Metastatic plasma cell leukemia to the skin: A case report with review of the literature.

Plasma cell leukemia (PCL) is a rare variant of leukemia with an aggressive clinical course and a poor prognosis. The cutaneous involvement in PCL is very rare either at clinical presentation of leukemia, namely leukemia cutis, or in the metastatic PCL to the skin. We present a case of eruptive multiple cutaneous nodules in a 56-year-old man with metastatic PCL. Histologically, a diffuse dermal and subcutaneous infiltration of ovoid cells with amphophilic cytoplasm and eccentrically located nucleus consistent with plasmacytoid morphology was observed. Neoplastic cells showed strong immunoexpression for CD138 and CD38 consistent with plasma cells phenotype, and loss of expression of CD56. Kappa light chain restriction similar to the phenotype of his PCL was demonstrated. We suggest that the evaluation of new skin lesions in leukemic patients should include a histopathologic examination to establish the diagnosis as soon as possible and a correct management of the disease.

Cortactin expression in non-Hodgkin B-cell lymphomas: a new marker for the differential diagnosis between chronic lymphocytic leukemia and mantle cell lymphoma.

Cortactin is a cytoskeletal-remodeling adaptor protein, playing an oncogenic role in solid tumors. Little is known on cortactin expression in non-Hodgkin B-cell lymphomas (B-NHLs). The present study aimed to characterize cortactin expression in B-NHLs and to assess its role in the differential diagnosis of such entities. Cortactin protein expression was first assessed by immunohistochemistry in a series of 131 B-NHLs, including B-cell chronic lymphocytic leukemia (CLL; n = 17), mantle cell lymphoma (MCL; n = 16), follicular lymphoma (FL; n = 25), marginal zone lymphoma (MZL; n = 30), hairy cell leukemia (HCL; n = 10), splenic diffuse red pulp small B-cell lymphomas (SDRPBL; n = 3), and diffuse large B-cell lymphoma (DLBCL; n = 30) cases. Cortactin was expressed in 14 of 17 CLLs, 10 of 10 HCLs, and 22 of 30 DLBCLs. MCLs, SDRPBLs, most FLs, and MZLs were cortactin negative. The immunohistochemical results were in keeping with in silico gene expression data. In CLL, cortactin positivity did correlate with LEF1 and CD200 expression, and the combined positivity for ≥2 markers strongly predicted CLL diagnosis. Such preliminary data suggested a role for cortactin in the differential diagnosis between CLL and MCL. This hypothesis was confirmed in a large validation set of 112 CLLs (n = 55) and MCLs (n = 57), which also disclosed rare cortactin-expressing MCLs. The immunohistochemical and gene expression results were sustained by flow cytometry and Western blot analysis on CLL and MCL cell lines. In conclusion, cortactin is mainly expressed in subsets of CLL and DLBCL and in HCL. Cortactin may represent a novel marker for the differential diagnosis between CLL and MCL.

Prevalence of ALK gene alterations among the spectrum of plexiform spitzoid lesions.

BACKGROUND: ALK receptor tyrosine kinase gene (ALK) rearrangements have been described in spitzoid lesions with a plexiform growth pattern. OBJECTIVE: To investigate the prevalence of ALK alterations in a large series of spitzoid lesions. METHODS: ALK immunohistochemical and fluorescence in situ hybridization analyses of 78 spitzoid plexiform lesions including 41 Spitz nevi, 29 atypical Spitz tumors (ASTs), and 8 spitzoid melanomas. RESULTS: ALK immunohistochemical staining was observed in 14.6% of Spitz nevi (6 of 41) and 13.8% of ASTs (4 of 29); the spitzoid melanomas were ALK negative. Fluorescence in situ hybridization confirmed ALK translocation in 9 cases and amplification in 1 case. In 2 of the translocated cases it was possible to determine the fusion partner gene (ie, tropomyosin 3 gene [TPM3] or dynactin 1 gene [DCTN1]). Of the 4 cases of AST examined, 2 carried the B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) V600E mutation. The 10 patients had a mean age of 18.7 years (range, 1-39) and a female predominance (female-to-male ratio, 7:3). Seven lesions arose on the extremities; the 2 lesions occurring in infants were located on the face. The lesions' mean diameter was 6.2 mm (range, 3-13), and their mean Breslow thickness was 1.83 mm (range, 0.6-3.6). The results of sentinel node biopsy were negative in 2 ASTs. LIMITATIONS: BRAF status was tested in only 4 of 10 samples because of the limited amount of material. CONCLUSION: ALK alterations characterize a significant subset of spitzoid lesions.

MiR-21 up-regulation in ampullary adenocarcinoma and its pre-invasive lesions.

Poor information is available on the molecular landscape characterizing the carcinogenetic process leading to ampullary carcinoma. MiR-21 is one of the most frequently up-regulated miRNAs in pancreatic adenocarcinoma, a tumor sharing similar molecular features with ampullary adenocarcinomas (AVCs), above all with the pancreatic-biliary type. We profiled, by in situ hybridization (ISH), miR-21 expression in a series of 26 AVCs, 50 ampullary dysplastic lesions (35 low-grade [LG-IEN] and 15 high-grade [HG-IEN]) and 10 normal duodenal mucosa samples. The same series was investigated by immunohistochemistry for ß-catenin, p53 and HER2 expression. HER2 gene amplification was evaluated by chromogenic in situ hybridization. To validate miR-21 ISH results we performed miR-21 qRT-PCR analysis in a series of 10 AVCs and their matched normal samples. All the normal control samples showed a negative or faint miR-21 expression, whereas a significant miR-21 up-regulation was observed during the carcinogenetic cascade (p < 0.001), with 21/26 (80.8%) of cancer samples showing a miR-21 overexpression. In comparison to control samples, a significant overexpression was found in samples of LG-IEN (p = .0003), HG-IEN (p = .0001), and AVCs (p < 0.0001). No significant difference in miR-21 overexpression was observed between LG-IEN, HG-IEN and AVCs. By qRT-PCR analysis, AVCs showed a 1.7-fold increase over the controls (p = .003). P53 was frequently dysregulated in both dysplastic and carcinoma samples (44 out of 76; 57.9%). A 20% (10/50) of dysplastic lesions and 11% (3/26) of carcinomas were characterized by a nuclear localization of ß-catenin. Only 2 AVCs (7.7%; both intestinal-type) showed a HER2 overexpression (both 2+), which corresponded to a HER2 gene amplification at CISH analysis. This is the first study demonstrating a miRNA dysregulation in the whole spectrum of ampullary carcinogenesis. MiR-21 overexpression is an early molecular event during ampullary carcinogenesis and its levels increase with the neoplastic progression.

PD-L1 overexpression in ampulla of Vater carcinoma and its pre-invasive lesions.

AIMS: PD-1/PD-L1 checkpoint immunotherapy has been proposed recently as a promising treatment in relapsed/refractory disease, used eventually in combination with traditional chemotherapy in different cancer settings. To date, no data are available concerning PD-L1 expression in ampulla of Vater carcinoma and its pre-invasive lesions. METHODS AND RESULTS: We assessed the immunohistochemical expression of PD-L1 in a series of 26 ampullary adenocarcinomas, 50 ampullary dysplastic lesions and 10 normal duodenal mucosa samples. Moreover, in all cases DNA mismatch repair proteins status was investigated. PD-L1 was expressed in seven of 26 (26.9%) invasive carcinomas and three of 50 (6.0%) dysplastic samples. Most of the PD-L1-positive tumours (seven of 10) were intestinal-type and poorly differentiated (G3). The number of PD-L1-positive stromal lymphoid cells was significantly higher in dysplastic and invasive lesions than in the normal samples (P = 0.011). Nineteen dysplastic lesions and eight invasive carcinomas did not show any evident epithelial or stromal PD-L1 expression. Four of the carcinomas were mismatch repair-deficient and two of these were PD-L1-positive. Furthermore, mismatch repair-deficient lesions showed a significantly higher average of PD-L1-positive stromal lymphoid cells than those of neoplastic PD-L1-negative samples (62.8 versus 21.6; P < 0.001). CONCLUSIONS: The present results suggest a role of the PD-1/PD-L1 axis in ampullary adenocarcinomas, and therefore this may also prompt consideration of checkpoint immunotherapy as a novel promising treatment for these tumours.

Pigmented trichoblastoma developed in a sebaceous nevus: HRAS mutation as a common molecular driver.

A 40-year-old woman presented with a pigmented nodule on a previously existing yellowish, verrucous plaque on the scalp. The histological diagnosis was consistent with a pigmented trichoblastoma developed within a sebaceous nevus (SN). A multigene hotspot mutational profiling of the BRAF, NRAS, HRAS and KRAS genes was carried out, and a shared G13R HRAS mutation in both the trichoblastoma and the sebaceous nevus components was found. These data support a common molecular landscape of the two lesions.

Early miR-223 Upregulation in Gastroesophageal Carcinogenesis.

OBJECTIVES: To test miR-223 upregulation during gastric (intestinal-type) and Barrett esophageal carcinogenesis. METHODS: miR-223 expression was assessed by quantitative reverse transcription polymerase chain reaction in a series of 280 gastroesophageal biopsy samples representative of the whole spectrum of phenotypic changes involved in both carcinogenetic cascades. The results were further validated by in situ hybridization on multiple tissue specimens obtained from six surgically treated gastroesophageal adenocarcinomas. miR-223 expression was also assessed in plasma samples from 30 patients with early stage (ie, stages I and II) gastroesophageal adenocarcinoma and relative controls. RESULTS: In both gastric and esophageal models, miR-223 expression significantly increased along with the severity of the considered lesions (analysis of variance, P < .001). Among atrophic gastritis and long-segment Barrett esophagus samples, miR-223 overexpression was significantly associated with the score of intestinal metaplasia. miR-223 plasma levels were significantly upregulated in patients with cancer compared with controls ( t test, both P < .001). CONCLUSIONS: miR-223 early upregulation observed in tissue samples and its diagnostic value in discriminating patients with early adenocarcinoma by plasma testing provide a solid rationale for further exploring the diagnostic reliability of this microRNA as a novel biomarker in gastroesophageal adenocarcinoma secondary prevention strategies.

Cortactin, a Lyn substrate, is a checkpoint molecule at the intersection of BCR and CXCR4 signalling pathway in chronic lymphocytic leukaemia cells.

Cortactin (CTTN) is a substrate of the Src kinase Lyn that is known to play an actin cytoskeletal regulatory role involved in cell migration and cancer progression following its phosphorylation at Y421. We recently demonstrated that Cortactin is overexpressed in patients with chronic lymphocytic leukaemia (CLL). This work was aimed at defining the functional role of Cortactin in these patients. We found that Cortactin is variably expressed in CLL patients both in the peripheral blood and lymph nodes and that its expression correlates with the release of matrix metalloproteinase 9 (MMP-9) and the motility of neoplastic cells. Cortactin knockdown, by siRNA, induced a reduction in MMP-9 release as well as a decrease of migration capability of leukaemic B cells in vitro, also after chemotactic stimulus. Furthermore, Cortactin phosphorylation was lowered by the Src kinase-inhibitor PP2 with a consequent decrease of MMP-9 release in culture medium. An impaired migration, as compared to control experiments without Cortactin knockdown, was observed following CXCL12 triggering. Reduced Cortactin expression and phosphorylation were also detected both in vivo and in vitro after treatment with Ibrutinib, a Btk inhibitor. Our results highlight the role of Cortactin in CLL as a check-point molecule between the BCR and CXCR4 signalling pathways.

The molecular landscape of colitis-associated carcinogenesis.

In spite of the well-established histopathological phenotyping of IBD-associated preneoplastic and neoplastic lesions, their molecular landscape remains to be fully elucidated. Several studies have pinpointed the initiating role of longstanding/relapsing inflammatory insult on the intestinal mucosa, with the activation of different pro-inflammatory cytokines (TNF-α, IL-6, IL-10, IFN-γ), chemokines and metabolites of arachidonic acid resulting in the activation of key transcription factors such as NF-κB. Longstanding inflammation may also modify the intestinal microbiota, prompting the overgrowth of genotoxic microorganisms, which may act as further cancer promoters. Most of the molecular dysregulation occurring in sporadic colorectal carcinogenesis is documented in colitis-associated adenocarcinoma too, but marked differences have been established in both their timing and prevalence. Unlike sporadic cancers, TP53 alterations occur early in IBD-related carcinogenesis, while APC dysregulation emerges mainly in the most advanced stages of the oncogenic cascade. From the therapeutic standpoint, colitis-associated cancers are associated with a lower prevalence of KRAS mutations than the sporadic variant. Epigenetic changes, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, are significantly involved in colitis-associated cancer development and progression. The focus now is on identifying diagnostic and prognostic biomarkers, with a view to ultimately designing patient-tailored therapies.

Extraskeletal Myxoid Chondrosarcoma of the Foot Clinically Mimicking Plantar Fibromatosis.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma usually presenting in proximal extremities of middle-aged men. The authors discuss a unique case of EMC, localized in the plantar foot of a 76-year-old woman, clinically suspected as plantar fibromatosis. It is important to avoid misdiagnosis of EMC because of their propensity for late recurrence and their metastatic potential.

From Barrett metaplasia to esophageal adenocarcinoma: the molecular background.

The molecular landscape of Barrett's esophagus and Barrett-related neoplastic lesions is still far from being completely elucidated. Both in vitro and in vivo studies pinpointed the pathogenetic role of different morphogenic pathways (the para-homeobox, the Notch and the Sonic Hedgehog families in particular) implicated in the acquisition of the metaplastic phenotype of the esophageal mucosa. On the other hand, the most common genetic alterations observed during Barrett's carcinogenesis include disorders of major regulators of the cell cycle, as well as deregulation of the TGF-ß/Smad and receptor tyrosine kinases signalling pathways. Recent comprehensive mutational profiling studies identified that the inactivation of the TP53 and of the SMAD4 tumour suppressor genes occurred in a stage-specific manner, confined to (high grade) dysplastic and neoplastic lesions, respectively. The next step will be the correlation of these findings into multidisciplinary diagnostic approaches integrating endoscopy, histology, molecular profiling and liquid biopsies. This will allow the introduction of innovative strategies for secondary prevention of esophageal adenocarcinoma based on biological rationales, and the implementation of potential novel therapeutic targets.

Let-7c down-regulation in Helicobacter pylori-related gastric carcinogenesis.

Aberrant let-7c microRNA (miRNA) expression has been observed in Helicobacter pylori-related gastric cancer (GC) but fragmentary information is available on the let-7c dysregulation occurring with each phenotypic change involved in gastric carcinogenesis. Let-7c expression was assessed (qRT-PCR) in a series of 175 gastric biopsy samples representative of the whole spectrum of phenotypic changes involved in H. pylori-related gastric oncogenesis including: i) normal gastric mucosa, as obtained from dyspeptic controls (40 biopsy samples); ii) non-atrophic gastritis (40 samples); iii) atrophic-metaplastic gastritis (35 samples); iv) intra-epithelial neoplasia (30 samples); v) GC (30 samples). Let-7c expression was also tested in 20 biopsy samples obtained from 10 patients before and after H. pylori eradication therapy (median follow-up: 10 weeks; range: 7-14). The results obtained were further validated by in situ hybridization on multiple tissue specimens obtained from 5 surgically treated H. pylori-related GCs. The study also included 40 oxyntic biopsy samples obtained from serologically/histologically confirmed autoimmune gastritis (AIG: 20 corpus-restricted, non-atrophic; 20 corpus-restricted, atrophic-metaplastic). Let-7c expression dropped from non-atrophic gastritis to atrophic-metaplastic gastritis, intra-epithelial neoplasia, and invasive GC (p<0.001). It rose again significantly following H. pylori eradication (p=0.009). As in the H. pylori model, AIG also featured a significant let-7c down-regulation (p<0.001). The earliest phases of the two pathways to gastric oncogenesis (H. pylori-environmental and autoimmune host-related) are characterized by similar let-7c dysregulations. In H. pylori infection, let-7c down-regulation regresses after the bacterium's eradication, while it progresses significantly with the increasing severity of the histological lesions.

YAP immunoreactivity is directly related to pilomatrixoma size and proliferation rate.

Organ size regulation is a highly coordinated process involving complex mechanisms. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif, also known as WWTR1 (TAZ) have recently been linked to organ size determination and cell proliferation. Pilomatrixoma (PM) is a benign tumor of the adnexal appendages with a certain degree of differentiation toward the matrix of the hair follicle. PM presents as a dermal nodule that usually ranges from 0.5 to 2 cm, rarely exceeding 3 cm. We recently observed a case of unusual "giant" (6.5 cm) PM. Our hypothesis was that YAP and TAZ could be related to PM growth. We analyzed YAP and TAZ immunohistochemical expression in the giant and in ten usual size PMs in relation with tumor size and proliferation rate. YAP nuclear expression was remarkably higher in the giant PM in comparison with usual size PMs and statistically correlated, in a direct manner, with size and proliferation rate of PMs. Contrariwise, TAZ nuclear expression seemed stochastic. Our findings suggest that YAP could play a role in PM growth.

Secondary prevention of epidemic gastric cancer in the model of Helicobacter pylori-associated gastritis.

Irrespective of its etiology, long-standing, non-self-limiting gastric inflammation (mostly in Helicobacter pylori-associated cases) is the cancerization ground on which epidemic (intestinal-type) gastric carcinoma (GC) can develop. The natural history of invasive gastric adenocarcinoma encompasses gastritis, atrophic mucosal changes, and intraepithelial neoplasia (IEN). The topography, the extent and the severity of the atrophic changes significantly correlate with the risk of developing both IEN and GC. In recent years, both noninvasive (serological) tests and invasive (endoscopy/biopsy) procedures have been proposed to stratify patients according to different classes of GC risk. As a consequence, different patient-tailored GC secondary prevention strategies have been put forward. This review summarizes the histological features of H. pylori-related gastritis and the natural history of the disease. Histological and serological strategies to assess GC risk as well as the clinical management of atrophic gastritis patients are also discussed.