Plasma levels of lysophospholipids were evaluated as potential biomarkers for colorectal cancer (CRC), where a highly reliable and minimally invasive blood test is lacking.
Patients with CRC (n = ...133) and control subjects (n = 125) were recruited through the Cleveland Clinic. Preoperative plasma samples were analyzed for lysophospholipid levels using liquid chromatography mass spectrometry in a blinded fashion. Participants were randomly divided in a 2:1 ratio into a "training set" (TS) and a "validation set" (VS). Logistic regression models were used in the TS to identify markers that best discriminated between CRC and controls. A cutoff point for the final discriminating model was developed using the receiver operating characteristic curve to achieve 95% specificity. All analyses were then independently validated in the VS.
Plasma levels of several lysophosphatidylcholines (LPCs), including 18:1- and 18:2-LPC, were significantly decreased in CRC patients compared with controls (P < .001). A model based on total saturated LPC and the difference between the proportional amounts of 18:2-LPC and 18:1-LPC in the unsaturated LPC fraction was derived from the TS. This model achieved a sensitivity and specificity of 82% and 93%, respectively, in the VS. Overall, 118 (94%) of 125 control subjects and 113 (85%) of 133 CRC cases were correctly identified, including eight (89%) of nine CRC cases with stage T1 disease.
Percentage of 18:1-LPC or 18:2-LPC plasma levels compared with total saturated LPC levels, either individually or in combination, may represent potential biomarkers for CRC.
Primary cutaneous gamma-delta (γδ) T-cell lymphoma is a rare disease that typically involves the dermis and subcutis. Cases of primary cutaneous T-cell lymphomas showing γδ phenotype and ...predominantly epidermotropic pattern (EγδTCL) are not well defined. In this series, cases of primary cutaneous T-cell lymphomas showing γδ phenotype were reviewed and classified as predominantly epidermotropic (EγδTCL) when >75% of lymphoma cells resided in the epidermis or predominantly dermal and/or subcutaneous (DSγδTCL). Clinical, pathologic, and immunophenotypic features were compared in 27 biopsies from 13 patients of EγδTCL and 13 biopsies from 7 patients of DSγδTCL. The lymphoma cells were diffusely positive for CD3 and T-cell receptor (TCR)γ, mostly positive for granzyme B and TIA-1, variably positive for CD8, CD7, and CD30, and negative for CD4 and TCRβ. Two patients with EγδTCL had dissemination to lymph nodes and 1 to the lung; 1 patient with DSγδTCL had gastrointestinal involvement. The median survival of patients with EγδTCL was not reached, and with a median follow-up of 19.2 months, 3/13 died. In contrast, the median survival of patients with DSγδTCL was 10 months, and after a median follow-up of 15.6 months, 5/5 died (P<0.01). EγδTCL is a rare presentation of cutaneous T-cell lymphoma that can be distinguished from DSγδTCL based on the extent of epidermotropism and has a better prognosis and longer median survival than DSγδTCL. However, although EγδTCL resembles mycosis fungoides clinically and histologically, a subset of EγδTCL is more likely to behave more aggressively than typical mycosis fungoides.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcome. BPDCN diagnostically overlaps with entities such as acute myeloid leukemia, ...histiocytic/dendritic cell neoplasms, and natural killer/T-cell lymphomas. Unfortunately, large, patient-centered studies that comprehensively analyze clinical, pathologic, and other diagnostic features are lacking. As such, there is an incomplete understanding of this disease.
To better characterize BPDCN, a multicenter working group consisting of hematopathologists and dermatopathologists gathered in person and remotely to review the current understanding of BPDCN, discuss specific issues regarding the diagnosis and differential diagnosis, and perform a retrospective analysis of the literature.
The working group curated a database of published BPDCN patient cases (BPDCN Network literature database), and following careful discussion and review, 361 articles were identified, comprising a total of 1513 individually annotated patients.
By conducting an in-depth analysis, not only did we confirm known findings such as frequent skin involvement (84% of patients; 861 of 1028) and a male predominance among older patients (>60 years old; male to female ratio of 3.5:1; 617:177), but we also identified a number of underrecognized features, such as significant central nervous system involvement (38% of cases; 24 of 64), and a more equal male to female prevalence among patients younger than 40 years (male to female ratio of 1.25:1; 167:134). Furthermore, we were able to accurately summarize the immunophenotypic, cytogenetic, and molecular features of this disease. BPDCN is a complex disease with distinct morphologic, immunophenotypic, and molecular findings. Continual updates of the literature database generated here and further analysis can allow for prospective refinement of our understanding of this orphan disease.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic ...malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein.
Pathological staging of primary anorectal mucosal melanoma is often performed according to the American Joint Commission on Cancer (AJCC) guidelines for cutaneous melanoma, as an anorectal ...melanoma-specific staging system does not exist. However, it remains unknown whether prognostic factors derived for cutaneous melanoma also stratify risk in anorectal melanoma. We retrospectively determined correlations between clinicopathological parameters and disease-specific survival in 160 patients. Patients were grouped by clinical stage at presentation (localized disease, regional or distant metastases). Cox proportional hazards regression models determined associations with disease-specific survival. We also summarized the somatic mutations identified in a subset of tumors analyzed for hotspot mutations in cancer-associated gene panels. Most of the patients were white (82%) and female (61%). The median age was 62 years. With a median follow-up of 1.63 years, median disease-specific survival was 1.75 years, and 121 patients (76%) died of anorectal melanoma. Patients presenting with regional (34%) or distant metastases (24%) had significantly shorter disease-specific survival compared to those with disease localized to the anorectum (42%). Of the 71 anorectal melanoma tumors analyzed for hotspot genetic alterations, somatic mutations involving the KIT gene (24%) were most common followed by NRAS (19%). Increasing primary tumor thickness, lymphovascular invasion, and absence of regression also correlated with shorter disease-specific survival. Primary tumor parameters correlated with shorter disease-specific survival in patients presenting with localized disease (tumor thickness) or regional metastases (tumor thickness, absence of regression, and lymphovascular invasion), but not in patients presenting with distant metastases. Grouping of patients according to a schema based on modifications of the 8th edition AJCC cutaneous melanoma staging system stratified survival in anorectal melanoma. Our findings support stage-specific associations between primary tumor parameters and disease-specific survival in anorectal melanoma. Moreover, the AJCC cutaneous melanoma staging system and minor modifications of it predicted survival among anorectal melanoma patients.
Summary New York esophageal squamous cell carcinoma-1 (NY-ESO-1), a cancer testis antigen, is an ideal target for adoptive cell transfer immunotherapy. Evidence from several clinical trials in ...melanoma and other malignancies shows the potential value of targeting the NY-ESO-1 antigen in immune-based therapy of metastatic tumors. However, the incidence of NY-ESO-1 expression in metastatic melanoma is unknown, and thus, it is unclear how many patients might benefit from this therapy. In this study, we analyzed NY-ESO-1 expression in 222 melanoma specimens, including 16 primary and 206 metastatic tumors. Our results support previous findings showing higher expression of NY-ESO-1 in metastatic (58/206; 28.2%) versus primary (0/16) tumors. In addition, our results show that the epithelioid subtype of melanoma has the highest incidence of NY-ESO-1 expression. These findings provide evidence of the value of this specific adoptive cell transfer therapy for the treatment of metastatic melanoma.
Mantle cell lymphoma (MCL) rarely involves the skin and the histologic and immunohistochemical features of this neoplasm at this site are under described. In this study, we report 37 skin specimens ...involved by MCL, representing 1.4% of total MCL biopsy specimens in our institution. The median age at time of skin involvement was 66 years (range, 36 to 85 y) and there was a male predilection of 2.7 to 1. The most frequently involved site was the skin of extremities, in 59.3% of patients, and 30 (81.1%) patients had advanced stage (III/IV) disease. Eleven (29.7%) patients presented with skin lesions as the first manifestation of MCL and 26 (70.3%) patients presented as relapse or progression of previously documented MCL and despite therapy for systemic MCL. Multiple skin lesions were more common (81.8%) in the former group whereas a solitary skin lesion was more frequent (65.4%) in the relapse/progression group (P=0.01). Thirty (81.1%) patients had skin nodules. Microscopically, the epidermis was spared with a grenz zone in all cases. A diffuse pattern of involvement was the most common architectural pattern (66.7%). In 27 (72.9%) patients, the MCL was either blastoid or pleomorphic variant, in 9 (24.3%) patients classic variant, and the disease was not further classified in 1 (2.7%) patient. The Ki-67 proliferation rate was higher in aggressive variants as compared with classic variant MCL (median 90% vs. 20%, P <0.01). In patients who presented skin lesions as a manifestation of disease relapse or progression, 16 patients initially had classic variant MCL and in 10 of the patients the MCL evolved over time (median interval: 4.1 y) to an aggressive variant at progression or relapse. The overall survival of patients with aggressive variant MCH was inferior to that of patients with classic variant MCL (median: 59 vs. 155.8 mo, P<0.05). In summary, MCL rarely involves the skin and correlates with relapse or progression of disease, aggressive morphologic features, and a poorer prognosis.
Dermatofibrosarcoma protuberans (DFSP) is a dermal malignant mesenchymal tumor. Most variants are associated with a high risk of local recurrence and a low risk of metastasis. The classic ...histomorphology of this tumor is made up of uniform, spindle-shaped cells, arranged in a storiform pattern. Tumor cells characteristically infiltrate the underlying subcutis in a honeycomb pattern. Less common variants of DFSP have been identified: myxoid, pigmented, myoid, granular cell, sclerosing, atrophic, and fibrosarcomatous. Only the fibrosarcomatous variant has been shown to differ significantly from classic DFSP in terms of clinical outcome; fibrosarcomatous DFSP has been shown to be associated with a greater risk of local recurrence and metastatic potential than classic DFSP. However, the other variants may pose diagnostic difficulty as they resemble other types of spindle cell neoplasms, especially in small biopsy specimens. This article reviews the clinical, histologic, and molecular features of DFSP variants, as well as possible pitfalls in their diagnosis and how to resolve them.
Summary Primary neuroendocrine (NE) tumors of the kidney (PNRTs) are rare and frequently mistaken for other renal and urothelial cancers. We evaluated morphological and molecular findings of 11 PNRTs ...classified according to the World Health Organization classification of lung NE tumors. Patients included 5 men and 6 women with a median age of 50 years. These tumors occurred in the left (5/11), right (3/11), and horseshoe (1/11) kidney. The histologic patterns were predominantly solid, trabecular, and pseudoglandular. Lymphovascular invasion and calcification were found in 3 and 1 cases, respectively. There were 2 atypical and 9 typical carcinoids. At the time of surgery, 2 patients with atypical carcinoids had hepatic metastasis, and 1 of the typical carcinoid patients had lymph node metastasis. All cases showed <1% proliferative rate, except 2 cases with hepatic metastasis, which showed 3% to 5% with MIB1/Ki-67 immunostaining. Immunostainings were frequently positive for synaptophysin, chromogranin, CD56, CD99, and neuron-specific enolase. Follow-up data (average 4 years) were available for 6 patients. Two patients with distant metastasis were alive with disease, and four patients with no metastasis were alive without disease. We evaluated the association of PNRT and loss of heterozygosity (LOH) on chromosome 3p21 and found LOH in 2 of 3 cases. However, the comparative genomic hybridization study (2/2) did not demonstrate significant chromosomal imbalances. We conclude that PNRTs are positive for NE markers and may have LOH on chromosome 3p21. PNRTs should be classified as NE tumors in other sites, and proliferative rate can be an indicator of aggressive behavior/metastasis.
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