Metastatic Mimics of Primary Cutaneous Lesions: Averting Diagnostic Pitfalls With Significant Repercussions.

Cutaneous metastases by solid malignancies often signify advanced disease and portend severely limited survival. Appropriate diagnosis of these lesions is particularly hampered when they closely resemble primary cutaneous tumors. In this article, we present two diagnostically challenging cases of metastatic lesions to the scalp bearing striking histologic resemblance to primary cutaneous neoplasms. One case of a metastatic urothelial carcinoma showed epidermotropism as well as histologic and immunohistochemical features virtually indistinguishable from those of a poorly differentiated squamous cell carcinoma. Next generation sequencing was performed on both the primary urothelial carcinoma and scalp malignancy revealing an identical BRAF p. S467L somatic mutation, confirming the diagnosis. Another case of metastatic renal cell carcinoma showed clinical and histomorphologic features highly reminiscent of a pyogenic granuloma. These cases demonstrate the potential of metastatic lesions to assume a myriad array of innocuous disguises and underscore the vigilance required to avoid misdiagnosis. In addition, we highlight the emerging role of molecular strategies in resolving these problematic cases.

Lacrimal tissue resection in Fasanella Servat operation and the correlation to dry eye.

Purpose: Fasanella-Servat operation (FSO) was previously reported to be associated with post-operative dry eyes due to accessory lacrimal gland resection during the surgery.We performed a retrospective, cohort study to determine the frequency of lacrimal tissue resection during FSO and its correlation with post-operative eye dryness and keratopathy.Methods: Review of all patients who underwent FSO at New York-Presbyterian Weill Cornell Hospital over a two-year period (2013-2015). Patients were included only if they had adequate histopathological specimens of the resected tissue obtained during surgery. Outcomes included the study of the pathological specimen for the presence of lacrimal tissue; Post-operative dry eye symptoms and pre- and post-operative corneal epitheliopathy.Results: 46 patients with a total of 58 eyelid resections were studied.Eight eyelids (13.7%) were found to have lacrimal tissue present in the pathology specimens.Postoperatively, nine patients reported some symptoms of dry eye and new-onset keratopathy was noted in four eyes (6.8%), only one of which had lacrimal tissue present in histopathology specimen obtained from surgery.Discussion: Previous studies found lacrimal tissue present in up to 43% of specimens resected during FSO. Our data found a lower rate of lacrimal tissue resection during FSO, and did not find an association between lacrimal tissue resection and post-operative dryness or epitheliopathy.Conclusion: Our study is one of few to examine histopathological resections from the FSO.We found that lacrimal tissue is not frequently resected during FSO, and when it is resected, there is no increased incidence of post-operative dryness or keratopathy.

Post-thymic CD4 positive cytotoxic T cell infiltrates of the skin: A clinical and histomorphologic spectrum of the unique CD4 positive T cell of immunosenescence.

T cell lymphoproliferative disorders that arise in the skin are mainly derived from post thymic T cells most commonly of CD4 subset. Human CD4 positive T cells are dynamic exhibiting phenotypic and functional malleability. For example, with repetitive antigen exposure most commonly associated with age, CD4 positive T cells acquire a cytotoxic phenotype. The authors present four cases characterized by cutaneous infiltrates of cytotoxic CD30 negative CD4 positive T cells in the skin; three cases were forms of malignant lymphoma other than mycosis fungoides and one case was a reactive lymphomatoid photodermatosis associated with underlying collagen vascular disease. The three patients with lymphoma were adult men, two above 50 years of age and all with disseminated cutaneous disease. One of these patients whose biopsy showed a large cell morphology succumbed to the disease while one patient with localized disease responded to local radiation. In all three cases there was a nodular and diffuse pan-dermal infiltrate which was predominated by non-cerebriform atypical lymphocytes ranging from small to intermediate sized cells in two cases to a large cell dominant morphology in one case. The biopsies showed some degree of epidermotropism, and in one case it was striking. Neoplastic cells were positive for CD4, and at least one cytotoxic protein (i.e. granzyme and/or TIA). CD56, CD57 or CD30 were negative. In addition, CD28, the naïve T cell marker, was negative. Based on the few cases reported herein, one might suggest that the prognosis mirrors that seen in other forms of cutaneous T cell lymphoma with mature small cell dominant infiltrates exhibiting an indolent pattern while a CD30 negative large cell T cell lymphoma would be expected to demonstrate an aggressive clinical course.

CD30 Positive Lymphomatoid Angiocentric Drug Reactions: Characterization of a Series of 20 Cases.

INTRODUCTION: Lymphomatoid drug reactions are atypical T cell cutaneous lymphocytic infiltrates induced by pharmacological therapy. Due to phenotypic abnormalities, clonality, and their close clinical and morphologic resemblance to T cell lymphomas, these eruptions have been categorized as drug-associated reversible granulomatous T cell dyscrasias. DESIGN: A total of 20 cases were encountered in which a diagnosis of CD30 lymphomatoid drug reaction was rendered. RESULTS: There were 11 women and 9 men ranging from 31 to 86 years of age presenting with a sudden onset often generalized cutaneous papular eruption. Two patients had vasculitic lesions. In all cases, a positive drug history was elicited and in most the initiation of the drug was temporally associated with the cutaneous eruption. Among the implicated drugs were statins (6 cases), immunomodulators (4 cases), ACE inhibitors (3 cases), antibiotics (3 cases), chemotherapy agents (3 cases), and antidepressants (1 case). Biopsies demonstrated a similar morphology, namely a superficial angiocentric lymphocytic infiltrate containing many immunoblasts. Tissue eosinophilia, interface dermatitis, and supervening eczematous changes in the overlying epidermis were observed in most cases. In all cases, the angiocentric infiltrate was highlighted by CD3, CD30, and CD4. Cytotoxic protein granule expression or monoclonality was not observed. In all cases, there was improvement or complete regression of the eruption upon drug modulation. CONCLUSION: The CD30 positive lymphomatoid angiocentric drug reaction poses a diagnostic challenge because of its close resemblance to type A lymphomatoid papulosis and potential confusion with a peripheral T cell lymphoma with large cell transformation.

CD30+ T cell enriched primary cutaneous CD4+ small/medium sized pleomorphic T cell lymphoma: A distinct variant of indolent CD4+ T cell lymphoproliferative disease.

Primary cutaneous CD4+ small/medium sized pleomorphic T-cell lymphoma (SMPTCL) is unique among the peripheral T-cell lymphomas because of its indolent nature, typically presenting as a solitary nodule or plaque in the head and neck area of middle-aged and older adults. Recent studies have suggested a follicular helper cell origin for these lesions. MATERIALS AND METHODS: A retrospective review was conducted on all cases of SMPTCL diagnosed between 2008 and 2017. The goal of our study was to better categorize the clinical, pathologic and molecular features of cases of SMPTCL showing a significant degree of CD30 neoplastic large cell infiltration. RESULTS: Fifteen patients (10 male, 5 female) were encountered (age 33-86years at presentation). All lesions were solitary and the head and neck region was the most common area of involvement (7 cases). Surgical excision alone was performed in 6 cases and was supplemented with radiation in 5 cases. Disease recurrence did not occur. Spontaneous regression following biopsy was reported and two patients had a history compatible with lymphomatoid papulosis. All cases showed pathologic features characteristic of SMPTCL. Additionally, there were many larger CD30+ T-cells occupying 15-30% of the infiltrate. Monoclonality was demonstrated in 5 of 10 cases in which clonality studies were performed. CONCLUSION: CD30 positivity amidst large neoplastic T-cells is not uncommon in SMPTCL. The extent of CD30 positivity in SMPTCL needs to be defined further along with its association with other forms of CD30+ lymphoproliferative disease including its potential categorization as a form of endogenous CD30+ lymphoproliferative disease.

Upregulation of inhibitory signaling receptor programmed death marker-1 (PD-1) in disease evolution from cutaneous lymphoid dyscrasias to mycosis fungoides and Sezary's syndrome.

BACKGROUND: Negative immunoregulatory checkpoints impede effective immune responses to tumor and reduce the action of anticancer agents. One such example is programmed death marker-1 (PD-1), an inhibitory signaling receptor expressed on activated and regulatory T-cells. PD-1 expression was reported in a few reports, but the expression profile of PD-1 and mycosis fungoides (MF) remains largely to be characterized. DESIGN: In this study, skin biopsies from 42 prelymphomatous T-cell dyscrasias (CLD), 9 Sezary's syndrome (SS), 103 MF, and 20 CD30+ lymphoproliferative diseases (LPD) were examined for PD-1 expression using immunohistochemistry. RESULTS: PD-1 staining was observed amidst many neoplastic T-cells in 6/9(66.7%) and 62/103 (60.2%) cases of SS and MF respectively, while only 6/42 (14.3%) cases of CLD and 0/20 (0%) cases of CD30+ LPD (P<0.001). Three cases are from same patients representing different stages of disease evolution from CLD to MF and SS with a corresponding enrichment of PD-1 positivity. In all cases there was variable staining of PD-1 amidst macrophages. There was no correlation with disease progression among MF cases. Twenty cases of CD30+ LPD did not show any PD-1 positivity. CONCLUSION: PD-1 seems to correlate with disease progression in epitheliotropic T cell dyscrasias ranging from minimal staining in prelymphomatous dyscrasias to significant staining in MF, likely reflecting the effects of PD-1 on inhibiting tumor surveillance regulatory T cell populations. PD-1 was consistently expressed in MF while it was consistently negative in primary CD30+ LPD, suggesting the possibility of using PD-1 as a means of distinguishing CD30+ MF from primary cutaneous ALCL.

Primary cutaneous interdigitating dendritic cell sarcoma is a morphologic and phenotypic simulator of poorly differentiated metastatic melanoma: A report of 2 cases and review of the literature.

Interdigitating dendritic cell sarcoma (IDS) is a rare form of hematologic malignancy associated with an aggressive clinical course. Only 4 prior cases have been described as originating in the skin. We encountered two male patients ages 47 and 61years of age who presented with solitary cutaneous neoplasms diagnosed as IDS. Histologic exam showed a coalescing nested and multinodular proliferation of large pleomorphic epithelioid cells. In one case an initial diagnosis of melanoma was rendered. A recurrence 8months later was then interpreted as a primary cutaneous IDS. This patient died of widespread metastatic disease within 2years from his initial surgery. The other patient has recently undergone wide excision and radiation without any recurrence or metastatic disease during this short follow up time period. Both patients had a tumor exhibiting the same phenotypic profile comprising leukocyte common antigen, SOX10, S100, CD68, and CD163 positivity. In reviewing the 4 other reported cases, there is a similar older male predominance (mean age of 58years) although women affected were significantly younger (mean age of 28years); there was a predilection for the proximal extremities and the face. Patients treated with excision only developed recurrent disease with one patient subsequently dying of metastatic disease. Primary cutaneous IDS is a highly aggressive hematologic malignancy that has many overlapping features with poorly differentiated epithelioid and spindle cell melanoma including SOX10 staining. An aggressive treatment protocol at the beginning could optimize patient survival.

An Index Case of Cutaneous Hodgkin Lymphoma and Review of the Literature.

Hodgkin lymphoma (HL), although a common hematopoietic malignancy, presents as a primary cutaneous form in extraordinarily rare instances. In this study, we present a remarkable case of a 76-year-old woman with a history of bony metastatic breast cancer who developed multiple subcutaneous nodules on the left neck and scalp. A biopsy revealed the histological and immunohistochemical findings of classic HL. She was treated with systemic chemotherapy and quickly achieved disease remission. Five months later, she was alive and without evidence of lymphoma, consistent with our understanding of primary cutaneous HL as an indolent variant of HL.

Primary Cutaneous Anaplastic Large-Cell Lymphoma With 6p25.3 Rearrangement in a Cardiac Transplant Recipient: A Case Report and Review of the Literature.

Posttransplant lymphoproliferative disorders define an important form of lymphoproliferative disease causally linked with a state of iatrogenic immune dysregulation inherent to the posttransplant setting. Most posttransplant lymphoproliferative disorders are in the context of Epstein-Barr virus-associated B-cell lymphoproliferative disease, most notably diffuse large-cell B-cell lymphoma. A less common variant falls under the rubric of posttransplant T-cell lymphoproliferative disease, which is largely unrelated to Epstein-Barr virus infection. Anaplastic large-cell lymphoma (ALCL) is the most recognized form of posttransplant T-cell lymphoproliferative disease. Although the 6p25.3 translocation is seen in a variety of B-cell lymphoproliferative disorders, this particular translocation in the spectrum of T-cell lymphoproliferative disease is a fairly specific finding pointing toward a diagnosis of primary cutaneous ALCL and a rare subset of lymphomatoid papulosis. This translocation in the peripheral T-cell lymphoma setting serves as a favorable prognostic predictor. We report a case of an 81-year-old heart transplant recipient who developed an expansile neck mass 17 years after his heart transplant. A diagnosis of cutaneous ALCL was subsequently made with cytogenetic analysis yielding the 6p25.3 translocation. The characteristic biphasic morphology of a small-cell epidermotropic neoplastic cell populace in concert with a dermal based large-cell infiltrate characteristic for those cases of ALCL harboring this translocation was seen. After excision of the nodule, his azathioprine was withheld. He is currently alive and well without evidence of disease.

Primary Cutaneous Diffuse Large B-Cell Lymphoma With a MYC-IGH Rearrangement and Gain of BCL2: Expanding the Spectrum of MYC/BCL2 Double-Hit Lymphomas.

Aggressive extracutaneous B-cell lymphomas span the various stages of B-cell ontogeny and include B-cell lymphoblastic lymphoma, Burkitt lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Diffuse large B-cell lymphomas represent the most common histologic subtype of non-Hodgkin lymphomas, comprising 30% of adult non-Hodgkin lymphomas in the United States. A distinctive form of diffuse large B-cell lymphoma is the double-hit lymphoma, with most cases exhibiting a combined MYC and BCL2 rearrangement, leading some hematopathologists to propose the term MYC/BCL2 lymphoma. More recently, MYC rearrangement with multiple copies/gain of BCL2 or multiple copies/gain of MYC with a BCL2 rearrangement have been described and exhibit a very similar clinical course to conventional double-hit lymphomas. We report the seventh case of diffuse large B-cell lymphoma exhibiting this distinct cytogenetic abnormality and the first reported case in the skin. The patient's clinical course was aggressive, succumbing to disease 18 months after his initial presentation.

ß2-adrenergic receptor genotype and other variables that contribute to labor pain and progress.

BACKGROUND: ß2-Adrenergic receptor (ß2AR) activity influences labor. Its genotype affects the incidence of preterm delivery. We determined the effect of ß2AR genotype on term labor progress and maternal pain. METHODS: We prospectively enrolled 150 nulliparous parturients in the third trimester and obtained sensory thresholds, demographic information, and DNA. Cervical dilation, pain scores, and labor management data were extracted with associated times. The association of genetic and demographic factors with labor was tested using mixed effects models. RESULTS: Parturients who express Gln at the 27 position of the ß2AR had slower labor (P < 0.03). They progressed from 1-10 cm dilation in approximately 21 h compared with 14 h among other patients. Asian ethnicity, previously associated with slower labor, is highly associated with this polymorphism (P < 0.0001). Heavier and black patients had slower latent labor (P < 0.01, 0.01). Neuraxial analgesia was associated with slower labor progress (P < 0.0001). It could take up to 36 h for parturients who were black and/or more than median weight (165 lb) to transition from 1 cm cervical dilation to active labor. However, after this active phase began, labor rates among these patients were similar to that of other parturients. CONCLUSIONS: We detected a strong association between ß2AR genotype and slower labor. Asian ethnicity may be a proxy for ß2AR genotype. Black women and those of higher than average weight have slower latent labor. These results confirm many of the associations found when this mathematical model was applied to a large retrospective cohort, further validating this approach to description and analysis of labor progress.

Nicotine nasal spray as an adjuvant analgesic for third molar surgery.

PURPOSE: To determine the efficacy of preoperatively administered nicotine nasal spray (3 mg) for analgesia after third molar (TM) surgery. MATERIALS AND METHODS: A single-center, prospective, randomized, double-blind, crossover trial was conducted. The study population consisted of 20 nonsmoking patients referred to the Department of Oral and Maxillofacial Surgery of Columbia University College of Dental Medicine for extraction of all 4 TMs. Each patient received nicotine nasal spray or placebo spray before TM surgery. At a subsequent visit the contralateral TMs were removed with prior administration of the alternate treatment. For an hour postoperatively, subjects reported information on pain and nausea, and hemodynamic variables were recorded at 15-minute intervals. Telephone follow-up was recorded for 5 days postoperatively, where patients reported information on pain, nausea, and use of hydrocodone/acetaminophen as rescue analgesia. RESULTS: Nicotine treatment was associated with a highly significant decrease in pain reported during the 5 days after TM surgery. There was no difference in the amount of hydrocodone/acetaminophen used or amount of nausea reported. There was a small but significant increase in heart rate after nicotine treatment compared with placebo during the first hour after surgery. There was no difference in blood pressure between groups. CONCLUSION: Pain is well controlled by hydrocodone/acetaminophen in most patients after TM surgery. However, there is significant variability in pain reported. Nicotinic agonists represent a new class of analgesic that can be considered for patients who are expected to have significant opioid-resistant pain after TM surgery. Caution should be used with patients in whom a small increase in heart rate would be deleterious.

Expanding Our Understanding of Nevogenesis: Copy Number Gain of Chromosome 15q in Melanocytic Nevi Is Associated With Distinct Histomorphologic Findings.

As the landscape of melanomagenesis becomes better refined through increasingly detailed schema grounded in distinct clinicopathologic-molecular pathways, the stepwise process and variations of molecular nevogenesis have largely remained elusive. Herein, we present a series of 8 melanocytic nevi in patients ranging from 40 to 74 years of age (median: 59.5 y), which demonstrated a reproducible constellation of histomorphologic features as well as a copy number gain of the long arm of chromosome 15 (15q). The most characteristic histologic feature was sclerosis with maturation at the base of the lesion. All cases demonstrated a dome-shaped configuration and epidermal acanthosis with hyperpigmentation. However, the cytologic features ranged in their appearances from that of a banal nevus with ovoid nuclei, inconspicuous nucleoli, and minimal cytoplasm to enlarged, epithelioid forms with central nucleoli and abundant cytoplasm. No lesions showed staining with BRAF V600E or NRAS Q61R immunohistochemistry. Single-nucleotide polymorphism-based chromosome microarray analysis revealed a monoaberrant 15q gain in all cases. The histology was sufficiently distinctive in the initial 6 cases encountered to allow for prospective identification of 2 additional cases harboring a 15q gain. The clinical follow-up did not reveal recurrence in any case. Although adverse outcomes were not observed in our cohort, future studies are needed to more adequately characterize the clinical and biological behavior of these lesions.

Targeting the epichaperome as an effective precision medicine approach in a novel PML-SYK fusion acute myeloid leukemia.

The epichaperome is a new cancer target composed of hyperconnected networks of chaperome members that facilitate cell survival. Cancers with an altered chaperone configuration may be susceptible to epichaperome inhibitors. We developed a flow cytometry-based assay for evaluation and monitoring of epichaperome abundance at the single cell level, with the goal of prospectively identifying patients likely to respond to epichaperome inhibitors, to measure target engagement, and dependency during treatment. As proof of principle, we describe a patient with an unclassified myeloproliferative neoplasm harboring a novel PML-SYK fusion, who progressed to acute myeloid leukemia despite chemotherapy and allogeneic stem cell transplant. The leukemia was identified as having high epichaperome abundance. We obtained compassionate access to an investigational epichaperome inhibitor, PU-H71. After 16 doses, the patient achieved durable complete remission. These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted.

A first-order system least-squares finite element method for the Poisson-Boltzmann equation.

The Poisson-Boltzmann equation is an important tool in modeling solvent in biomolecular systems. In this article, we focus on numerical approximations to the electrostatic potential expressed in the regularized linear Poisson-Boltzmann equation. We expose the flux directly through a first-order system form of the equation. Using this formulation, we propose a system that yields a tractable least-squares finite element formulation and establish theory to support this approach. The least-squares finite element approximation naturally provides an a posteriori error estimator and we present numerical evidence in support of the method. The computational results highlight optimality in the case of adaptive mesh refinement for a variety of molecular configurations. In particular, we show promising performance for the Born ion, Fasciculin 1, methanol, and a dipole, which highlights robustness of our approach.

A transdermal nicotine patch is not effective for postoperative pain management in smokers: a pilot dose-ranging study.

BACKGROUND: Nicotine has an antinociceptive effect in animal models. The analgesic effect in humans has been examined, but studies have had mixed results. A proposed etiology is variability in chronic nicotine exposure because of differences in tobacco smoking rates and second-hand smoke exposure. In this study, we examined the postoperative analgesic effect of a transdermal nicotine patch in smokers in a parallel design to a previous study in nonsmokers. METHODS: We conducted a randomized, double-blind, prospective, placebo-controlled trial of 28 patients undergoing abdominal or pelvic surgery who required patient-controlled analgesia and an overnight hospital stay. Before anesthetic induction, a transdermal nicotine patch was applied (0, 5, 10, or 15 mg). The primary outcome variable was postoperative pain reported over the first hour and over the next 5 days using a standard numerical rating scale. Secondary outcome variables were pain medication use, hemodynamic values, nausea, and sedation. RESULTS: Patients treated with nicotine reported higher pain scores than those treated with placebo over the first hour after surgery (P < 0.01, average numerical rating scale increase = 0.67) and there was no difference between groups in the subsequent 5 days (P > 0.05). There was no significant dose effect. Diastolic blood pressure in the first hour was higher in the placebo group compared with the nicotine-treated group (P < 0.01, average increase = 11 mm Hg). There was no difference in nausea or sedation. CONCLUSIONS: Transdermal nicotine, 5-15 mg, failed to relieve postoperative pain or reduce opioid use in smokers.

Linear scleroderma "en coup de sabre" with extensive brain involvement-Clinicopathologic correlations and response to anti-Interleukin-6 therapy.

Linear scleroderma "en coup de sabre" (LSES) variant is a cephalic subtype of localized scleroderma that can be associated with extracutaneous stigmata, such as epilepsy, dementia syndromes, as well as focal central nervous system neurologic deficits. While the pathophysiology of cutaneous linear scleroderma includes endothelial cell injury and up regulation of pro-fibrogenic pathways, the basis of LSES-associated neurologic complications is largely unknown. We report a patient with a history of LSES who developed intractable epilepsy and cognitive decline. Magnetic resonance imaging (MRI) of the brain exhibited numerous persistently enhancing brain lesions. Due to progressive neurologic deterioration over a period of 7 years, despite interventional therapy, a brain biopsy was performed. Neuropathologic analysis exhibited acute and chronic cortical ischemia associated with a small vessel lymphocytic vasculitis. Direct immunofluorescent studies showed C5b-9 and IgG deposition on endothelium while indirect immunofluorescent studies demonstrated reactivity of the patient's serum with the microvasculature of the patient's own brain tissue and generic human umbilical vein endothelial cells indicative of anti-endothelial cell antibodies. Therapy focusing on damaged endothelium was implemented. The interleukin-6 (IL-6) receptor inhibitor tocilizumab was used and the patient improved dramatically, likely reflecting the drug's effect on the replenishment of endothelial progenitor cells.