Cyclin D1 Immunohistochemistry Research Articles

Clinicopathological characteristics of extranodal Rosai-Dorfman disease: A retrospective case series of 25 patients

Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis, classically affecting the lymph nodes. Even rarer extranodal disease is diagnostically challenging due to overlapping histologic features with other entities and lack of a universally agreed set of biomarkers. Cyclin D1 immunohistochemistry (IHC) may serve as a useful adjunct in diagnosing extranodal RDD. We present a retrospective case series of patients diagnosed with extranodal RDD between January 2013 and December 2023. IHC staining for cyclin D1 was performed on archived tissue samples. Baseline IHC results for biomarkers supporting the RDD diagnosis were recorded along with patient demographic characteristics, clinical features, and disease outcomes. A total of 25 patients with extranodal RDD were included: 21 women (84 %) and 4 men (16 %). The mean age at diagnosis was 42.6 years. Cutaneous and deep tissue involvement was seen in 5 (20 %) and 20 (80 %) patients, respectively. 11 patients (44 %) had disease localized to the trunk and extremities, and 13 had disease in the head and neck region (52 %), of which 5 occurred in the nose and paranasal tissues. Available follow-up data showed most patients fully recovered (n = 11; 78.6 %). However, 1 patient had disease recurrence, 1 developed blindness, and 1 developed deafness. Cyclin D1 IHC was positive in all samples (100 %), consistent with previous studies. The clinicopathologic findings in this study highlight the spectrum of potential disease sites, possible morbid outcomes related to disease site, and the diagnostic utility of cyclin D1 IHC.

Copy Number Alteration of Cyclin D1 (CCND 1) Gene as a Prognostic Factor in Oral Squamous Cancers and its Correlation with Immunohistochemistry (IHC)

Background Oral squamous cancers remain the most common cancers among males in India and the third most common cancer among men and women combined, with an age standardized ratio of 9.1 per 100,000 population. Surgery and chemoradiation have not improved survival rates significantly and hence, newer therapeutic targets are needed. Cyclin D1 (CCND1) is a proto-oncogene which is located on chromosome 11q13 and has been found to be amplified in many cancers including oral cancers. It is said to correlate with aggressive tumor growth and a poorer prognosis. Aim This article correlates cyclin D1 (CCND1) gene copy number alteration with clinicopathologic prognostic factors in oral squamous cancers. Materials and Methods Sixty-three patients who underwent surgery for oral cancer between January and June 2022 were included in the study after obtaining informed consent and ethics approval. Copy number alteration of CCND1 was assessed using quantitative polymerase chain reaction (Qf PCR) and correlated with clinical and histopathological prognostic factors, including short-term recurrence. Statistical analysis was performed using the SPSS software. Results A statistically significant correlation was determined between the Qf PCR values of CCND1 gene and locoregional recurrence. Gene copy number alteration also correlated strongly with a higher grade of the primary tumor. There was also a significant correlation between the Qf PCR values and the immunohistochemistry for cyclin D1. Conclusion Cyclin D1 offers a new therapeutic target in oral cancers and may improve survival without significant treatment-related morbidity.

Primary Rosai-Dorfman disease of the central nervous system: A clinical, histological, and molecular appraisal.

Rosai-Dorfman disease (RDD) is characterized by clonal proliferation of S-100 positive histiocytes and variable emperipolesis. It commonly affects cervical lymph nodes. Central nervous system (CNS) involvement is extremely rare. We attempted to evaluate the Cyclin D1 expression and frequency of KRAS and BRAF mutations in the RDD involving the CNS. All patients with histopathologically diagnosed RDD involving CNS were recruited from 2011 to 2022. All cases were subjected to immunohistochemistry for CD68, CD163, S100, CD1a, GFAP, CD207, EMA, ALK, BRAFV600E, IgG4, IgG, and CyclinD1. The real-time polymerase chain reaction (RT-PCR) for hotspot mutation analysis of KRAS (exons 2, 3, and 4) and BRAF (V600E) was conducted on formalin-fixed paraffin-embedded tissue using a commercial kit (EntroGen). A total of seven cases were included. The median age was 31 years, with six men and one woman. It showed spinal cord (n = 4) and intracranial (n = 3) involvement. Histologically, all cases showed histiocyte-rich inflammation with evidence of emperipolesis. These histiocytes were positive for S100, CD68, CD163, and Cyclin D1, whereas negative for CD1a, CD207, and EMA. BRAF V600E was expressed in a single case. None of the control cases (demyelination and infarction) with histiocytic infiltrate showed Cyclin D1 expression. Four RDD cases showed increased IgG4-positive plasma cells (>10/HPF) and IgG4/IgG ratio (>40%). BRAF V600E mutation was detected in one case (14.28%), while none showed KRAS mutation. RDD involving CNS is extremely rare and diagnostically challenging. Nuclear Cyclin D1 expression along with S-100 positivity in the tumor cells is a strong diagnostic clue. BRAF and KRAS mutations are rare in CNS RDD.

Evaluation of Immunohistochemical Expression of Cyclin D1 and its Clinicopathological Correlation in Oral Carcinoma

Introduction: The present study aimed to evaluate the expression of cyclin D1 in oral carcinoma and to find the association of the expression of cyclin D1 with different histological types, grades and other clinicopathological findings. Materials and Methods: A 50 formalin fixed paraffin embedded tumor sections, stained with haematoxylin & eosin were graded and immunohistochemistry for cyclin D1 evaluated as expression score (ES), intensity score (IS) and total score (TS) was calculated. Results: A significant association was seen between total score of cyclin D1 expression with tumor types squamous cell carcinoma (Grade 1 and Grade 2) and verrucous carcinoma. Conclusion: In the present study for cyclin D1 evaluation, its expression was found in all oral carcinoma cases. A strong association was found between cyclin D1 total score with squamous cell carcinoma (Grade 1 and Grade 2) and verrucous carcinoma. We did not find a significant association between cyclin D1 total score and age, gender, tumor grades, site, laterality, PNI, LVI, pathological and clinical staging.

Antitumor Effect of Epigallocatechin Gallate and Vincristine in Mice with L5178Y Lymphoma.

The main objective of research into new therapies is the search for more efficacy and fewer toxic effects in cancer treatments. On one hand, vincristine (VCR) is a chemotherapeutic used in different kinds of tumors. On the other hand, epigallocatechin gallate (EGCG) is a green tea metabolite that has shown an antineoplastic effect in diverse investigations, so the objective of this work is to evaluate the antitumor effects of the EGCG/VCR combination on tumor volume and survival. To achieve this objective, the solid model of lymphoma L5178Y was used in BALB/c mice with different doses of VCR, EGCG, and their combination allowed tumor growth and survival time recording. After tumor collection, measurements, and immunohistochemistry for p53, Bcl2, and Cyclin D1 were performed. The results showed that the EGCG/vincristine combination had a greater antitumor effect than those effects of vincristine and EGCG. It can be attributed to the fact that the greatest inhibition of Bcl2 was present in gathering of EGCG harvest with vincristine. Therefore, the combination of EGCG with vincristine has a better antineoplastic effect by inhibiting tumor development and increasing survival on both substances independently.

Down-regulated MiRNA 29-b as a diagonistic marker in colorectal cancer and its correlation with ETV4 and Cyclin D1 immunohistochemical expression.

Colorectal cancer (CRC) is the most common malignant tumor of the gastrointestinal tract with unfavorable prognosis. Therefore, novel biomarkers that may be used for new diagnostic strategies and drug-targeting therapy should be developed. To investigate the expression of miR-29b in CRC and its association with ETV4 and cyclin D1 expression. Moreover, the current work aims to investigate the association between them and the clinicopathological features of CRC. The expression of miR-29b and ETV4 (by qRT-PCR) and ETV4 and cyclin D1 (immunohistochemistry) was investigated in 65 cases of colon cancer and surrounding healthy tissues. MiR-29b down-regulated and ETV4 and Cyclin D1 up-regulated significantly in colon cancer tissues compared to normal nearby colonic tissues. In addition, significant associations between ETV4 and cyclin D1 expressions and progressive stage and lymph node (LN) metastasis (P< 0.001 for each) were found. Furthermore, there was a negative correlation between miR-29b gene expression and ETV4 gene expression (r=-0.298, P<0.016). Down-regulation of miR-29b and over-expression of ETV4 and cyclin D1 may be utilized as early diagnostic marker for development of colon cancer. ETV4 and cyclin D1 correlate with poor prognostic indicators and considered as a possible target for therapy in colon cancer.

Comprehensive FISH testing using FFPE tissue microarray of primary lymph node tissue identifies secondary cytogenetic abnormalities in Mantle Cell Lymphoma

IntroductionMantle Cell Lymphoma (MCL), is characterised by the reciprocal translocation t(11;14) resulting in CCND1-IGH gene fusion and subsequent upregulation of the CCND1 gene. Rearrangements of MYC and losses of CDKN2A and TP53 have been identified as biomarkers informing prognostic and potentially therapeutic information however these are not routinely assessed in MCL investigation. We aimed to identify additional cytogenetic changes using fluorescence in situ hybridisation (FISH) on formalin fixed paraffin embedded (FFPE) primary lymph node tissue microarrays in a cohort of 28 patients diagnosed with MCL between 2004 and 2019. FISH results were compared with corresponding immunohistochemistry (IHC) biomarkers to determine if IHC was a reliable screening tool to direct FISH testing. MethodFFPE lymph node tissue samples were constructed into tissue microarrays (TMA) which were stained with 7 immunohistochemical biomarkers: Cyclin D1, c-Myc, p16, ATM, p53, Bcl-6 and Bcl-2. The same TMAs were hybridised with FISH probes for the corresponding genes; CCND1-IGH, MYC, CDKN2A, ATM, TP53, BCL6 and BCL2. FISH and the corresponding IHC biomarkers were analysed to determine if secondary cytogenetic changes could be identified and if IHC could be used as a reliable, inexpensive predictor of FISH abnormalities to potentially direct FISH testing. ResultsCCND1-IGH fusion was detected in 27/28 (96%) of samples. Additional cytogenetic changes were identified by FISH in 15/28 (54%) of samples. Two additional abnormalities were detected in 2/28 (7%) samples. Cyclin D1 IHC overexpression was an excellent predictor of CCND1-IGH fusion. MYC and ATM IHC were useful screening tests to direct FISH testing and identified cases with poor prognostic features including blastoid change. IHC did not show clear concordance with FISH for other biomarkers. ConclusionFISH using FFPE primary lymph node tissue can detect secondary cytogenetic abnormalities in patients with MCL which are associated with an inferior prognosis. An expanded FISH panel including MYC, CDKN2A, TP53 and ATM should be considered in cases where anomalous IHC expression or is seen for these markers or if the patient appears to have the blastoid variant of the disease.

Clinical Characteristics and Outcomes of Cyclin D1-Positive AL Amyloidosis.

To demonstrate the clinical features and prognostic impact of cyclin D1 positivity in patients with amyloid light chain amyloidosis (AL). We consecutively included 71 patients diagnosed with AL with cyclin D1 positivity between February 2008 and January 2022. t(11;14) was examined through interphase fluorescence in situ hybridization using bone marrow cells. The median age of the patients was 73 years, and 53.5% were male. The underlying diseases included symptomatic multiple myeloma, smoldering multiple myeloma, Waldenström macroglobulinemia, and monoclonal gammopathy of undetermined significance, representing 33.8%, 26.8%, 2.8%, and 36.6%, respectively. The prevalence of cyclin D1 and t(11;14) was 38.0% and 34.7%, respectively. Higher frequency of light chain paraprotein type was seen in cyclin D1-positive patients with AL than in cyclin D1-negative patients (70.4% vs 18.2%). The median overall survival (OS) of patients with AL with and without cyclin D1 expression was 18.9 months and 73.1 months, respectively (P = .019). Early death occurred in 44.4% of cyclin D1-positive patients and 31.8% of cyclin D1-negative patients. Moreover, 83.3% of cyclin D1-positive patients and 21.4% of cyclin D1-negative patients died of cardiac causes. Cyclin D1 immunohistochemistry accurately identified patients with t(11;14). Cyclin D1-positive patients had significantly inferior OS compared with cyclin D1-negative patients.

Usefulness of SynCAM3 and cyclin D1 immunohistochemistry in distinguishing superficial CD34-positive fibroblastic tumor from its histological mimics.

Superficial CD34-positive fibroblastic tumor (SCPFT) is a fibroblastic/myofibroblastic soft tissue tumor of rarely metastasizing intermediate malignancy. Some recent studies have described a relationship between SCPFT and PRDM10-rearranged soft tissue tumor (PRT) based on SynCAM3 and PRDM10 expression on immunohistochemistry. We performed CD34, cytokeratin AE1/AE3, SynCAM3, and PRDM10 immunohistochemistry in SCPFT and its histological mimics, including myxoinflammatory fibroblastic sarcoma (MIFS), superficially localized myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma. We also examined cyclin D1 expression because it is expressed in MIFS and MFS. We conducted fluorescence in situ hybridization (FISH) of PRDM10 rearrangement in SCPFT cases. On immunohistochemistry, only SCPFT showed strong and diffuse SynCAM3 expression. SCPFT also exhibited strong nuclear and weak cytoplasmic cyclin D1 expression, which was similar to that observed in MIFS. Two of five SCPFT cases exhibited nuclear PRDM10 expression. FISH revealed PRDM10 split signals in 44% and 24% of tumor cells in two SCPFT cases showing nuclear PRDM10 expression on immunohistochemistry, respectively. A minority of non-SCPFT cases showed focal SynCAM3 expression, but a combination of SynCAM3 and cyclin D1 in addition to CD34 and cytokeratin AE1/AE3 may be useful for the differential diagnosis of SCPFT and its histological mimics.

Simulated galactic cosmic radiation (GCR)-induced expression of Spp1 coincide with mammary ductal cell proliferation and preneoplastic changes in ApcMin/+ mouse

Female astronauts inevitably exposed to galactic cosmic radiation (GCR) are considered at a greater risk for mammary cancer development. The purpose of this study is to assess the status of mammary cancer-associated preneoplasia markers after GCR and γ-ray irradiation using a mouse model of human mammary cancer. Female ApcMin/+ mice were irradiated to 50 cGy of either γ-ray (137Cs) or full-spectrum simulated galactic cosmic radiation (GCR) (33-beam), and at 110 – 120 days post-irradiation mice were euthanized, and normal-appearing mammary tissues were analyzed for histological and molecular markers of preneoplasia. Whole-mount staining, hematoxylin and eosin-based histological assessment, and Cyclin D1 immunohistochemistry (IHC) were performed to analyze ductal outgrowth and cell proliferation. Additionally, mRNA expression of known mammary preneoplasia markers (Muc1, Exo1, Foxm1, Depdc1a, Nusap1, Spp1, and Rrm2) was analyzed using qPCR, and their respective protein expression was validated using immunohistochemistry. A significant increase in ductal outgrowth and cell proliferation in mammary tissues of GCR-irradiated mice was noted which indicates a higher risk of mammary cancer, relative to γ-rays. Increased mRNA and protein expression of Spp1 was observed in the GCR group, relative to γ-rays. This study demonstrates the plausibility of Spp1 as a preneoplasia marker in the early detection of mammary cancer after space radiation exposure.

Cyclin D1 Expression and Molecular Genetic Findings in Periocular Histiocytoses and Neoplasms of Macrophage-Dendritic Cell Lineage

Frequent activating mutations in the mitogen-activated protein kinase (MAPK) pathway genes have been identified in histiocytoses. MAPK signaling consistently upregulates cyclin D1. The goal of this study was to determine whether cyclin D1 expression by immunohistochemistry is a useful diagnostic marker for periocular histiocytoses and to further characterize their genetic basis. Retrospective observational case series. Pathology records were searched for all patients with histiocytoses diagnosed between 1995 and 2020. Eleven histiocyte-rich inflammatory lesions and 10 xanthelasma served as controls. Cyclin D1 immunohistochemistry was performed on all tissues. A subset of histiocytoses was evaluated by next-generation sequencing (NGS) and droplet digital PCR (ddPCR). There were 36 patients, 15 males (42%) and 21 females (58%), with histiocytoses: 9 juvenile xanthogranuloma (25%), 8 adult-onset asthma and periocular xanthogranuloma (22%), 7 Langerhans cell histiocytosis (19%), 5 Rosai-Dorfman disease (14%), 5 xanthogranuloma-not otherwise specified (14%), 1 Erdheim-Chester disease (3%), and 1 histiocytic sarcoma (3%). Moderate to strong nuclear cyclin D1 expression was present in ≥50% of lesional cells in histiocytoses (23/36, 64%), significantly more when compared to histiocyte-rich inflammatory lesions (0/11, 0%, P<.001) and xanthelasma (0/10, 0%, P<.001). Cyclin D1 was expressed in <10% of lesional cells in all 11 histiocyte-rich inflammatory lesions (P<.001) and all 10 xanthelasma lesions (P<.001). MAPK pathway gene mutations were detected in 12 of 14 (86%) histiocytoses successfully assayed by NGS and/or ddPCR. Our study confirms that the cyclin D1 immunohistochemical stain is a useful diagnostic marker for periocular histiocytoses, correlating with underlying mutations in MAPK pathway genes.

Absence of Differential Cyclin D1 Immunohistochemical Protein Expression in Nevi and Melanoma Evaluated by Digital Image Analysis.

Distinction of superficial spreading melanoma (SSM) from compound nevi (CN) sometimes poses difficult diagnostic challenges. Herein, we studied cyclin D1 protein expression by immunohistochemistry in SSM and CN and evaluated the results by digital image analysis. A total of 13 CN and 12 SSM cases were retrospectively reviewed and cyclin D1 immunohistochemistry was performed. Immunohistochemical stained slides were evaluated by digital imaging analysis that included quantification and staining intensity of the cyclin D1 expressing dermal cells. Cyclin D1 expression was observed in all CN and SSM. CN-positive staining was present in 30% to 93% of the dermal nevocytes, more positive in the upper (mean 85%), than lower half (mean 57%). SSM-positive staining was present in 44% to 96% of the dermal lesion, more positive in the upper (mean 88%) than lower half (mean 49%). When analyzed based on 3+ strong staining intensity, similar regional differences in cyclin D1 expression were observed. Digital image analysis of Cyclin D1 expression showed no differences between CN and SSM. Quantity and regional distribution of cyclin D1 positivity were found to be similar in both lesions. Our findings argue against the routine use of cyclin D1 immunohistochemistry as a diagnostic tool for differentiating CN from SSM.

Diagnostic significance of CyclinD1 and D2-40 expression for follicular neoplasm of the thyroid

ObjectivesTo evaluate the expression and differential diagnostic significance of CyclinD1 and D2–40 in follicular neoplasm (FN) and other thyroid adenomatoid lesions. MethodsA total of 144 cases of thyroid adenomatoid lesions were enrolled. Immunohistochemistry for CyclinD1 and D2–40 was performed. ResultsWe found two patterns of CyclinD1 expression: nuclear (N) and cytoplasmic (C). The expression of N-CyclinD1 / C-CyclinD1 in FN (77.4%, 48/62; 50.0%, 31/62) was much higher than that in multinodular goiters with dominant nodules (MNG-DN) (16.4%, 10/61; 4.9%, 3/61) (p < 0.05). In contrast, the expression of D2–40 in MNG-DN (82.0%,50/61) was much higher than that in FN (4.8%, 3/62) (p < 0.05). In addition, unique staining patterns were observed: CyclinD1 showed no immunostaining only in all 8 cases of oncocytic cell tumors (OCT); D2–40 staining showed the characteristic wide distribution of lymphatic vessels in all 8 cases of poorly differentiated thyroid carcinoma (PDTC). Finally, the expression of CyclinD1 and D2–40 did not differ among follicular thyroid adenoma and follicular thyroid carcinoma / noninvasive follicular thyroid neoplasm with papillary-like nuclear features (p > 0.05). ConclusionsCyclinD1 and D2–40 are helpful diagnostic markers of FN, which can assist to discern FN from MNG-DN / OCT / PDTC.

WT1 and Cyclin D1 Immunohistochemistry: A Useful Adjunct for Diagnosis of Pediatric Small Round Blue Cell Tumors on Small Biopsies

Pediatric small round blue cell tumors (SRBCTs) are a heterogeneous group of neoplasms with overlapping morphological appearance. Accordingly, their diagnosis is one of the most difficult in the field of surgical pathology. The most common tumors include rhabdomyosarcoma, Ewing’s sarcoma, neuroblastoma, lymphoblastic lymphoma and Wilms’ tumor (the blastemal component). Over time their diagnosis has become more difficult due to the increasing use of small biopsies. However, the advent of immunohistochemistry has improved the quality of diagnosis in most cases by the application of an adequate panel of immunomarkers. Recently, WT1 and Cyclin D1 have been shown to be useful in the differential diagnosis of SRBCTs on surgically-resected specimens, showing a diffuse cytoplasmic positivity of the former in all RMSs and a diffuse nuclear staining of the latter in both EWS and NB. The aim of the present study was to investigate the expression of WT1 and Cyclin D1 on small biopsies from a series of 105 pediatric SRBCTs to evaluate their diagnostic utility. Both immunomarkers were differentially expressed, with a diffuse and strong cytoplasmic staining for WT1 limited to all cases of RMS, and a diffuse nuclear staining for cyclin D1 restricted to all cases of EWS and NB. Notably, the expression of WT1 and cyclin D1 was also retained in those cases in which the conventional tumor markers (myogenin, desmin and MyoD1 for RMS; CD99 for EWS; NB84 for NB) were focally expressed or more rarely absent. The present study shows that WT1 and Cyclin D1 are helpful immunomarkers exploitable in the differential diagnosis of pediatric SRBCTs on small biopsies, suggesting their applicability in routine practice.

Role of Cyclin D1 and BCOR Immunohistochemistry in Differentiating Clear Cell Sarcoma of Kidney From its Mimics.

Clear cell sarcoma of kidney (CCSK) is the second most common pediatric renal malignancy, constituting ∼3% of renal tumors. Due to its morphologic diversity, the diagnosis of CCSK is often challenging. Recent studies have identified internal tandem duplication of BCL6 corepressor (BCOR) gene in CCSKs which coupled with cyclin D1 immunoreactivity, is helpful in differentiating it from its mimics, particularly blastema-rich Wilms tumor (WT), malignant rhabdoid tumor (MRT), and congenital mesoblastic nephroma (CMN). We aimed to evaluate the utility of cyclin D1 and BCOR immunohistochemistry in differentiating CCSK from its morphologic mimics. Our cohort comprised of 38 pediatric renal tumors which included CCSK (n=18), WT (n=10), MRT (n=5), and CMN (n=5) cases. A detailed clinicopathologic analysis was performed, and tissue microarray were constructed for CCSK and WT, while MRT and CMN tumors were individually stained. The age ranged from 2 months to 16 years with male:female ratio of 3:1. Strong, diffuse nuclear immunoreactivity for cyclin D1 and BCOR was noted in 61% (n=11/18) and 83% (n=15/18) of CCSK, respectively, while it was significantly less in WT (n=3/10 for cyclin D1) (n=2/10 for BCOR). None of the MRT and CMN examples demonstrated any immunoreactivity. Interestingly, only the blastemal component of WTs showed distinct, rare nuclear immunoreactivity for cyclin D1 or BCOR and the combination of these was never positive in a given case. Our results provide evidence that concurrent immunopositivity with cyclin D1 and BCOR is helpful in distinguishing CCSK from its morphologic mimics.

CCND1 copy number increase and cyclin D1 expression in acral melanoma: a comparative study of fluorescence in situ hybridization and immunohistochemistry in a Chinese cohort

BackgroundCCND1 copy number increase is characteristic of acral melanoma and is useful in distinguishing benign and malignant acral melanocytic lesions. Increase of the gene copy number may result in protein overexpression. This raises the possibility that detection of high expression of cyclin D1 by immunohistochemistry (IHC) may be used as a surrogate for direct evaluation of increase in the CCND1 gene copy number.MethodsWe examined increases in CCND1 copy number with fluorescence in situ hybridization (FISH), and examined cyclin D1 protein expression with IHC in 61 acral melanomas.ResultsUsing FISH, 29 acral melanomas (29/61, 47.5%) showed increase in the CCND1 copy number, including 8 (8/61, 13.1%) which showed low-level increase in the CCND1 copy number and 21 (21/61, 34.4%) with high-level increase in the CCND1 copy number. By analysis of IHC, the median IHC score was 15% (range: 1–80%) in acral melanomas with no CCND1 copy number alteration. In acral melanomas with low-level CCND1 copy number increase, the median IHC score was 25% (range: 3–90%). In acral melanomas with high-level CCND1 copy number increase, the median IHC score was 60% (range: 1–95%). Comparing FISH and IHC, cyclin D1 protein expression level has no corelation with the CCND1 copy number in acral melanomas which have no CCND1 copy number alteration and low-level CCND1 copy number increase (P = 0.108). Cyclin D1 protein expression level correlated positively with CCND1 copy number in acral melanomas with high-level CCND1 copy number increase (P = 0.038). The sensitivity, specificity and positive predictive value of using cyclin D1 IHC to predict CCND1 FISH result was 72.4, 62.5 and 63.6%. Increase in CCND1 copy number was associated with Breslow thickness in invasive acral melanoma.ConclusionHigh-level increase in the CCND1 copy number can induce high cyclin D1 protein expression in acral melanomas. However low-level increase and normal CCND1 copy number have no obvious correlation with protein expression. Cyclin D1 IHC cannot serve as a surrogate for CCND1 FISH in acral melanomas.

Cyclin D1 expression in ganglioglioma, pleomorphic xanthoastrocytoma and pilocytic astrocytoma

Ganglioglioma, pleomorphic xanthoastrocytoma (PXA) and pilocytic astrocytoma are rare brain neoplasms with frequent activation of mitogen-activated protein (MAP) kinase pathway. A downstream marker of MAP-kinase pathway activation is cyclin D1. However, the expression of cyclin D1 has not been studied in the differential diagnosis between these brain tumors.The aim of this work is to compare the expression of cyclin D1 in ganglioglioma, PXA, pilocytic astrocytoma. We also compared cyclin D1 expression in giant cell glioblastoma and in IDH wild type glioblastoma.Our work shows that roughly half of gangliogliomas have ganglion cells stained by cyclin D1 while two third of PXA have pleormophic cells stained by cyclin D1 and 15% of giant cell glioblastoma have pleomorphic cells stained by cyclin D1 (p < 0.001). Cyclin D1 never stains normal neurons either in the adjacent cortex of circumscribed tumor, or in entrapped neurons in IDH wild type glioblastomas.The expression of cyclin D1 is correlated to the presence of BRAF V600E mutation in ganglioglioma and PXA (p = 0.002).To conclude, cyclin D1 positivity might be used to confirm the neoplastic nature of ganglion cells. Cyclin D1 is expressed in most cases of BRAF V600E mutated gangliogliomas but also in cases without BRAF mutations suggesting an activation of MAP-kinase pathway through another way. Cyclin D1 immunohistochemistry has currently no or little role in the differential diagnosis of pilocytic astrocytoma. Its role in the differential diagnosis between PXA and giant cell glioblastoma needs to be further investigated on external series.

Cyclin D1: potential utility as marker for Langerhans cell histiocytosis

ABSTRACT Langerhans cell histiocytosis (LCH) is a rare disorder of unknown etiopathogenesis. Diagnosis is based on the identification of CD1a positive histiocytic infiltrate. Activation of the mitogen-activated-protein-kinase (MAPK) is constantly observed in LCH and therefore downstream markers such as cyclin D1 may be a useful marker for LCH. The aim of this study was to investigate the expression of cyclin D1 in LCH. We assessed the immunohistochemical expression of cyclin D1 (clone SP4-R) in series of 16 cases of confirmed LCH. Expression of Cyclin D1 was scored as weak, moderate, and strong nuclear staining and results were interpreted by two pathologists. The percentage of positivity was assessed. The mean age of patients was 13.7 years old with a male to female ratio of 1:3. The most common involved site was bone (n = 9; 56,3%), followed by lymph node (n = 5; 31,2%) and skin (n = 2; 12,5%). All cases showed nuclear staining for cyclin D1 with variable intensity. It was assessed moderate in 43,8% (n = 7) and strong in 56,2% (n = 9). The percentage of positive cells was >50% in 13 cases and <50% in 3 cases. Our results have shown that all cases of Langerhans cell histiocytosis from various sites express cyclin D1. This finding may be attributed to MAPK pathway activation that has been described in LCH. Otherwise, cyclin D1 is not significantly expressed in reactive Langerhans cell proliferations. Therefore, cyclin D1 immunohistochemistry may be useful as a diagnostic marker and in excluding non-neoplastic mimics of LCH.

Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma

AbstractMantle cell lymphoma (MCL) is a distinct clinicopathologic entity of non-Hodgkin’s lymphoma, characterized by a monotonous proliferation of small to medium-sized lymphocytes with co-expression of CD5 and CD20, an aggressive and incurable clinical course, and frequent t(11;14)(q13;q32) translocation. We examined 151 cases of lymphoma with MCL morphology from a viewpoint of cyclin D1 overexpression, which is now easily detectable by immunohistochemistry. 128 cases (85%) showed positive nuclear staining for cyclin D1, while the remaining 23 (15%) were negative. Except for cyclin D1 immunohistochemistry, current diagnostic methods, including morphological and phenotypical examinations, could not make this distinction. Although both the cyclin D1-positive and -negative groups were characterized by male predominance, advanced stages of the disease, frequent extranodal involvement, and low CD23 reactivity, the cyclin D1-positive group showed a higher age distribution (P = .04), larger cell size (P = .02), higher mitotic index (P = .01), more frequent gastrointestinal involvement (P = .05), higher international prognostic index score (P = .05), and lower p27KIP1 expression (P < .0001). Of particular interest is that cyclin D1-positive MCL showed significantly worse survival than cyclin D1-negative lymphoma (5-year survival: 30% versus 86%, P = .0002), which was confirmed by multivariate analysis to be independent of other risk factors. These data suggest that cyclin D1-positive and -negative groups may represent different entities and that the former closely fits the characteristics of classical, typical MCL. We therefore propose that cyclin D1-positivity should be included as one of the standard criteria for MCL, and that innovative therapies for this incurable disease should be explored on the basis of the new criteria. (Blood. 2000;95:2253-2261

ACTIVATION OF SHH SIGNALING PATHWAY AND RELATIONSHIP WITH MYOFIBROBLASTS

Objective: This study investigated components of the HH pathway (SHH, GLI1, and cyclin D1) in central giant cell granulomas (CGCG). The relationship between these proteins and myofibroblasts was also studied. Material and Methods: Twelve cases of non-aggressive CGCG and 11 cases of aggressive CGCG were studied using immunohistochemistry for SHH, GLI1, Cyclin D1, and SMA. Results: Associations between all proteins in non-aggressive and aggressive CGCG were not significant (P > .05). All cases of CGCG showed significantly higher expression of SMA compared to the other proteins (P < .01). A positive correlation (P = .04) was only observed between SHH and GLI1 for all cases of CGCG. Furthermore, a positive correlation between SHH and GLI1 in non-aggressive CGCG (P = .04) and between GLI1 and cyclin D1 in aggressive CGCG (P = .03) were observed. There was also a negative correlation between the expression of SHH and SMA in non-aggressive CGCG (P = .031). Conclusions: This study provided insights into the activation of the SHH pathway in CGCG. In addition, the activation of this pathway may play some role in the differentiation of stromal myofibroblasts, but this differentiation process would occur at the expense of maturation of these lesions. Objective: This study investigated components of the HH pathway (SHH, GLI1, and cyclin D1) in central giant cell granulomas (CGCG). The relationship between these proteins and myofibroblasts was also studied. Material and Methods: Twelve cases of non-aggressive CGCG and 11 cases of aggressive CGCG were studied using immunohistochemistry for SHH, GLI1, Cyclin D1, and SMA. Results: Associations between all proteins in non-aggressive and aggressive CGCG were not significant (P > .05). All cases of CGCG showed significantly higher expression of SMA compared to the other proteins (P < .01). A positive correlation (P = .04) was only observed between SHH and GLI1 for all cases of CGCG. Furthermore, a positive correlation between SHH and GLI1 in non-aggressive CGCG (P = .04) and between GLI1 and cyclin D1 in aggressive CGCG (P = .03) were observed. There was also a negative correlation between the expression of SHH and SMA in non-aggressive CGCG (P = .031). Conclusions: This study provided insights into the activation of the SHH pathway in CGCG. In addition, the activation of this pathway may play some role in the differentiation of stromal myofibroblasts, but this differentiation process would occur at the expense of maturation of these lesions.