Cutaneous Involvement by Mantle Cell Lymphoma: Expanding the Spectrum of Histopathologic Findings in a Series of 9 Cases.

Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm with cutaneous involvement in ∼1% of cases. We present a single institutional series of nine patients (12 specimens) with cutaneous involvement by systemic MCL and review the clinicopathologic features. Six males and 3 females (age range 55-87 years) were included. Sites of involvement were head and neck (n = 3), trunk (n = 5), and extremities (n = 4). Histopathologically, 3 showed classic cytomorphology, 2 were blastoid, 3 pleomorphic, and 1 showed features resembling marginal zone lymphoma. Two cases presented with cutaneous lesions as the first tissue manifestation of the disease. A second malignancy was identified in 3/9 cases (2 melanomas and 1 papillary thyroid carcinoma). In one patient, MCL was juxtaposed with metastatic melanoma within the same biopsy specimen. Fluorescence in situ hybridization studies, when available, demonstrated the characteristic t(11,14) translocation. Direct immunofluorescence was performed on one case and showed immunoglobulin M (IgM) expression on the tumor cells. Follow-up was available in 7 cases (mean 42 months, range 6-78 months) and revealed death from disease for 6 patients that occurred within 1 week to 11 months (mean 4 months) after cutaneous involvement. In our series, 6/9 cases demonstrated blastoid, pleomorphic, or marginal zone lymphoma-like morphologies that could potentially mimic other hematolymphoid neoplasms. MCL may show surface IgM expression on DIF or may occur in association with other solid tumors. Immunohistochemistry for cyclin D1 and/or SOX-11 may be helpful for diagnosis, and imaging studies may be necessary to detect systemic involvement when cutaneous involvement is the first manifestation of the disease.

Lobular neutrophilic panniculitis associated with DNA methyltransferase inhibitors in the treatment of myeloid disease.

Cutaneous toxicities to DNA methyltransferase inhibitors are variable and include localized injection site reactions, ecchymoses, maculopapular eruptions, and neutrophilic dermatoses including pyoderma gangrenosum, Sweet syndrome, and neutrophilic eccrine hidradenitis. This series describes two patients diagnosed with lobular neutrophilic panniculitis arising during treatment of acute myelogenous leukemia with "hypomethylating drugs," including the first report of its occurrence with a next-generation agent. Differential diagnoses, histopathologic characteristics, treatment considerations, and proposed pathogenesis will be discussed.

Detection of Borrelia in Ixodes scapularis ticks by silver stain, immunohistochemical and direct immunofluorescent methods.

BACKGROUND: Lyme disease (LD) is one of the most common tick-borne diseases caused by several Borrelia species of spirochetes. Ixodes scapularis is responsible for the transmission of LD in the northeastern United States. The rate of infection varies with the duration of tick attachment to the host; however, this information may be unknown. In skin biopsies, it is often difficult to identify spirochetes. Testing of ticks is not routinely performed. Treatment is established by clinical presentation. OBJECTIVE: To test paraffin-embedded I. scapularis ticks for Borrelia by different methods. MATERIALS/METHODS: We examined 20 paraffin-embedded ticks by silver stain, immunohistochemical (IHC) and direct immunofluorescent (DIF) methods and compared the percentage of positivity with DIF results from the Connecticut Agricultural Experiment Station. RESULTS: The results were similar by DIF, which proved to be the most sensitive method, followed by the silver stain and IHC. CONCLUSION: We found that the identification of spirochetes in paraffin-embedded ticks was less difficult than in tissue with a comparable turnaround time to that of a routine biopsy. Timely identification of Borrelia in ticks may influence the clinical management of the patients.

How to take better photomicrographs: A step-wise approach.

The objective of our study was to establish a detailed photomicrographing protocol for pathologists and dermatopathologists using standard overhead camera and image editing packages. Through a trial-and-error approach we devised a series of steps that comprise our photomicrographing protocol. Descriptive and interpretive data analyses were performed to highlight how each step improves tinctorial quality of digital photomicrographs.

Well-differentiated neuroendocrine tumors in skin: Terminology and diagnostic utility of cytokeratin 5/6 and p63.

BACKGROUND: Well-differentiated neuroendocrine tumors (WDNETs) in skin include metastases from visceral primary sites and very uncommonly, primary cutaneous carcinoid tumors. Cutaneous WDNET may present a diagnostic challenge and in particular can be mistaken for a benign skin adnexal tumor. In contrast to cutaneous adnexal tumors, metastatic adenocarcinomas to the skin are cytokeratin 5/6 (CK5/6) and p63 negative in the majority of cases. It is unclear if failure to stain with CK5/6 and p63 would be helpful in differentiating WDNETs from cutaneous adnexal neoplasms. METHODS: We reviewed 10 cases of cutaneous WDNETs (8 cases of metastatic disease and 2 presumed primary carcinoid tumors of the skin) and performed immunohistochemical stains for CK5/6 and p63 on all cases. RESULTS: All 10 cases were negative with both CK5/6 and p63. CONCLUSION: Negative staining for CK5/6 and p63 can be helpful to distinguish WDNETs from cutaneous adnexal neoplasms. It is important to consider WDNETs in the differential diagnosis of cutaneous adnexal neoplasms as low-grade tumors may be the first sign of aggressive metastatic disease.

Diagnosing nephrogenic systemic fibrosis in the post-FDA restriction era.

The emergence of an association between gadolinium-based contrast agents (GBCA) and the rare condition nephrogenic systemic fibrosis (NSF) led to a warning in 2006 from the Food and Drug Administration (FDA) restricting the use of the GBCAs to patients with an estimated glomerular filtration rate of >30 mL/min/1.73m(2) . We discuss our experience with a post-FDA restriction presentation of NSF and subsequent patient death in which the prolonged lead-time of ∼5.5 years led to challenges in ensuring a secure diagnosis of NSF and establishing risk exposures. Accurate contemporary records of contrast administration and clinical factors alongside clinical and pathological expertise ensured that we were able to confidently diagnose NSF, despite the length of lead time and confounding factors.

Pediatric nephrogenic systemic fibrosis is rarely reported: a RADAR report.

BACKGROUND: Nephrogenic systemic fibrosis is a fibrosing disorder associated with exposure to gadolinium-based contrast agents in people with severely compromised renal function. OBJECTIVE: The purpose of this study was to determine the reported number of cases of nephrogenic systemic fibrosis in children using three distinct publicly available data sources. MATERIALS AND METHODS: We conducted systematic searches of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), the International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR) registry and published literature from January 1997 through September 2012. We contacted authors of individual published cases to obtain follow-up data. Data sets were cross-referenced to eliminate duplicate reporting. RESULTS: We identified 23 children with nephrogenic systemic fibrosis. Seventeen had documented exposure to gadolinium-based contrast agents. Six children had been reported in both the FAERS and the literature, four in the FAERS and the ICNSFR registry and five in all three data sources. CONCLUSION: Nephrogenic systemic fibrosis has been rarely reported in children. Although rules related to confidentiality limit the ability to reconcile reports, active pharmaco-vigilance using RADAR (Research on Adverse Drug events And Reports) methodology helped in establishing the number of individual pediatric cases within the three major data sources.

Case experience of 308-nm excimer laser therapy compatibility with PUVA and oral bexarotene for the treatment of cutaneous lesions in mycosis fungoides.

Little is known about the safety and effectiveness of excimer laser therapy when used in conjunction with other therapies in the treatment of mycosis fungoides (MF) lesions. We describe the use of adjunctive excimer laser therapy in combination with psoralen plus ultraviolet A (PUVA) and oral bexarotene for the treatment of recalcitrant and sanctuary plaques in a patient with MF. In our patient, this regimen successfully induced clinical and histologic resolution in MF plaques with minimal side effects limited to mild, short-lived tenderness and, rarely, local erythema. Our experience suggests that adjunctive excimer laser therapy with PUVA and oral bexarotene has the potential to be a safe, well-tolerated, and effective focal treatment regimen for cutaneous MF lesions.

Linking drugs to obscure illnesses: lessons from pure red cell aplasia, nephrogenic systemic fibrosis, and Reye's syndrome. a report from the Southern Network on Adverse Reactions (SONAR).

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Mycosis fungoides exhibiting features of a dermatofibroma: a case report and review of the literature.

We present the case of a 60-year-old male with known stage IA mycosis fungoides (MF) who developed a suspicious tumor within a pre-existing lymphomatous plaque of the right forearm. Microscopy revealed an unusual mixed fibrohistiocytic proliferation as well as atypical intraepidermal and dermal lymphocytes. There was no evidence of large-cell transformation. Histopathological, immunohistochemical and clinical clues suggest this lesion might not have represented a dermatofibroma, but rather a hitherto unreported dermatofibroma-like process arising within a lesion of MF. The potential impact of this atypical lesion on the prognosis and clinical management of this patient highlights the importance of recognizing unusual clinical presentations of more common, benign lesions within this patient population.

Renal transplantation for nephrogenic systemic fibrosis: a case report and review of the literature.

Nephrogenic systemic fibrosis (NSF) is a rare fibrosing disorder described among patients with renal disease. Currently, no standard therapy exists, although therapeutic modalities have included plasmapheresis, extracorporeal photopheresis, sodium thiosulphate, imatinib and renal transplantation. We describe a patient with NSF who was physically debilitated and underwent renal transplantation. After transplantation, the patient's lesions improved clinically, and the patient was ambulatory. Despite developing worsening renal function, her lesions remained unchanged. We conclude that renal transplantation improves symptoms of NSF, and believe that in patients with NSF, careful consideration should be made for early renal transplantation.

Nephrogenic systemic fibrosis: clinicopathological definition and workup recommendations.

BACKGROUND: The condition that came to be known as nephrogenic systemic fibrosis (NSF) was first reported in 2000 and, in 2001, was termed "nephrogenic fibrosing dermopathy." Since then, NSF has been the subject of a wide-ranging multidisciplinary medical investigation that has proven an indisputable link to renal disease and a compelling association with the increasing use of gadolinium-containing magnetic resonance imaging contrast agents in the renally impaired. OBJECTIVE: Although precise causation and risk factors continue to be elucidated, the need for reproducible prospective epidemiologic data demands clear and objective criteria for the diagnosis of NSF. METHODS: Experts in NSF diagnosis used their experience and the resources of the Yale International NSF Registry to develop a clinicopathological diagnostic system for NSF. RESULTS: A consensus scoring system incorporating a clinical and histopathological atlas was devised to guide and standardize the evaluation and diagnosis of NSF. LIMITATIONS: There is no laboratory test that can be used as a gold standard to diagnose NSF. To overcome this, we relied on classic clinicopathological presentations, published sources, and consensus clinical expertise to ensure the integrity of the study population. CONCLUSION: The clinicopathological definition of NSF provides guidance to physicians for the evaluation and diagnosis of NSF. Clinical, laboratory, and histopathological features comprise a schema that excludes conditions mimicking NSF while facilitating its reproducible and accurate diagnosis, even among physicians with little prior clinical experience with this entity. This definition can serve as a working diagnostic standard for future research and as the basis for adjudicating borderline cases.

Morphea after Borrelia-induced facial nerve palsy.

Morphea, also known as localized scleroderma, is characterized by inflammation and fibrosis of the skin. The exact pathogenesis of morphea is unknown, but generally includes genetic predisposition to autoimmunity combined with an environmental insult. Previous cases have been associated with active Borrelia infection; however, Borrelia infection as a direct cause of morphea was not generalizable to most patients. Within endemic areas, Borrelia burgdorferi is the most common cause of facial nerve paralysis, another autoimmune phenomenon. We report a case of facial morphea in a young man with family history of autoimmune disease who developed morphea in the same location as two previous episodes of Borrelia-induced facial nerve palsy. This case is remarkable because it suggests Borrelia burgdorferi induced loss of local immune tolerance to host antigens, first with facial nerve palsy and followed years later by development of morphea.

What's Eating You? Caterpillars.

Caterpillar envenomation is a worldwide problem, with manifestations ranging from dermatitis to iridocyclitis and a fatal hemorrhagic diathesis. This article focuses on the diagnosis and management of dermatoses related to caterpillars.

Squamoid eccrine ductal carcinoma: a case report and review of the literature.

Eccrine ductal carcinoma is a rare adnexal tumor. Squamoid eccrine ductal carcinoma (SEDC) represents an exceptionally rare variant with only 6 cases reported to date. This neoplasm is deeply infiltrative and may provide a diagnostic challenge in superficial shave biopsies of skin. We present a case of SEDC in an immunocompromised patient, who, after an initial shave biopsy for diagnostic purposes, underwent a complete excision of his tumor by Mohs micrographic surgery. A combined histologic and immunohistochemical approach is necessary to identify and confirm the unique characteristics of SEDC. Because this cancer is very rare and little is known about its biologic behavior, optimal diagnostic and treatment guidelines need to be developed.

High-throughput quantitative histology in systemic sclerosis skin disease using computer vision.

BACKGROUND: Skin fibrosis is the clinical hallmark of systemic sclerosis (SSc), where collagen deposition and remodeling of the dermis occur over time. The most widely used outcome measure in SSc clinical trials is the modified Rodnan skin score (mRSS), which is a semi-quantitative assessment of skin stiffness at seventeen body sites. However, the mRSS is confounded by obesity, edema, and high inter-rater variability. In order to develop a new histopathological outcome measure for SSc, we applied a computer vision technology called a deep neural network (DNN) to stained sections of SSc skin. We tested the hypotheses that DNN analysis could reliably assess mRSS and discriminate SSc from normal skin. METHODS: We analyzed biopsies from two independent (primary and secondary) cohorts. One investigator performed mRSS assessments and forearm biopsies, and trichrome-stained biopsy sections were photomicrographed. We used the AlexNet DNN to generate a numerical signature of 4096 quantitative image features (QIFs) for 100 randomly selected dermal image patches/biopsy. In the primary cohort, we used principal components analysis (PCA) to summarize the QIFs into a Biopsy Score for comparison with mRSS. In the secondary cohort, using QIF signatures as the input, we fit a logistic regression model to discriminate between SSc vs. control biopsy, and a linear regression model to estimate mRSS, yielding Diagnostic Scores and Fibrosis Scores, respectively. We determined the correlation between Fibrosis Scores and the published Scleroderma Skin Severity Score (4S) and between Fibrosis Scores and longitudinal changes in mRSS on a per patient basis. RESULTS: In the primary cohort (n = 6, 26 SSc biopsies), Biopsy Scores significantly correlated with mRSS (R = 0.55, p = 0.01). In the secondary cohort (n = 60 SSc and 16 controls, 164 biopsies; divided into 70% training and 30% test sets), the Diagnostic Score was significantly associated with SSc-status (misclassification rate = 1.9% [training], 6.6% [test]), and the Fibrosis Score significantly correlated with mRSS (R = 0.70 [training], 0.55 [test]). The DNN-derived Fibrosis Score significantly correlated with 4S (R = 0.69, p = 3 × 10- 17). CONCLUSIONS: DNN analysis of SSc biopsies is an unbiased, quantitative, and reproducible outcome that is associated with validated SSc outcomes.

Gadolinium-containing magnetic resonance image contrast agent promotes fibrocyte differentiation.

Gadolinium-containing magnetic resonance imaging (MRI) contrast agents such as Omniscan are associated with nephrogenic systemic fibrosis (NSF). To determine if Omniscan can affect the differentiation of monocytes into fibroblast-like cells called fibrocytes that are found in the fibrotic lesions of NSF, peripheral blood mononuclear cells (PBMCs) from NSF patients, hemodialysis patients without NSF, and healthy, renally sufficient controls were exposed to Omniscan in a standardized in vitro fibrocyte differentiation protocol. When added to PBMCs, the gadolinium-containing MRI contrast agent Omniscan generally had little effect on fibrocyte differentiation. However, 10(-8) to 10(-3) mg/mL Omniscan reduced the ability of the fibrocyte differentiation inhibitor serum amyloid P (SAP) to decrease fibrocyte differentiation in PBMCs from 15 of 17 healthy controls and one of three NSF patients. Omniscan reduced the ability of SAP to decrease fibrocyte differentiation from purified monocytes, indicating that the Omniscan effect does not require the presence of other cells (such as T cells) in the PBMCs. Omniscan also reduced the ability of a different fibrocyte differentiation inhibitor, interleukin-12, to decrease fibrocyte differentiation. These data suggest that Omniscan interferes with the regulatory action of signals that inhibit the differentiation of monocytes to fibrocytes. J. Magn. Reson. Imaging 2009;30:1284-1288. (c) 2009 Wiley-Liss, Inc.

Pathology of spontaneous and immunotherapy-induced tumor regression in a murine model of melanoma.

We evaluated the spontaneous and immunotherapy-induced histological changes in the tumor microenvironment of a mouse melanoma regression model consisting of immunocompetent C57BL/6J mice implanted with syngeneic YUMMER1.7 melanoma cells. We focused on tumor regression phenotypes and spatial relationships of melanoma cells with B cells and neutrophils since this was not previously described. We found common themes to the host response to cancer irrespective of the mode of tumor regression. In nonregression tumors, melanoma cells were epithelioid shaped and tightly packed. In regression tumors, melanoma cells were spindle shaped and discohesive. B cells including plasmablasts and plasma cells were numerous and were increased with immunotherapy. Neutrophils were in direct contact with dead or dying melanoma cells. Immunotherapy increased neutrophil counts and induced neutrophil extracellular traps (NETs)-like formations and geographic necrosis. Beyond tumor regression, the increase in the B cell and neutrophil response could play a role in immunotherapy-induced adverse reactions.