Human Placenta-Derived Mesenchymal Stromal-Like Cells Enhance Angiogenesis via T Cell-Dependent Reprogramming of Macrophage Differentiation.

Peripheral arterial disease (PAD) is a leading cause of limb loss and mortality worldwide with limited treatment options. Mesenchymal stromal cell (MSC) therapy has demonstrated positive effects on angiogenesis in preclinical models and promising therapeutic efficacy signals in early stage clinical studies; however, the mechanisms underlying MSC-mediated angiogenesis remain largely undefined. Here, we investigated the mechanism of action of human placenta-derived MSC-like cells (PDA-002) in inducing angiogenesis using mice hind limb ischemia model. We showed that PDA-002 improved blood flow and promoted collateral vessel formation in the injured limb. Histological analysis demonstrated that PDA-002 increased M2-like macrophages in ischemic tissue. Analysis of the changes in functional T cell phenotype in the draining lymph nodes revealed that PDA-002 treatment was associated with the induction of cytokine and gene expression signatures of Th2 response. Angiogenic effect of PDA-002 was markedly reduced in Balb/c nude mice compared with wild type. This reduction in efficacy was reversed by T cell reconstitution, suggesting T cells are essential for PDA-002-mediated angiogenesis. Furthermore, effect of PDA-002 on macrophage differentiation was also T cell-dependent as a PDA-002-mediated M2-like macrophage skewing was only observed in wild type and T cell reconstituted nude mice, but not in nude mice. Finally, we showed that PDA-002-treated animals had enhanced angiogenic recovery in response to the second injury when PDA-002 no longer persisted in vivo. These results suggest that PDA-002 enhances angiogenesis through an immunomodulatory mechanism involving T cell-dependent reprogramming of macrophage differentiation toward M2-like phenotype. Stem Cells 2017;35:1603-1613.

Primary cutaneous marginal zone lymphoma with subclinical cutaneous involvement and biclonality.

Primary cutaneous extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) represents a monoclonal B-cell neoplasm that typically presents with papules, plaques or nodules. We describe a patient with a primary cutaneous MALT lymphoma with unusual clinical features and an unusual immunophenotype. Conventional microscopy together with immunohistochemistry and in-situ hybridization showed the presence of lymphoma in normal-appearing and minimally erythematous skin as well as in clinically involved skin. Furthermore, at least two distinct clones were shown, one of which had κ-light chain restriction, and the other of which had λ-light chain restriction. This case represents a newly described clinical appearance of primary cutaneous MZL and shows that some patients may have more than one neoplastic clone.

Cutaneous marginal zone lymphomas have distinctive features and include 2 subsets.

Cutaneous marginal zone lymphomas (CMZL) were segregated in the WHO/EORTC consensus classification but grouped with other MALT lymphomas in the subsequent WHO classification. It has been suggested, however, that CMZL have distinctive features and might include 2 subsets. To address these issues, the clinicopathologic, phenotypic and, when possible, genotypic features of 29 CMZL with plasmacytic differentiation were assessed. The monotypic plasma cells had class-switched heavy chain expression in 22 cases, technically inadequate staining in 1 case (included with class-switched cases for analysis) and 6 were IgM. The class-switched cases had a predominance of T cells in 22 out of 23 cases with a CD4:CD8>1 in 15 out of 16 cases, usually showed nodules and scattered small B cells often with IgD apparently nonneoplastic follicles, lacked CXCR3 B-cell expression, never showed a totally diffuse growth pattern, often had prominent mast cells, and lacked known extracutaneous involvement. The IgM cases showed a predominance of B cells in 5 out of 6 (P=0.0003), a diffuse proliferation of CD20 B cells in all (P<0.0001), CXCR3+ B cells in 2 out of 5 (P<0.04), and extracutaneous disease in 3 out of 6 (P<0.008). CD21 usually disrupted follicular dendritic meshworks were seen in 9 out of 12 class-switched and 5 out of 5 IgM cases. CD123 plasmacytoid dendritic cells, PD1+ T follicular helper cells, CD25 or FOXP3+ regulatory T cells, and TIA1/granzyme B cytotoxic cells were never numerous. Only 1 out of 14 tested cases showed a low-level clonal/oligoclonal T cell receptor γ gene rearrangement. These findings support the presence of 2 types of cutaneous MALT lymphomas with the class-switched cases being the most distinctive but still sharing significant features with MALT lymphomas from other sites, specifically an extranodal extramedullary CD5-, CD10- indolent small B cell lymphoma with plasmacytic differentiation, frequent benign follicular structures, and not fulfilling the criteria for any other well-defined lymphoma.

Intracranial angiomatoid fibrous histiocytoma presenting as recurrent multifocal intraparenchymal hemorrhage.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft-tissue neoplasm that most commonly appears in the limbs, typically affecting children and young adults. The tumor has a propensity for local recurrence and recurrent hemorrhage but rarely for remote metastasis. To date, only 2 reports have documented an intracranial occurrence of the tumor (1 of which was believed to be metastatic disease). This is the second report of primary intracranial AFH. Additionally, hemorrhage from an intracranial AFH lesion has yet to be reported, and little is known about the radiographic characteristics and biological behavior of these lesions. In this report, the authors describe the case of a patient with recurrent hemorrhage due to primary multifocal intracranial AFH. Initially misdiagnosed as a cavernous malformation and then an unusual meningioma, the tumor was finally correctly identified when there was a large enough intact resection specimen to reveal the characteristic histological pattern. The diagnosis was confirmed using immunohistochemical and molecular studies.

CD30 expression and proliferative fraction in nontransformed mycosis fungoides.

The major differential diagnosis for a primary cutaneous T-cell lymphoproliferative disorder with CD30 (Ki-1) positivity includes primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, pagetoid reticulosis and transformed mycosis fungoides (MF). Little is known, however, about CD30 expression in nontransformed MF, whether it simply reflects the proliferative fraction and if either CD30 staining or the proliferative fraction are of prognostic significance. Therefore, 47 nontransformed MF biopsies were stained for CD30 and Ki-67. The proportions of positive cells were determined and correlated with each other as well as with age, stage at diagnosis, maximum stage and survival. All cases had at least rare dermal CD30-positive cells. Higher percentages of dermal CD30 and Ki-67-positive cells were associated with a higher stage at diagnosis, and together with epidermal CD30, associated with a higher maximum stage. The proportion of CD30 and Ki-67-positive cells did not correlate with each other. Survivals were shorter if the dermal CD30 or epidermal or dermal Ki-67% were greater than the median (4.7%, 14%, 13%) and in patients of greater than or equal to 60 years of age or with a high stage. Dermal Ki-67 as a continuous variable was an independent prognostic indicator (P<0.001), as were dermal Ki-67 (P=0.004) and dermal CD30 (P=0.027) when analyzed as dichotomous variables but not stage. Therefore, CD30 expression is not restricted to transformed MF but higher levels of dermal CD30 expression and, even more so, dermal Ki-67 levels are independent adverse prognostic indicators.

Two cutaneous malignant melanomas at the same anatomic site: a case report with molecular evaluation.

Patients who have had malignant melanoma are at an increased risk of developing a second primary melanoma compared with the general population risk of developing a first melanoma. Many of these second primary melanomas occur at a similar anatomic site as the first lesion. Determining whether a second lesion is indeed a separate primary vs. a metastasis or locoregional recurrence can be very difficult histologically. We report the case of a patient who developed a second melanoma, 2 years after the initial diagnosis, within 3 cm of the site of the original lesion. Because of distinct histomorphologic features, the second lesion was favored to be a separate primary. However, because of the nearly identical anatomic location, molecular testing for loss of heterozygosity and BRAF mutation was performed to help further make this distinction. The first lesion was found to have loss of heterozygosity and a BRAF mutation that were not present in the second lesion. While these tests cannot elucidate the true molecular origin of these lesions, they provide a useful clinical tool to assess whether a second lesion should be treated as a recurrence or as a separate lesion with unique biologic potential.

Bilateral peritonsillar abscesses: a challenging diagnosis.

Peritonsillar abscess is the most common complication of acute tonsillitis. Bilateral peritonsillar abscesses are much less common, and they may be more difficult to detect on physical examination because the oropharynx often appears to be symmetrical rather than asymmetrical, as is the case in unilateral abscess. Previous steroid treatment may also complicate the diagnosis by masking the signs and symptoms of abscess. We describe the case of a young woman who presented to the emergency department with relatively mild symptoms despite having large bilateral peritonsillar abscesses. We believe that her symptoms had been masked by previous steroid therapy. We also review the treatment and microbiology of peritonsillar abscess.