Proliferative Nodules Research Articles

A clinical and biologic review of congenital melanocytic nevi.

Congenital melanocytic nevi (CMN) are the result of aberrations in the mitogen-activated protein kinase signal transduction pathway caused by postzygotic somatic mutations. The estimated incidence of newborns with CMN is 1%-2%. The main complications of CMN include proliferative nodules, melanomas, and neurocutaneous melanosis, and the latter two are the most troublesome issues to address. Treatments are primarily taken into account for aesthetic purposes and the reduction of melanoma risk. Due to the much lower incidence of malignant transformation observed in recent studies than in previous data, clinical management paradigms for CMN patients have gradually shifted towards conservative observation and close monitoring. Surgery and lasers are still the main treatments, and targeted therapy may be a promising strategy to help manage complications. With the increase in awareness of mental health, increasing focus has been placed on the quality of life (QoL) and psychological issues of both CMN patients and their parents. Recent studies have revealed that families coping with CMN might endure intense pressure, a major loss in QoL, and psychological problems after diagnosis and during treatment. Here, we sought to present an overview of genetic basis, complications, treatments, and psychological issues related to CMN and hope to provide better management for patients with CMN.

Systemic avian poxvirus infections associated with the B1 subclade of canarypox virus.

Avian poxvirus infections typically manifest as 2 forms: cutaneous ("dry") pox, characterized by proliferative nodules on the skin, and diphtheritic ("wet") pox, characterized by plaques of caseous exudate in the oropharynx and upper respiratory and gastrointestinal tracts. Systemic spread of virus to visceral organs beyond the skin and mucous membranes is rarely reported. Out of 151 cases diagnosed with avian poxvirus over a 20-year period at a zoological institution, 22 were characterized as having systemic involvement based on histopathology and molecular findings. Gross lesions in systemic cases included soft white nodules scattered throughout the liver, spleen, and kidneys. Two histopathologic patterns emerged: (1) widespread histiocytic inflammation in visceral organs with intrahistiocytic viral inclusions and (2) severe, localized dry or wet pox lesions with poxvirus-like inclusions within dermal and subepithelial histiocytes. In situ hybridization targeting the core P4b protein gene confirmed the presence of poxvirus DNA within histiocytes in both patterns. Polymerase chain reaction was performed targeting the reticuloendothelial virus long terminal repeat (REV LTR) flanking region and the core P4b protein gene. Sequences of the REV LTR flanking region from all systemic pox cases were identical to a previously described condorpox virus isolated from an Andean condor with systemic pox. Sequences of the core P4b protein gene from all systemic pox cases grouped into cluster 2 of the B1 subclade of canarypox viruses. Systemic involvement of avian poxvirus likely occurs as a result of infection with certain strain variations in combination with various possible host and environmental factors.

Clinicopathological characteristics of Klinefelter syndrome: a testicular biopsy analysis of 87 cases

Objective: To investigate the clinicopathological characteristics of testicular biopsies from Klinefelter syndrome (KS) patients. Methods: The testicular biopsy specimens of 87 patients with KS (a total of 107 biopsy specimens) were collected from the Department of Pathology, Peking University Third Hospital, Beijing, China from January 2017 to July 2022. All patients were diagnosed as KS by peripheral blood karyotyping analysis. The testicular histopathologic features, testicular volume and hormone levels were evaluated retrospectively. The histopathologic analysis was used to assess the quantity and morphology of Leydig cells, the spermatogenic state of seminiferous tubules, the thickening of the basement membrane of seminiferous tubules and the changes of stroma. Results: Leydig cell proliferative nodules were seen in 95.3% (102/107) of KS testicular biopsy tissues. The eosinophilic inclusion bodies and lipofuscin in Leydig cells were found in 52.3% (56/107) and 57.9% (62/107) of specimens, respectively. The Sertoli cell only seminiferous tubules and the hyalinized tubules were found in 66.4% (71/107) and 76.6% (82/107) of the examined tissues, respectively. The tubules with complete spermatogenic arrest were found in 15.9% (17/107) of specimens, and 5.6% (6/107) of the specimens showed low spermatogenesis or incomplete spermatogenic arrest. In 85.0% (91/107) of the specimens, increased thick-walled small vessels with hyaline degeneration were identified. Conclusions: The most common features of KS testicular specimens are Leydig cell proliferative nodules, hyaline degeneration of seminiferous tubules and proliferation of thick-walled blood vessels. Testicular biopsy specimens of KS are rare. The pathologists can make a tentative diagnosis of KS based on the histological findings, combined with the ultrasound and laboratory results, which is helpful for further diagnosis and treatment of KS.

PRAME Immunohistochemical Expression and TERT Promoter Mutational Analysis as Ancillary Diagnostic Tools for Differentiating Proliferative Nodules From Melanoma Arising in Congenital Nevi.

Proliferative nodules (PNs) are benign melanocytic proliferations that typically develop within congenital melanocytic nevi. These tumors have overlapping histological features with melanoma. Ancillary immunohistochemistry and genomic sequencing are often used in diagnostically challenging cases. To assess the utility of preferentially expressed antigen in melanoma (PRAME) immunoreactivity and telomerase reverse transcriptase (TERT) promoter mutation analysis in distinguishing PNs from melanoma arising in congenital nevi cases. Twenty-one PNs and 2 melanomas arising in congenital nevi were immunohistochemically stained with PRAME. Cases with adequate tissue were also assessed for TERT promoter mutations through sequencing studies. The positivity rates in the PN cases were compared with those of the melanomas. Two of 21 PN cases were diffusely positive for PRAME (≥75% of the tumor cells positive). Two of 2 melanomas arising in congenital nevus cases were also diffusely PRAME positive. The difference was statistically significant using a Fisher exact test. None of the tumors harbored TERT promoter mutations. PRAME immunohistochemical marker may have diagnostic value in distinguishing diagnostically challenging PNs from melanoma, but diffuse expression is not specific for melanoma.

26856 Proliferative nodule resembling angiomatoid Spitz with pronounced degenerative atypia arising within a giant congenital nevus

Proliferative nodules arising within congenital melanocytic nevi present a diagnostic challenge for dematopathologists given their close resemblance to melanoma. In difficult cases, ancillary molecular tests can be used to better exclude the possibility of malignancy. We report case of a biopsy and subsequent excision of an unusual proliferative nodule with overlapping features of angiomatoid Spitz tumor and ancient melanocytic nevus which demonstrated normal findings on both chromosomal microarray and a gene expression profiling assay.

Cutaneous Melanomas Arising during Childhood: An Overview of the Main Entities.

Cutaneous melanomas are exceptional in children and represent a variety of clinical situations, each with a different prognosis. In congenital nevi, the risk of transformation is correlated with the size of the nevus. The most frequent type is lateral transformation, extremely rare before puberty, reminiscent of a superficial spreading melanoma (SSM) ex-nevus. Deep nodular transformation is much rarer, can occur before puberty, and must be distinguished from benign proliferative nodules. Superficial spreading melanoma can also arise within small nevi, which were not visible at birth, usually after puberty, and can reveal a cancer predisposition syndrome (CDKN2A or CDK4 germline mutations). Prognosis is correlated with classical histoprognostic features (mainly Breslow thickness). Spitz tumors are frequent in adolescents and encompass benign (Spitz nevus), intermediate (atypical Spitz tumor), and malignant forms (malignant Spitz tumor). The whole spectrum is characterized by specific morphology with spindled and epithelioid cells, genetic features, and an overall favorable outcome even if a regional lymph node is involved. Nevoid melanomas are rare and difficult to diagnose clinically and histologically. They can arise in late adolescence. Their prognosis is currently not very well ascertained. A small group of melanomas remains unclassified after histological and molecular assessment.

The ferroptosis and iron-metabolism signature robustly predicts clinical diagnosis, prognosis and immune microenvironment for hepatocellular carcinoma

BackgroundIn this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC.MethodsIntegrated analysis, cox regression and the least absolute shrinkage and selection operator (LASSO) method of 104 ferroptosis- and iron metabolism-related genes and HCC-related RNA sequencing were performed to identify HCC-related ferroptosis and iron metabolism genes.ResultsFour genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) were identified to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P < 0.001, HR = 0.27) and test cohort (P < 0.001, HR = 0.27). The diagnostic models successfully distinguished HCC from normal samples and proliferative nodule samples. Compared with low-risk groups, high-risk groups had higher TMB; higher fractions of macrophages, follicular helper T cells, memory B cells, and neutrophils; and exhibited higher expression of CD83, B7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression, and it was showed to affect Th17 cell differentiation and IL-17 signaling pathway through bioinformatics analysis, indicating it a potential agent of cancer immunotherapy.ConclusionsThe prognostic and diagnostic models based on the four genes indicated superior diagnostic and predictive performance, indicating new possibilities for individualized treatment of HCC patients.6i5hPu8DcyHvJLmULV1p7nVideo Graphical abstract

Causes of false negatives in technetium-99m methoxyisobutylisonitrile scintigraphy for hyperparathyroidism: influence of size and cysts in parathyroid lesions.

The aim of this study was to elucidate the causes of false-negative cases of technetium-99m methoxyisobutylisonitrile scintigraphy (MIBI) for hyperparathyroidism. Consecutive MIBI examinations performed in 154 patients between April 2011 and March 2017 were retrospectively reviewed. Sensitivities of MIBI, CT and US were calculated. The effects of serum calcium, phosphorus, PTH, weight of parathyroid lesions, use of NSAIDs and Ca-channel blocker (CCB), presence of cyst in parathyroid lesions, and a number of lesions observed by MIBI were investigated. Seventy-nine patients (21 men and 58 women), ranging from 18 to 88years of age (mean ± SD: 57.6 ± 15.3years), who underwent parathyroidectomy, were included. MIBI and preoperative US were performed in the 79 patients and single-phase parenchymal contrast-enhanced CT (CE-CT) was performed in 55 patients. A total of 120 parathyroid proliferative nodules were detected by MIBI and US, and 92 lesions were detected by CE-CT. In the lesion base, MIBI detected 82 out of the 120 lesions (sensitivity = 68.3%), US detected 103 out of the 120 lesions (sensitivity = 85.8%), CE-CT detected 63 out of the 92 lesions (sensitivity = 68.5%), and MIBI plus CE-CT detected 72 of the 92 lesions (sensitivity = 78.3%). A significant difference in the sensitivity was found between US and MIBI (P < 0.01), and between US and CT (P < 0.01). In the patient base, MIBI detected 67 out of the 79 patients (sensitivity = 84.8%), US detected 74 out of the 79 patients (sensitivity = 93.7%), CE-CT detected 45 out of the 55 patients (sensitivity = 81.8%), and MIBI plus CE-CT detected 52 out of the 55 patients (sensitivity = 94.5%). No significant difference was observed in any of the comparisons. A significant difference was observed in lesion weight (P < 0.01), single or multiple lesions (P = 0.02), and presence of cyst (P < 0.01) between the MIBI false-negative (n = 38) and the true-positive groups (n = 82). The presence of cyst in parathyroid proliferative lesions as well as small size and multiple number of parathyroid lesions contribute to false negative in parathyroid MIBI scan.

Genetic changes and biological potential of proliferative nodule in congenital pigmented nevus

Objective: To study the genetic changes and biological potential of proliferative nodule in congenital melanocytic nevus. Methods: Whole-exome sequencing was carried out using the technique of next-generation sequencing (NGS) in order to detect the genomic alterations of two cases of proliferative nodules (PN) in congenital melanocytic nevi (CMN). Twelve cases of CMN and ten cases of malignant melanoma were used as benign and malignant controls, respectively. Mutated genes that possessed statistically significant difference between benign and malignant controls were listed, according to what benign and malignant statuses were classified and clustered. The heatmaps of clustering analyses were depicted using heatmap package. Fluorescence in situ hybridization (FISH) was also used to validate the above results. Results: Eighty-six common somatic gene mutations were detected in two samples of PN. Compared with CMN, PN had 52 more mutated genes. Furthermore, 22 of these 52 mutated genes were also detected in malignant melanoma samples. Two cases of PN fell between benign CMN and malignant melanoma in germline mutation clustering. Both cases of PN were positive in the FISH tests. Conclusions: The genetic changes of PN partially overlap with those of CMN and malignant melanoma. Therefore, although most of the PN manifest as a benign lesion clinically, it may have certain malignant potential at the genetic level, and warrant long-term monitoring and follow-up.

Identification and validation of the angiogenic genes for constructing diagnostic, prognostic, and recurrence models for hepatocellular carcinoma.

Since angiogenesis has an indispensable effect in the development and progression of tumors, in this study we aimed to identify angiogenic genes closely associated with prognosis of HCC to establish diagnostic, prognostic, and recurrence models. We analyzed 132 angiogenic genes and HCC-related RNA sequence data from the TCGA and ICGC databases by Cox and least absolute shrinkage and selection operator (LASSO) regression, and identified four angiogenic genes (ENFA3, EGF, MMP3 and AURKB) to establish prognosis, recurrence and diagnostic models and corresponding nomograms. The prognostic and recurrence models were determined to be independent predictors of prognosis and recurrence (P < 0.05). And compared with the low-risk group, patients in the high-risk group had worse overall survival (OS) rates in training cohort (P < 0.001) and validation cohort (P < 0.001), and higher recurrence rates in training cohort (P<0.001) and validation cohort (P=0.01). The diagnostic models have been validated to correctly distinguish HCC from normal samples and proliferative nodule samples. Through pharmacological analysis we identified piperlongumine as a drug for targeting angiogenesis, and it was validated to inhibit HCC cell proliferation and angiogenesis via the EGF/EGFR axis.

Systematic Expression Analysis of the Ferroptosis and Iron-Metabolism Transcriptomic Profile for Hepatocellular Carcinoma

Considering the crucial effects of ferroptosis and iron metabolism on the occurrence and progression of hepatocellular carcinoma (HCC), in this study, we performed a comprehensive analysis of genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC. We integrated 104 genes related to ferroptosis and iron metabolism and HCC-related RNA sequencing to identify HCC-related ferroptosis and iron metabolism genes. Through Cox regression and the least absolute shrinkage and selection operator (LASSO) method, we screened four genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P < 0.001, HR = 0.27) and test cohort (P < 0.001, HR = 0.27). The prognostic signature was determined to be an independent predictor of prognosis. The diagnostic models were validated in terms of correctly distinguishing between HCC and normal samples, as well as HCC and proliferative nodule samples. In addition, compared with low-risk groups, high-risk groups had higher TMB; higher fractions of macrophages, follicular helper T cells, memory B cells, and neutrophils; and exhibited higher expression of CD83, B7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression. Through bioinformatics analysis, erastin was showed to affect TH17 cell differentiation and the IL-17 signaling pathway, indicating that erastin is a potential targeted drug for immunotherapy. Funding Statement: This study was supported by National Natural Science Foundation of China (Nos. 81803778), and The Key Research and development Project of Zhejiang Province (No. 2018C03024), and The Public Welfare Research Program of Zhejiang Province (Nos. LQ20H160056 and LGD19h160002), The Natural Science Foundation of Zhejiang Province (No. LYQ20H280003). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The authors reported that since the data of the TCGA database and the ICGC database are open to the public and can be downloaded freely, and this study strictly followed the publication guidelines and access policies of the databases, ethical review and approval from an Ethics Committee are not required for the study.

Giant congenital melanocytic nevus with neurotized lesions mimicking neurofibromas – A rare presentation

Giant congenital melanocytic nevus (GCMN) is a deeply pigmented lesion, often associated with hypertrichosis and multiple scattered satellite lesions. During infancy apart from textural changes, rapidly growing “proliferative nodules” mimicking melanoma can occur in the nevus. Areas of the nevus may be infiltrated by an overgrowth of fat or nerve tissue, so-called lipomatous or neurotized areas, respectively, common in larger nevi. We report a case of GCMN associated with multiple neurotized areas mimicking large neurofibromas, a rare phenomenon.

Características de nevos melanocíticos congénitos gigantes: presentación de 8 casos

IntroductionGiant congenital melanocytic nevi (GCMN) are benign proliferations of melanocytes present at birth or until the first 2-3 years of life. They could measure at least 20cm in their largest diameter in adulthood. Although rare they do affect the quality of life, as well as being associated with melanoma and neurocutaneous melanosis (NCM), for which certain clinical features are risk markers. MethodologyAn observational retrospective study was performed using the clinical records and photographic files of the GCMN diagnosed from November 2009 to March 2018 in the Paediatric Dermatology Unit of the Pereira Rossell Hospital in Montevideo-Uruguay. Using the information gathered, a descriptive analysis was performed on the clinical features and their association with melanoma and NCM. ResultsOut of the 8 GCMN diagnosed (5 boys), 5 were located on the back, 2 in the extremities, and 1 in head/neck region. Five showed satellite nevi, 7 with roughness and hair, 4 with colour heterogeneity, and 2 developed proliferative nodules. Five patients were evaluated with brain and spinal magnetic resonance imaging, and 3 with transfontanelle and spinal ultrasound. One showed NCM compatible findings. None showed neurological symptoms, and none of them had developed melanoma. ConclusionsIn a period of 8.3 years, 8 GCMN were diagnosed, mainly in boys, and on the back. Most of them showed hypertrichosis, roughness, and satellite nevi. The largest 2GCMN were located in the posterior midline, and showed nodules and> 20 satellite nevi. These have been associated with a greater risk of NCM, but were present in only one of these patients.

Piperlongumine Achieves Antitumor Effects by Targeting Angiogenic Genes that Have Predictive Value for the Diagnosis, Prognosis and Recurrence of Hepatocellular Carcinoma

Background: In the context of the high recurrence rate and poor clinical prognosis of hepatocellular carcinoma (HCC), and considering the indispensable effect of angiogenesis in the development and metastasis of tumors, we analyzed HCC-related RNA sequence data to identify angiogenic genes closely associated with the prognosis of HCC. We used the identified genes to establish diagnostic, prognostic, and recurrence models to help clinicians effectively develop individualized treatment strategies for HCC. Method: We comprehensively analyzed 132 angiogenic genes and HCC-related RNA sequence data from the TCGA and the ICGC databases by Cox regression and least absolute shrinkage and selection operator(LASSO) regression to identify angiogenic genes; the genes were used to establish prognosis, recurrence and diagnostic models and to construct corresponding predictive nomograms. Pharmacological analysis was performed to detect target angiogenic drugs. Subsequently, in vitro cell experiments and western blot experiments were used to explore the anti-tumor effect and possible molecular mechanism of an angiogenesis-targeting target drug. Results: Four angiogenic genes (ENFA3, EGF, MMP3 and AURKB) were used to establish prognostic, relapse and diagnostic models. Through the prognostic model, we found that the overall survival (OS) of the high-risk group in the training cohort (P < 0.001, HR = 0.33) and validation cohort (P < 0.001, HR = 0.33) were significantly worse than those of the low-risk group. The recurrence model also demonstrated that in the training cohort (P<0.001, HR= 0.42) and validation cohort (P=0.01, HR=0.5), the recurrence rate of the high-risk group was significantly higher than that of the low-risk group. In addition, angiogenic genes were an independent predictor of prognosis and recurrence (P < 0.05). The diagnostic model has been validated in terms of correctly distinguishing between HCC and normal samples, as well as between HCC and proliferative nodule samples, with high sensitivity and high specificity. Through pharmacological analysis, we identified piperlongumine as a drug for targeting angiogenesis. Subsequent targeted drug cell experiments suggested that the anti-tumor effect of piperlongumine was achieved by inhibiting angiogenesis via the EGF/EGFR axis. Conclusion: We identified and validated the predictive properties of the diagnostic, recurrence, and prognostic models of four key angiogenic genes and confirmed the value of these four genes for constructing models. Piperlongumine was confirmed to inhibit HCC cell proliferation and angiogenesis via the EGF/EGFR axis. These findings may help to provide new individualized treatment ideas for HCC patients. Funding Statement: This study was supported by National Natural Science Foundation of China (Nos. 81803778), and The Key Research and development Project of Zhejiang Province (No. 2018C0302), and Public Welfare Project of Zhejiang Province (Nos. LGF19H180010, LGD19H160002 and LGF19H180009), and Medical and Health Care Key Project of Zhejiang Province (Nos. 2016146810, 2018KY197 and 2018KY932). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: Since these mRNA-sequencing data were obtained from TCGA and ICGC databases and were freely available to the public, and as this study also strictly followed the publication guidelines and access policies of these databases, this study does not require ethical review and approval from an Ethics Committee.

Does the gene matter? Genotype-phenotype and genotype-outcome associations in congenital melanocytic naevi.

SummaryBackgroundGenotype–phenotype studies can identify subgroups of patients with specific clinical features or differing outcomes, which can help shape management.ObjectivesTo characterize the frequency of different causative genotypes in congenital melanocytic naevi (CMN), and to investigate genotype–phenotype and genotype–outcome associations.MethodsWe conducted a large cohort study in which we undertook MC1R genotyping from blood, and high‐sensitivity genotyping of NRAS and BRAF hotspots in 156 naevus biopsies from 134 patients with CMN [male 40%; multiple CMN 76%; projected adult size (PAS) > 20 cm, 59%].ResultsMosaic NRAS mutations were detected in 68%, mutually exclusive with BRAF mutations in 7%, with double wild‐type in 25%. Two separate naevi were sequenced in five of seven patients with BRAF mutations, confirming clonality. Five of seven patients with BRAF mutations had a dramatic multinodular phenotype, with characteristic histology distinct from classical proliferative nodules. NRAS mutation was the commonest in all sizes of CMN, but was particularly common in naevi with PAS > 60 cm, implying more tolerance to that mutation early in embryogenesis. Facial features were less common in double wild‐type patients. Importantly, the incidence of congenital neurological disease, and apparently of melanoma, was not altered by genotype; no cases of melanoma were seen in BRAF‐mutant multiple CMN, however, this genotype is rare.Conclusions CMN of all sizes are most commonly caused by mutations in NRAS. BRAF is confirmed as a much rarer cause of multiple CMN, and appears to be commonly associated with a multinodular phenotype. Genotype in this cohort was not associated with differences in incidence of neurological disease in childhood. However, genotyping should be undertaken in suspected melanoma, for guidance of treatment. What's already known about this topic? Multiple congenital melanocytic naevi (CMN) have been shown to be caused by NRAS mosaic mutations in 70–80% of cases, by BRAF mosaicism in one case report and by inference in some previous cases.There has been debate about genotypic association with different sizes of CMN, and no data on genotype–outcome. What does this study add? NRAS mosaicism was found in 68%, BRAF in 7% and double wild‐type in 25% of cases of CMN. NRAS was the commonest mutation in all sizes of CMN, but was nearly universal in projected adult size > 60 cm. BRAF is often associated with a distinct multinodular clinical/histological phenotype.Adverse outcomes did not differ between genotypes on current numbers.

Atypical proliferative nodule in congenital melanocytic nevus with dural invasion: a case report.

Here we report a case of a focal atypical proliferative nodule (PN) arising from a congenital melanocytic nevus (CMN). Diagnosis was challenging because it had both benign and malignant clinical features. Unusual histopathology, immunohistochemistry, and intraoperative findings of this atypical PN are discussed. A 5-year-old girl was admitted for a congenital 5× 5 cm sized scalp mass. This hemangioma-like soft mass showed biphasic characteristics such as a slow, gradual, and benign increase in size but worrisome dural invasion with cranial bone defect. We removed the scalp mass with clear resection margins. Interoperatively, we found that the cranial bone defect had already filled. Histopathologic examination showed CMN with focal atypical PN. The nodule showed sharp demarcation and cellular pleomorphism. However, in immunohistochemical study, Ki-67 proliferation index and expression levels of protein S-100 and Melan-A were very low. These were unusual findings of atypical PNs. Despite her worrisome preoperative radiologic features, she showed an indolent clinical course compatible with previously reported biologic behavior. The patient underwent follow-up inspection with magnetic resonance imaging every 6 months for up to 3 years. The nodule appeared to be stationary at the last visit.

Loss of Primary Cilia Results in the Development of Cancer in the Murine Thyroid Gland.

Communications at the interface between the apical membrane of follicular cells and the follicular lumen are critical for the homeostasis of thyroid gland. Primary cilia at the apical membrane of thyroid follicular cells may sense follicular luminal environment and regulate follicular homeostasis, although their role in vivo remains to be determined. Here, mice devoid of primary cilia were generated by thyroid follicular epithelial cell-specific deletion of the gene encoding intraflagellar transport protein 88 (Ift88 ). Thyroid follicular cell-specific Ift88-deficient mice showed normal folliculogenesis and hormonogenesis; however, those older than 7 weeks showed irregularly dilated and destroyed follicles in the thyroid gland. With increasing age, follicular cells with malignant properties showing the characteristic nuclear features of human thyroid carcinomas formed papillary and solid proliferative nodules from degenerated thyroid follicles. Furthermore, malignant tumor cells manifested as tumor emboli in thyroid vessels. These findings suggest that loss-of-function of Ift88/primary cilia results in malignant transformation from degenerated thyroid follicles.

Common and not so Common Melanocytic Lesions in Children and Adolescents.

The acquired melanocytic nevus is the most common lesion encountered by pediatric pathologists and dermatopathologists in their daily practice. In most cases, there are few difficulties in histopathologic diagnosis. However, it is the acquired melanocytic lesion known as the Spitz nevus, with its intrinsic atypical features which becomes the challenge since it exists along a histopathologic and biologic continuum from the atypical Spitz tumor to spitzoid melanoma. The frustration with some of these spitzoid lesions is that even the "experts" cannot agree as to the differentiation of one from the other even at the level of molecular genetics. Other melanocytic lesions are discussed including the congenital melanocytic nevus with its proliferative nodule(s) and melanoma as the ultimate complication. Although uncommon, cutaneous melanoma in the first 2 decades is emerging as a clinical problem especially in young women in the second decade of life. These are ultraviolet-associated neoplasms whose histopathologic and prognostic features are identical to the adult experience. Considerable progress has been made over the past 15 to 20 years in our understanding of cutaneous melanocytic lesions, but gaps still exist in the important group of spitzoid lesions. It can also be anticipated that more cutaneous melanomas in children will be seen in the future based upon epidemiologic studies.

A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures

Breast cancer mortality predominantly results from dormant micrometastases that emerge as fatal outgrowths years after initial diagnosis. In order to gain insights concerning factors associated with emergence of liver metastases, we recreated spontaneous dormancy in an all-human ex vivo hepatic microphysiological system (MPS). Seeding this MPS with small numbers (<0.05% by cell count) of the aggressive MDA-MB-231 breast cancer cell line, two populations formed: actively proliferating ("growing"; EdU+), and spontaneously quiescent ("dormant"; EdU-). Following treatment with a clinically standard chemotherapeutic, the proliferating cells were eliminated and only quiescent cells remained; this residual dormant population could then be induced to a proliferative state ("emergent"; EdU+) by physiologically-relevant inflammatory stimuli, lipopolysaccharide (LPS) and epidermal growth factor (EGF). Multiplexed proteomic analysis of the MPS effluent enabled elucidation of key factors and processes that correlated with the various tumor cell states, and candidate biomarkers for actively proliferating (either primary or secondary emergence) versus dormant metastatic cells in liver tissue. Dormancy was found to be associated with signaling reflective of cellular quiescence even more strongly than the original tumor-free liver tissue, whereas proliferative nodules presented inflammatory signatures. Given the minimal tumor burden, these markers likely represent changes in the tumor microenvironment rather than in the tumor cells. A computational decision tree algorithm applied to these signatures indicated the potential of this MPS for clinical discernment of each metastatic stage from blood protein analysis.

Atypical Proliferative Nodule with Melanocytic Intraepidermal Pagetoid Spreading Arising within a Congenital Melanocytic Nevus in a Pregnant Woman.

Atypical Proliferative Nodule with Melanocytic Intraepidermal Pagetoid Spreading Arising within a Congenital Melanocytic Nevus in a Pregnant Woman.