in severe ocular rupture.

AIM: To evaluate the long-term effect of foldable capsular vitreous body (FCVB) in the treatment of severe ocular rupture to provide a practical basis for clinical selection. METHODS: A total of 26 patients (26 eyes), 23 men and 3 women, with severe ocular rupture who underwent FCVB implantation between March 2018 and September 2018 were retrospectively analysed. All open ocular wounds located in zone III, with preoperative visual acuity grade IV and above (Snellen less than 4/200). The best corrected visual acuity (BCVA), intraocular pressure (IOP), cornea, anterior chamber, iris, lens, choroid, and retina were evaluated before and after the surgery. The subjective feeling and the location of FCVB were also assessed. RESULTS: The average age of the 26 patients was 36y (20-60y). Postoperative follow-up was from 10 to 14mo. At the end of follow up, BCVA was light perception (LP) in 10 cases, no light perception (NLP) in 13 cases, hand motions (HM) in 3 cases. IOP was 11±5 mm Hg. Corneal degeneration was in 3 cases and corneal endothelial dystrophy was in 7 cases. Shallow anterior chamber was in 8 cases and hyphema was in 8 cases. Organized membrane in the pupil was in 14 cases. Epiphora occurred in 3 cases. FCVB drainage tube exposed in 3 cases. All FCVBs were in their normal location and no rejection occurred. CONCLUSION: FCVB implantation is a long-term effective treatment and may provide a practical selection for severe ocular rupture.

Correction to: Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects.

Following publication of the original article [1], the authors reported an error in Fig 5 of this article, graphs presenting FCM and immunofluorescent for CD4T, CD8T and NK cell of the Control Groups (LL2, LL2-irradation, MCS-irradiation) were inadvertently duplicated from another parallel experiment.

MicroRNA-137 regulates hypoxia-induced retinal ganglion cell apoptosis through Notch1.

The apoptosis of retinal ganglion cells (RGCs) is a hallmark of several optic neuropathies. MicroRNAs (miRNAs) are recently identified regulators of various biological processes. However, the role of miRNAs in regulating RGC apoptosis remains largely unknown. We herein aimed to demonstrate that miR-137 acts as a hypoxia-responsive gene in RGCs that is downregulated under hypoxic conditions. It was observed that overexpression of miR-137 markedly aggravated hypoxia-induced cell apoptosis, whereas inhibition of miR-137 effectively protected RGCs against hypoxia-induced apoptosis. Hypoxia induced Notch1 expression and signaling activation, while blocking Notch signaling significantly aggravated hypoxia-induced cell apoptosis. Further data revealed that the pro-survival Akt signaling pathway was involved in miR-137-Notch signaling pathway-mediated RGC protection. Knockdown of Notch significantly reversed the effect of anti­miR-137 on RGC protection and Akt signaling activation. In addition, blocking Akt signaling also significantly abrogated the protective effect of anti-miR-137 on hypoxia-induced cell injury. Overall, the results of the present study demonstrated that miR-137 targets Notch1 expression, revealing a novel link between miR-137 and Notch signaling, and suggesting that a miR-137/Notch1 axis may serve as a potential molecular target for the treatment of hypoxia-induced retinal diseases.

The outcomes of scleral buckling versus re-vitrectomy for the treatment of recurrent inferior retinal detachment in silicone oil tamponade eyes.

PURPOSE: In this retrospective study we evaluated the anatomic outcomes of scleral buckling (SB) versus re-vitrectomy for the treatment of recurrent inferior retinal detachment (RD) in silicone oil (SiO) tamponade eyes after primary vitrectomy. METHODS: There were 103 patients (103 eyes) enrolled in this study. All patients had recurrent inferior RD in the SiO-filled eyes within 6 months after the primary vitrectomy, and were treated by either SB or re-vitrectomy. Patients were divided into two groups based on different surgical procedures: the SB group (49 eyes) and the re-vitrectomy group (54 eyes). Anatomic reattachment of the retina was measured after reoperation. Based on different retinal proliferation states in different postoperative periods after primary vitrectomy, we also compared the anatomic outcomes of the two surgical procedures in two specific postoperative periods, early period (≤1 month) and late period (1-6 months). RESULTS: The SB and re-vitrectomy groups exhibited similar retinal reattachment rate (65.3% versus 72.2%, p = 0.449) after reoperation. In the re-vitrectomy group, the retinal reattachment rate was similar in the early period and the late period (70.8% versus 73.3%, p = 0.839). However, the retinal reattachment rate was significantly higher in the early period than that of the late period (80.8% versus 47.8%, p = 0.016) in the SB group. In the early surgery groups, the retinal reattachment rate was similar in the SB group compared to the re-vitrectomy group (80.8% versus 70.8%, p = 0.411). While in the late surgery groups, retinal reattachment rate was trended higher in the re-vitrectomy group compared to the SB group (73.3% versus 47.8%, p = 0.058). CONCLUSION: For recurrent inferior RD in SO-filled eyes, SB surgery provides similar therapeutic effectiveness with satisfactory anatomic outcomes compared to the re-vitrectomy. For eyes with recurrent inferior RD in the early period (≤1 month) after primary vitrectomy, SB surgery may be a better choice since it causes less complication; while in the late period (1-6 months) after primary vitrectomy, re-vitrectomy may be recommended, especially for the eyes with severe anterior proliferative vitreoretinopathy and retinal foreshortening.

Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects.

BACKGROUND: Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival. METHODS: The Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy. RESULTS: The studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro-inflammatory cytokines such as IL-18, GM-CSF, interferon-γ in serum, the proliferation of CD4+ IFN-γ+, CD8+ IFN-γ+ T lymphocytes in spleen and the infiltration of CD4+, CD8+ T in tumor. Furthermore, the mechanism of tumor-specific immune response was further proved by 51Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4+, CD8+ T lymphocytes. CONCLUSIONS: These results provide a new insight into therapeutic mechanisms of IL-18 plus GM-CSF modified tumor cell vaccine and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.

[Regulatory effects of ninjurin-1 on adhesion of myeloid cells in the retina at the early stage of diabetic rats].

OBJECTIVE: To investigate the regulatory effects of ninjurin-1 on adhesion of myeloid cells in the retina at the early stage of diabetic rats. METHODS: Experimental study. The rat diabetic model was induced by intraperitoneal injection of streptozotocin. After 2 months of diabetes induction, 27 diabetic rats were randomly chosen and assigned to 3 groups, including diabetes and phosphate buffered saline (PBS) injection group (group B), diabetes and anti-Ninj-1 injection group (group C) and diabetes and anti-IgG injection group (group D), with 9 rats in each group. Nine age matched health rats were chosen as control group (group A). Retinal leukostasis was quantified with acridine orange leukocyte fluorography. Retinal myeloid cell infiltration activity was measured by enzyme linked immunosorbent assay of myeloperoxidase (MPO). The differences of the mean values among the four groups were analyzed by one-factor analysis of variance. The multiple comparisons of the mean values among the four groups were analyzed by LSD-t analysis. RESULTS: According to the results of the acridine orange leukocyte fluorography, the numbers of leukocyte adhesion in the four groups were 49.66 ± 13.51, 153.66 ± 20.43, 85.33 ± 15.03 and 156.33 ± 11.53, respectively. The differences among them were significant (F = 143.34, P = 0.000). The numbers of leukocyte adhesion in the group C were significantly lower than that in group B (P = 0.000, 95%CI: -82.68 - -53.98). The levels of retinal MPO in the four groups were (15.66 ± 2.08), (27.66 ± 2.51), (18.02 ± 2.01) and (26.66 ± 3.21) µg/L, respectively. The differences among them were significant (F = 17.61, P = 0.010). The level of retinal MPO in the group C was significantly lower than that in group B (P = 0.010, 95%CI: -14.37 - -4.95). CONCLUSIONS: Ninj-1 may play a role in the mediation of the adhesion of myeloid cell to the rat retina of early-stage of diabetes in vivo.

Loss of SDHB and NF1 genes in a malignant phyllodes tumor of the breast as detected by oligo-array comparative genomic hybridization.

We report oligo-array comparative genomic hybridization findings in a case of malignant phyllodes tumor of the breast. In addition to gains of 1q and 5p, and losses of 10p and 13q14 approximately q22, this tumor had also losses of two regions to which tumor suppressor genes are mapped: 1p36 (SDHB) and 17q11.2 (NF1). Both genes are associated with hereditary cancer syndromes, including gastrointestinal stromal tumors. Whether these two genes played a role in the development or progression of this phyllodes tumor of the breast with a sarcomatous stromal component warrants further investigation of similar cases.

Rosai-Dorfman disease of the breast and parotid gland.

Rosai-Dorfman disease or sinus histiocytosis with massive lymphadenopathy (SHML) is a histiocytic proliferative disorder that typically involves the cervical lymph nodes with or without extranodal involvement of the skin, soft tissues, respiratory tract, or virtually any other site of the body. We present a case report of SHML involving the cervical lymph nodes, parotid gland and breast. There is only one other Rosai-Dorfman registered case that involves both breast and parotid disease and no previously published case reports. The patient presented atypically with breast masses found on screening mammogram rather than massive cervical lymphadenopathy. We describe the subsequent radiographic and surgical pathologic evidence that led to the diagnosis of this rare disease.

Terminal duct lobular units are scarce in the nipple: implications for prophylactic nipple-sparing mastectomy: terminal duct lobular units in the nipple.

BACKGROUND: The use of nipple-sparing mastectomy (NSM) for both breast cancer treatment and risk reduction is increasing. There is no randomized data comparing nipple-sparing mastectomy with standard mastectomy techniques. There is evidence to suggest that ductal and lobular breast cancer arises in the terminal duct/lobular unit (TDLU). This study was undertaken to determine whether TDLUs exist in the nipple and if so, to what extent. METHODS: At the time of mastectomy the nipple papilla was excised and submitted for separate pathological examination. The presence or absence of TDLUs was noted. RESULTS: Thirty-two nipples were studied in 22 patients. There were no TDLUs in 29 specimens. Three of 32 nipple specimens were found to contain TDLUs. The three nipples contain one, two, and three TDLUs respectively. All TDLUs were found at the base of the nipple, with none located near the tip. CONCLUSIONS: The infrequent occurrence of TDLUs in the nipple papilla supports the use of NSM for risk reduction surgery, including for those women with BRCA1/2 mutations.

Hepatitis C and hepatitis B nucleic acids are present in intrahepatic cholangiocarcinomas from the United States.

Intrahepatic cholangiocarcinomas (IHCs) are rare in the United States, but the prevalence is steadily increasing and risk factors are poorly understood. Tissues were obtained at the time of surgical resection, and 11 cases of IHC were retrospectively studied for the presence of hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) RNA. Hemi-nested and real-time polymerase chain reaction assays were used to detect HBV DNA, and nested reverse transcriptase-polymerase chain reaction was used to detect HCV RNA. Genotypes were determined for both HBV and HCV. The cases were predominantly from women (10/11), with an average age at surgery of 63 years and an average tumor size of 6 cm. Three cases (27%) were positive for either HBV or HCV nucleic acids: HBV alone (n = 1), HCV alone (1), coinfection with HBV and HCV (1). Both HBV-positive cases were genotype A, and both HCV cases were genotype 1a. Hepatitis B and C viral copy numbers were low in all cases. Evidence for active HBV replication was found in both HBV-positive cases, as they were positive for covalently closed circular DNA. In this study, 27% of ICC cases contained HBV and/or HCV nucleic acids, suggesting an etiologic role for these viruses in some cases of IHC.

Survivin overexpression in hepatocellular carcinoma is associated with p53 dysregulation.

BACKGROUND: Survivin is a recently described anti-apoptotic protein that is suppressed by wild-type p53 and is overexpressed in 41-70% of hepatocellular carcinomas from Asia. Two alternatively spliced transcripts have also been described: anti-apoptotic survivin-DeltaEx3 and non-anti-apoptotic survivin-2B. Survivin splice variant expression has not been studied in HCC, and little is known about survivin expression in hepatocellular carcinomas arising in other parts of the world, where risk factors are often different than they are in Asia. AIM OF THE STUDY: We studied survivin mRNA and protein expression in a United States cohort of hepatocellular carcinomas and correlated the findings with p53 immunopositivity. METHODS: RT-PCR was performed for survivin, survivin-2B, and survivin-DeltaEx3 in 20 HCCs and one intrahepatic cholangiocarcinoma. Expression levels of total survivin were evaluated with real-time PCR. Protein expression was examined by immunohistochemistry. RESULTS: Survivin was the major transcript, and all transcripts were present in all normal and neoplastic tissues; 11/20 (55%) HCCs and the one cholangiocarcinoma showed twofold or greater overexpression of survivin. Next, we examined survivin and p53 protein expression by immunohistochemistry on a separate series of 79 HCC, 13 fibrolamellar carcinomas, and 15 hepatic adenomas; 14/79 (17%) HCC, but none of the fibrolamellar carcinomas or hepatic adenomas, showed survivin protein overexpression, and 25/79 HCC (32%) showed abnormal nuclear accumulation of p53, which correlated with increased survivin expression. CONCLUSIONS: All three survivin transcripts are present in normal liver and HCC. Survivin is the dominant transcript in HCC and is overexpressed in 55% of cases. Survivin protein overexpression is associated with aberrant p53 nuclear positivity.

mTOR and P70 S6 kinase expression in primary liver neoplasms.

PURPOSE: mTOR and P70 S6 kinase (S6K) play a key role in regulating protein translation. The role of mTOR and S6K in hepatocellular carcinoma has not been investigated, but this pathway is of particular interest because an effective inhibitor, rapamycin, is available. This study was undertaken to determine the prevalence and clinicopathological correlates of mTOR pathway activation in hepatocellular carcinoma and to determine whether rapamycin inhibits the pathway in cell culture. EXPERIMENTAL DESIGN: Total and phosphorylated mTOR and S6K protein expression were studied by immunohistochemistry in hepatocellular carcinomas (n = 73), fibrolamellar carcinomas (n = 13), and hepatic adenomas (n = 15). Results were correlated with tumor growth pattern as defined by the WHO (trabecular, pseudoglandular/acinar, compact, and scirrhous), tumor size, Ki-67 proliferation index, and the modified Edmondson nuclear grade, which has a scale of 1 to 4. HepG2 and Hep3B cell lines were treated with rapamycin to see the effect on proliferation and S6K phosphorylation. RESULTS: Increased expression of total mTOR was seen in 5% of hepatocellular carcinoma, whereas overexpression of phospho-mTOR was evident in 15% of hepatocellular carcinoma. Phospho-mTOR positivity correlated with increased expression of total S6K, which was found in 45% of cases. Total S6K overexpression was positively correlated with tumor nuclear grade, inversely with tumor size, and was unassociated with the proliferation index or WHO growth pattern. Rapamycin treatment of HepG2 and Hep3B cell lines markedly inhibited cell proliferation and reduced S6K phosphorylation in both cell lines. CONCLUSIONS: The mTOR pathway is activated in a subset of hepatocellular carcinoma. Rapamycin can inhibit proliferation of neoplastic hepatocytes in cell culture.

Concurrent evaluation of p53, beta-catenin, and alpha-fetoprotein expression in human hepatocellular carcinoma.

Recent models suggest that hepatocellular carcinoma (HCC) develops through several independent pathways marked by key mutations in the beta-catenin or p53 gene. An additional pathway potentially is marked by aberrant expression of a-fetoprotein (AFP). To see whether these potential markers are expressed independently, we immunostained sequential sections from 55 HCCs. Of the cases, 30 (55%) were positive for 1 or more proteins: AFP, 19 cases (35%); p53, 12 cases (22%); and beta-catenin, 9 cases (16%). Seven tumors (13%) were positive for more than 1 protein, with 4 of 7 positive in the same area of tumor and 3 of 7 positive in different areas of the carcinomas. By statistical analysis, expression of the markers was independent of one another and of tumor size. Concurrent evaluation of p53, beta-catenin, and AFP protein expression showed no associations, supporting models in which these proteins might serve as markers of independent pathways in the development of HCC.

Leiomyosarcoma of the breast: a pathologic and comparative genomic hybridization study of two cases.

Leiomyosarcoma is an extremely rare form of primary breast sarcoma. We present the pathologic and genetic findings of two cases of leiomyosarcoma of the breast. The patients were 44 and 52 years of age and they presented with circumscribed masses of 3.0 and 4.5 cm, (greatest dimension) respectively. Microscopically, the two tumors showed diffuse proliferation of spindle cells with oval and blunt-ended nuclei arranged in short fascicles or bundles. There was moderate cytologic atypia in both cases, and 6 and 12 mitotic figures per 10 high power fields, respectively. No epithelial component was identified. The tumor cells were strongly immunoreactive for markers of smooth-muscle differentiation, including desmin, muscle-specific actin, and smooth-muscle actin. Comparative genomic hybridization analysis showed losses of 10q (two of two cases), 13q (two of two cases), 17p (one of two cases), and gains of 1q (one of two cases) and 17p (one of two cases). The patterns of chromosomal imbalances identified in leiomyosarcoma of the breast are similar to those reported in leiomyosarcoma of soft tissue and uterus and are different from those reported for leiomyoma, indicating that these alterations may be important for development of malignant smooth-muscle tumors regardless of site or organ of origin.

Bile ducts and ductules are positive for CD56 (N-CAM) in most cases of extrahepatic biliary atresia.

The diagnosis of extrahepatic biliary atresia can be challenging as the histologic features can overlap with other pediatric cholestatic liver diseases. Several previous studies have noted that biliary epithelium is positive for CD56 in the setting of extrahepatic biliary tract disease. Thus, we explored the use of CD56 in evaluating liver biopsy specimens for extrahepatic biliary atresia. A total of 22 cases were selected and immunostained for CD56, including 14 cases of confirmed extrahepatic biliary atresia and 8 cases of other cholestatic liver diseases in which the differential diagnosis included extrahepatic biliary atresia. Bile ducts and proliferating ductules were positive for CD56 in 13 of 14 cases of extrahepatic biliary atresia. The staining intensity was generally strong with most cases showing positivity in more than two thirds of portal tracts. The one negative case was a very small biopsy (<0.3 cm), and sampling may have played a role. In contrast, 4 of 8 cases in the control group were completely negative for CD56, with the remaining cases showing weak and focal positivity. In conclusion, bile ducts and ductules are CD56 positive in most cases of extrahepatic biliary atresia, and CD56 immunostaining can be a useful supplemental stain for diagnosing extrahepatic biliary atresia in its early, ductular proliferative phase when used in conjunction with traditional hematoxylin and eosin morphology and clinical information.

Uterine tumor resembling ovarian sex cord tumor: report of a case with t(X;6)(p22.3;q23.1) and t(4;18)(q21.1;q21.3).

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor of reproductive-age and postmenopausal women. We present the first case of UTROSCT with cytogenetic analysis. The tumor occurred in a 34-year-old woman who presented with menorrhagia and a uterine mass. Histologic examination showed tumor with features of sex cord-like epithelium and abundant fibromuscular stroma without an endometrial stromal sarcoma component. The tumor cells expressed cytokeratin, CD99, vimentin, desmin, smooth muscle actin, and estrogen and progesterone receptors. The majority of the cells analyzed by cytogenetic studies showed two balanced chromosomal translocations: t(X;6)(p22.3;q23.1) and t(4;18)(q21.1;q21.3). Several known tumor-related genes (bcl-2, MALT-1, FVT1, SCCA1, SCCA2, and DCC at 18q21; RAP1 at 4q21; and STL at 6q23) and a gonadal-development related gene (H-Y regulator gene at Xp22.3) are located at or near the translocation breakpoints. The tumor cells of sex cord-like elements were strongly and diffusely immunoreactive for bcl-2 antibody. These cytogenetic and immunohistochemical data may suggest potential molecular mechanisms of tumorigenesis of UTROSCT.

Expression of inducible nitric oxide synthase in paired neoplastic and non-neoplastic primary prostate cell cultures and prostatectomy specimen.

Nitric oxide (NO) is an important signaling molecule for ischemia, inflammation, angiogenesis, immune response, and cell growth and differentiation. It has recently been shown that increased production of NO within various human cancers may contribute to tumor angiogenesis, tumor growth and metastasis, and tumor-related immune suppression. NO can be produced by several NO synthases (NOS), including inducible synthase (iNOS), which is expressed during cell activation and produces NO in larger quantity and for a longer period of time than non-inducible NOSs. In this study, we examined the expression levels of iNOS mRNA and protein in prostate adenocarcinoma using a paired nonneoplastic and neoplastic primary prostate cell culture system and related prostatectomy specimens. Six pairs of neoplastic and nonneoplastic primary prostate cell cultures were established from radical prostatectomy specimens based on homogeneity of the originating tumor and the nonneoplastic tissue. Radioactive reverse transcriptase polymerase chain reaction and subsequent quantitative analysis of iNOS mRNA were performed on the cultures using beta-actin as an internal control. Immunohistochemical studies with an anti-iNOS monoclonal antibody were performed on the corresponding formalin-fixed paraffin-embedded prostatectomy tissue sections. We observed marked patient-to-patient variation in "normal" levels of iNOS mRNA. However, all six neoplastic cultures showed moderately to markedly higher mRNA levels than did their paired nonneoplastic cultures. In addition, iNOS protein levels were significantly higher in paraffin-embedded prostate cancer tissue sections than in adjacent nonneoplastic tissue. Overexpression of iNOS mRNA and protein levels is present in moderately differentiated prostate adenocarcinoma and may contribute to prostate cancer angiogenesis, tumor growth, and tumor-related immunosuppression.

Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases.

We reviewed 10 cases of pleomorphic lobular (ductal lobular) carcinoma in situ (PL/DLCIS) of the breast and compared them with 14 cases of pleomorphic lobular carcinoma in situ (PLCIS) found in association with invasive pleomorphic lobular carcinoma. The histologic features; immunohistochemical staining for estrogen receptors (ERs), p53, Ki67, E-cadherin, and gross cystic disease fluid protein-15 (GCDFP-15); and results of fluorescence in situ hybridization for HER-2/neu gene amplification were evaluated in all 24 cases. Histologically, PL/DLCIS cells were similar to those of PLCIS with invasion in that they were discohesive and medium to large in size with moderate to marked nuclear pleomorphism, small to prominent nucleoli, and moderate to abundant eosinophilic or vacuolated cytoplasm. In both groups, central necrosis was present in a small number of cases, and classic LCIS coexisted with the in situ lesion in less than half of the cases; in situ carcinomas were positive for ERs in 23 (100%) of 23 cases, p53 in 6 (25%) of 24 cases, and GCDFP-15 in 14 (74%) of 19 cases. The percentage of Ki67-positive tumor nuclei indicated moderate to high (more than 20%) proliferative activity in 8 (47%) of 17 cases. Immunostaining for E-cadherin was negative in all 24 cases. HER-2/neu gene amplification was observed in 1 (4%) of 23 cases. In cases with associated invasion, PLCIS had cytologic features and immunostaining patterns similar to those of the invasive pleomorphic component. Seven of the 10 patients who had PL/DLCIS without invasion underwent lumpectomy or simple mastectomy. Six of these patients had no evidence of disease in follow-up periods ranging from 4 to 32 months; the seventh patient developed recurrent disease 12 months after undergoing lumpectomy. We conclude that the cytologic features and biomarker expression profile of PL/DLCIS are similar to those of PLCIS with invasion but somewhat different from those of classic LCIS and ductal carcinoma in situ. Long-term follow-up studies are needed to further define the natural history of PL/DLCIS and its optimal management.