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Child's Nervous System : ChNS :... Jul 2023The recently updated World Health Organization classification of central nervous system (CNS) tumors, 5th edition, (CNS5) reclassifies pediatric tumors according to...
INTRODUCTION
The recently updated World Health Organization classification of central nervous system (CNS) tumors, 5th edition, (CNS5) reclassifies pediatric tumors according to their distinct molecular drivers, recognizing a new entity-infant-type hemispheric glioma (IHG). Defined by its unique epigenetic signature, and/or genomic fusions in ALK, ROS1, NTRK, or MET gene, IHG subsumes many cases previously classified as congenital glioblastoma (cGBM). Histologic features of IHG are still poorly defined with known overlap with a clinic radiologically similar entity-desmoplastic infantile ganglioglioma/astrocytoma (DIG).
METHODS
We revisited our cohort of cGBMs and DIGs, now reclassifying them according to CNS5 and compared the clinical, radiologic, molecular and histologic features between the two.
RESULTS
3/6 cases of cGBM that underwent targeted NGS fusion mutation panel were positive for ALK fusions (involving MAP4, MZT2Bex2, and EML4 genes as fusion partners), and 1/6 showed GOPC:ROS1 fusion. Interestingly, GOPC:ROS1 fusion was also shared by 1/5 cases of histologically defined DIG. DNA methylation profiling using the Heidelberg classifier (v12.3) recategorized 2/5 DIG cases as IHG (including the case with ROS1 alteration).
CONCLUSION
In conclusion, histology alone is insufficient to distinguish IHG from DIG, necessitating epigenomic and genomic testing for the diagnosis of early-life gliomas.
Topics: Infant; Child; Humans; Glioblastoma; Ganglioglioma; Protein-Tyrosine Kinases; Epigenomics; Brain Neoplasms; Proto-Oncogene Proteins; Astrocytoma; Genomics; Receptor Protein-Tyrosine Kinases
PubMed: 36707425
DOI: 10.1007/s00381-023-05848-w -
Cancers Dec 2022Almost half of all patients with colorectal cancer present with or eventually develop metastasis, most frequently in the liver. Understanding the histopathological... (Review)
Review
Almost half of all patients with colorectal cancer present with or eventually develop metastasis, most frequently in the liver. Understanding the histopathological growth patterns and tumor immune microenvironment of colorectal liver metastases may help determine treatment strategies and assess prognosis. A literature search was conducted to gather information on cancer biology, histopathological growth patterns, and the tumor immune microenvironment in colorectal liver metastases, including their mechanisms and their impact on clinical outcomes. A first consensus on histopathological growth patterns emerged in 2017, identifying five growth patterns. Later studies found benefits from a two-tier system, desmoplastic and non-desmoplastic, incorporated into the updated 2022 consensus. Furthermore, the tumor immune microenvironment shows additional characteristic features with relevance to cancer biology. This includes density of T-cells (CD8+), expression of claudin-2, presence of vessel co-option versus angiogenesis, as well as several other factors. The relation between histopathological growth patterns and the tumor immune microenvironment delineates distinct subtypes of cancer biology. The distinct subtypes are found to correlate with risk of metastasis or relapse, and hence to clinical outcome and long-term survival in each patient. In order to optimize personalized and precision therapy for patients with colorectal liver metastases, further investigation into the mechanisms of cancer biology and their translational aspects to novel treatment targets is warranted.
PubMed: 36612177
DOI: 10.3390/cancers15010181 -
HPB : the Official Journal of the... Apr 2022Microvascular invasion (MVI) is an established prognosticator in hepatocellular carcinoma (HCC). Histopathological growth patterns (HGPs) classify the invasive margin of...
BACKGROUND
Microvascular invasion (MVI) is an established prognosticator in hepatocellular carcinoma (HCC). Histopathological growth patterns (HGPs) classify the invasive margin of hepatic tumors, with superior survival observed for the desmoplastic HGP. Our aim was to investigate non-cirrhotic HCC in light of MVI and the HGP.
METHODS
A retrospective cohort study was performed in resected non-cirrhotic HCC. MVI was assessed prospectively. The HGP was determined retrospectively, blinded, and according to guidelines. Overall and disease-free survival (OS, DFS) were evaluated by Kaplan-Meier and multivariable Cox regression.
RESULTS
The HGP was determined in 155 eligible patients, 55 (35%) featured a desmoplastic HGP. MVI was observed in 92 (59%) and was uncorrelated with HGP (64% vs 57%, p = 0.42). On multivariable analysis, non-desmoplastic and MVI-positive were associated with an adjusted HR [95%CI] of 1.61 [0.98-2.65] and 3.22 [1.89-5.51] for OS, and 1.59 [1.05-2.41] and 2.30 [1.52-3.50] for DFS. Effect modification for OS existed between HGP and MVI (p < 0.01). Non-desmoplastic MVI-positive patients had a 5-year OS of 36% (HR: 5.21 [2.68-10.12]), compared to 60% for desmoplastic regardless of MVI (HR: 2.12 [1.08-4.18]), and 86% in non-desmoplastic MVI-negative.
CONCLUSION
HCCs in non-cirrhotic livers display HGPs which may be of prognostic importance, especially when combined with MVI.
Topics: Carcinoma, Hepatocellular; Hepatectomy; Humans; Liver Neoplasms; Neoplasm Invasiveness; Prognosis; Retrospective Studies
PubMed: 34393042
DOI: 10.1016/j.hpb.2021.07.009 -
ACS Nano Oct 2023In pancreatic cancer, excessive desmoplastic stroma severely impedes drug access to tumor cells. By reverting activated pancreatic stellate cells (PSCs) to quiescence,...
In pancreatic cancer, excessive desmoplastic stroma severely impedes drug access to tumor cells. By reverting activated pancreatic stellate cells (PSCs) to quiescence, all-trans retinoic acid (ATRA) can attenuate their stromal synthesis and remodel the tumor-promoting microenvironment. However, its modulatory effects have been greatly weakened due to its limited delivery to PSCs. Therefore, we constructed a tripeptide RFC-modified gelatin/oleic acid nanoparticle (RNP@ATRA), which delivered ATRA in an enzyme-triggered popcorn-like manner and effectively resolved the delivery challenges. Specifically, surface RFC was cleaved by aminopeptidase N (APN) on the tumor endothelium to liberate l-arginine, generating nitric oxide (NO) for tumor-specific vasodilation. Then, massive nanoparticles were pushed from the vessels into tumors, showing 5.1- and 4.0-fold higher intratumoral accumulation than free ATRA and APN-inert nanoparticles, respectively. Subsequently, in the interstitium, matrix metalloproteinase-2-induced gelatin degradation caused RNP@ATRA to rapidly release ATRA, promoting its interstitial penetration and PSC delivery. Thus, activated PSCs were efficiently reverted to quiescence, and stroma secretion and vascular compression were reduced, thereby enhancing intratumoral delivery of small-molecule or nanosized chemotherapeutics. Ultimately, RNP@ATRA combined with chemotherapeutics markedly suppressed tumor growth and metastasis without causing additional toxicities. Overall, this work provides a potential nanoplatform for the efficient delivery of PSC-modifying agents in pancreatic cancer and other stroma-rich tumors.
Topics: Humans; Matrix Metalloproteinase 2; Gelatin; Pancreatic Neoplasms; Tretinoin; Nanoparticles; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37805928
DOI: 10.1021/acsnano.3c03838 -
Cells Apr 2021Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this... (Review)
Review
Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as "desmoplastic reaction". This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.
Topics: Animals; Breast Neoplasms; Carcinogenesis; Extracellular Matrix; Female; Humans; Protein-Lysine 6-Oxidase; Signal Transduction
PubMed: 33946660
DOI: 10.3390/cells10051046 -
Cancer Medicine Jan 2020Desmoplastic melanoma (DM) is an uncommon type of melanoma. Two histological subtypes of DM can be distinguished: pure and mixed (PDM and MDM). We hypothesized that...
BACKGROUND
Desmoplastic melanoma (DM) is an uncommon type of melanoma. Two histological subtypes of DM can be distinguished: pure and mixed (PDM and MDM). We hypothesized that discrimination between these subtypes is associated with sentinel lymph node biopsy (SLNB) status and survival.
METHODS
Clinicopathological data from PALGA, the Dutch Pathology Register were retrieved from patients diagnosed with DM in The Netherlands between 2000 and 2014. Clinical and pathological variables were extracted from pathology text files, including pure or mixed desmoplastic morphology. A Cox proportional hazard model was performed for overall and recurrence-free survival (OS and RFS).
RESULTS
A total of 239 patients with DM were included, representing 0.4% of all primary cutaneous melanoma in The Netherlands. A total of 114 PDM and 125 MDM patients were identified. MDM was significantly associated with positive SLNB status (P = .035). In multivariable analysis, age (HR 1.10, 95% CI 1.07-1.14, P < .001) and ulceration (HR 1.98, 95% CI 1.05-3.75, P = .036) were significant predictors for OS. For RFS, mixed subtype (HR 2.72 95% CI 1.07-6.89, P = .035), male gender (HR 2.54, 95% CI 1.03-6.27, P = .043), and Breslow thickness (HR 1.13 per mm, 95% CI 1.05-1.21, P = .001) were significant predictors.
CONCLUSION
MDM is significantly associated with a positive SLNB status. Mixed subtype is significantly correlated with RFS, but not with OS. The distinction between pure and mixed desmoplastic subtype therefore seems to be of clinical importance.
Topics: Aged; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Male; Melanoma; Neoplasm Recurrence, Local; Netherlands; Prognosis; Retrospective Studies; Sentinel Lymph Node Biopsy; Skin Neoplasms; Survival Rate
PubMed: 31804771
DOI: 10.1002/cam4.2736 -
Digestion 2020Cancer tissues consist of cancer cells and stroma, the latter of which dictates cancer tissue microenvironment. We recently reported that the desmoplastic reaction (DR)... (Review)
Review
BACKGROUND
Cancer tissues consist of cancer cells and stroma, the latter of which dictates cancer tissue microenvironment. We recently reported that the desmoplastic reaction (DR) pattern at the invasive front in colorectal cancer (CRC) is a promising prognostic indicator. However, the molecular mechanisms of DR formation and contribution to patients' prognosis remain unclear.
SUMMARY
The tumor tissue microenvironment composed of extracellular matrix (ECM), soluble factors (growth factors/cytokine/cytokine), and stromal cells controls tumor growth and spread. Among stromal cells, cancer-associated fibroblasts (CAFs) play a key role in development of the cancer tissue microenvironment, and they are responsible for DR formation. CAFs express a disintegrin and metalloproteinases (ADAMs), which modulate cancer tissue microenvironmental factors. We isolated CAFs and normal fibroblasts from colon tissues of patients with CRC and characterized them. CAFs showed the increased expression of several ADAM species including ADAM9, ADAM10, ADAM12, and ADAM17, and the expression was further increased on the ECM-coated plates. Our in vitro and in vivo studies using CAFs and CRC cells suggest that ADAM expression is associated with the morphological DR category, and ADAMs may affect cancer malignancy through tumor proliferation in CRC. Key Message: This review summarizes the present knowledge on ADAMs in cancer and describes our recent findings regarding the molecular biological background of DR mainly by focusing on ADAMs.
Topics: ADAM Proteins; Animals; Biomarkers, Tumor; Cancer-Associated Fibroblasts; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Disease Progression; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Mice; Neoplasm Metastasis; Prognosis; Stromal Cells; Tumor Cells, Cultured; Tumor Microenvironment
PubMed: 31722362
DOI: 10.1159/000504087 -
Melanoma Research Oct 2020Desmoplastic melanoma (DM) is a rare and histopathologically as well as prognostically distinct subset of melanoma that arises in chronically sun-damaged skin. DM is... (Review)
Review
Desmoplastic melanoma (DM) is a rare and histopathologically as well as prognostically distinct subset of melanoma that arises in chronically sun-damaged skin. DM is typically and relatively indolent in nature with most cases not progressing to metastatic disease. DM has been managed with both radiation and surgical approaches. Medical options for the treatment of metastatic DM have traditionally been limited. Recent advances in immunotherapies have shown promising responses in DM ushering in a new class of treatment options. Additionally, with the advent of whole exome sequencing, the genetic make-up of DM has been further characterized creating new possibilities for future targeted therapies.
Topics: Biomarkers, Tumor; Female; Humans; Immunotherapy; Male; Melanoma; Prognosis
PubMed: 32590412
DOI: 10.1097/CMR.0000000000000679 -
International Journal of Surgical... Aug 2023Desmoplastic small round cell tumor (DSRCT) is a rare aggressive malignancy typically originating from the abdominal or pelvic cavity. DSRCT presenting as a primary head... (Review)
Review
Desmoplastic small round cell tumor (DSRCT) is a rare aggressive malignancy typically originating from the abdominal or pelvic cavity. DSRCT presenting as a primary head and neck tumor has rarely been described in the literature. We present three cases of DSRCT arising in the head and neck to further characterize its clinicopathological features. All three patients were male and aged 36, 30 and 17 years. The involved sites included the orbit (1 case) and submandibular gland (2 cases). The tumors ranged in size from 2.4 to 3.5 cm (mean, 2.1 cm). Histologically, all tumors showed irregular-shaped, variable-sized nests of small round cells deposited in an abundant desmoplastic stroma. Tumor cells contained scant amounts of eosinophilic cytoplasm and small hyperchromatic nuclei with inconspicuous nucleoli. Immunohistochemically, the tumors were positive for keratin (AE1/AE3) (3/3), desmin (3/3), vimentin (2/2), NSE (1/1) and EMA (1/1). Fluorescence in situ hybridization (FISH) analysis demonstrated the presence of and rearrangements in all three cases. All patients received surgery and adjuvant chemotherapy and/or radiotherapy. There was no evidence of recurrence and metastasis in two patients, and the third suffered lung metastasis. DSRCT arising in the head and neck represents an extremely rare condition. It is easily mistaken as poorly differentiated carcinoma due to similar morphology and expression of epithelial markers. Immunohistochemistry assay in conjunction with molecular detection of fusion will be helpful for arriving at an accurate diagnosis to avoid misdiagnosis and inappropriate treatment.
Topics: Male; Humans; Female; Desmoplastic Small Round Cell Tumor; In Situ Hybridization, Fluorescence; Head; Neck; Immunohistochemistry
PubMed: 36172631
DOI: 10.1177/10668969221117989 -
Cancers Jul 2022Pancreatic cancer remains one of the most lethal malignancies and is becoming a dramatically increasing cause of cancer-related mortality worldwide. Abundant... (Review)
Review
Pancreatic cancer remains one of the most lethal malignancies and is becoming a dramatically increasing cause of cancer-related mortality worldwide. Abundant desmoplastic stroma is a histological hallmark of pancreatic ductal adenocarcinoma. Emerging evidence suggests a promising therapeutic effect of several stroma-modifying therapies that target desmoplastic stromal elements in the pancreatic cancer microenvironment. The evidence also unveils multifaceted roles of cancer-associated fibroblasts (CAFs) in manipulating pancreatic cancer progression, immunity, and chemotherapeutic response. Current state-of-the-art technologies, including single-cell transcriptomics and multiplexed tissue imaging techniques, have provided a more profound knowledge of CAF heterogeneity in real-world specimens from pancreatic cancer patients, as well as in genetically engineered mouse models. In this review, we describe recent advances in the understanding of the molecular pathology bases of pancreatic cancer desmoplastic stroma at multilayered levels of heterogeneity, namely, (1) variations in cellular and non-cellular members, including CAF subtypes and extracellular matrix (ECM) proteins; (2) geographical heterogeneity in relation to cell-cell interactions and signaling pathways at niche levels and spatial heterogeneity at locoregional levels or organ levels; and (3) intertumoral stromal heterogeneity at individual levels. This review further discusses the clinicopathological significance of desmoplastic stroma and the potential opportunities for stroma-targeted therapies against this lethal malignancy.
PubMed: 35805064
DOI: 10.3390/cancers14133293