David P. Arps

Lupus Profundus (Panniculitis) A Potential Mimic of Subcutaneous Panniculitis-like T-Cell Lymphoma

Lupus profundus is a rare manifestation of cutaneous lupus erythematosus, seen in 1% to 3% of patients. It most commonly presents in association with classic chronic cutaneous lesions of discoid lupus erythematosus; however, such lesions, as well as a clinical history of lupus erythematosus, may be lacking. The differential diagnosis for lymphocytic lobular panniculitides is broad; however, the consideration of subcutaneous panniculitis-like T-cell lymphoma is most critical. Recently, there have been several reports emphasizing the overlapping histomorphologic features between lupus profundus and subcutaneous panniculitis-like T-cell lymphoma. Although this is controversial, some authors suggest that patients with lupus profundus are at risk for the development of abnormal, clonal T-cell proliferations and/or overt subcutaneous panniculitis-like T-cell lymphoma. In cases of atypical lymphocytic lobular panniculitis that fail to meet diagnostic criteria for subcutaneous panniculitis-like T-cell lymphoma, patients should be clinically followed indefinitely, as future subcutaneous lymphoma cannot be excluded.

Classic versus type II enteropathy-associated T-cell lymphoma: diagnostic considerations.

Enteropathy-associated T-cell lymphoma is a rare type of peripheral T-cell lymphoma that characteristically involves the jejunum or ileum. Awareness of the histologic and immunophenotypic features of this subtype of lymphoma is important for accurate subclassification. Enteropathy-associated T-cell lymphoma has 2 forms, classic and type II, with different clinical and pathologic features. The 2 types will be described and discussed, with an emphasis on how to differentiate these entities in routine practice.

Using Two‐Component Systems and Other Bacterial Regulatory Factors for the Fabrication of Synthetic Genetic Devices

Synthetic biology is an emerging field in which the procedures and methods of engineering are extended living organisms, with the long-term goal of producing novel cell types that aid human society. For example, engineered cell types may sense a particular environment and express gene products that serve as an indicator of that environment or affect a change in that environment. While we are still some way from producing cells with significant practical applications, the immediate goals of synthetic biology are to develop a quantitative understanding of genetic circuitry and its interactions with the environment and to develop modular genetic circuitry derived from standard, interoperable parts that can be introduced into cells and result in some desired input/output function. Using an engineering approach, the input/output function of each modular element is characterized independently, providing a toolkit of elements that can be linked in different ways to provide various circuit topologies. The principle of modularity, yet largely unproven for biological systems, suggests that modules will function appropriately based on their design characteristics when combined into larger synthetic genetic devices. This modularity concept is similar to that used to develop large computer programs, where independent software modules can be independently developed and later combined into the final program. This chapter begins by pointing out the potential usefulness of two-component signal transduction systems for synthetic biology applications and describes our use of the Escherichia coli NRI/NRII (NtrC/NtrB) two-component system for the construction of a synthetic genetic oscillator and toggle switch for E. coli. Procedures for conducting measurements of oscillatory behavior and toggle switch behavior of these synthetic genetic devices are described. It then presents a brief overview of device fabrication strategy and tactics and presents a useful vector system for the construction of synthetic genetic modules and positioning these modules onto the bacterial chromosome in defined locations.

Cutaneous Hypertrophic Lupus Erythematosus: A Challenging Histopathologic Diagnosis in the Absence of Clinical Information

Hypertrophic lupus erythematosus (HLE) is rare variant of chronic cutaneous lupus characterized histologically by irregular epidermal hyperplasia associated with features of classic chronic cutaneous lupus, including interface changes. Lesions frequently demonstrate reactive squamous atypia of the basal layer and may show histopathologic overlap with other more common cutaneous atypical squamoproliferative lesions. Typical histologic features of cutaneous lupus, such as follicular plugging, angiocentric lymphocytic inflammation, and dermal mucin, are very helpful clues to the diagnosis of hypertrophic lupus erythematosus. Recently, immunohistochemistry for CD123 used to detect increased plasmacytoid dendrocytes in hypertrophic lupus erythematosus has proven to be diagnostically useful. A high index of suspicion for hypertrophic lupus erythematosus is essential to avoid overdiagnosis of squamous neoplasia, particularly in limited cutaneous biopsies in the absence of adequate clinical information.

Primary cutaneous cribriform carcinoma: report of six cases with clinicopathologic data and immunohistochemical profile

Primary cutaneous cribriform carcinoma (PCCC) is a rare and under‐recognized variant of sweat gland carcinoma, characterized by anastomosing tubules and solid nests producing a sieve‐like appearance.

Selected Inflammatory Imitators of Mycosis Fungoides: Histologic Features and Utility of Ancillary Studies

Mycosis fungoides is the most common primary cutaneous lymphoma; however, it remains a significant diagnostic challenge, in part because of the overlap with several inflammatory dermatoses. Despite advances in immunohistochemistry and molecular diagnostics, false-positive, false-negative, and indeterminate diagnoses are not uncommon. In most cases, the overall balance of morphologic, immunophenotypic, and genetic features must be considered carefully because there are few sensitive and specific clues to the diagnosis. Moreover, an appropriate clinical presentation is essential to the diagnosis and helps to favor or exclude inflammatory/reactive processes. Herein, we discuss 3 important inflammatory dermatoses that may closely simulate mycosis fungoides, and we review the use of ancillary studies in these challenging cases.

Porocarcinomas harbor recurrent HRAS-activating mutations and tumor suppressor inactivating mutations.

Porocarcinomas are a rare eccrine carcinoma with significant metastatic potential. Oncogenic drivers of porocarcinomas have been underexplored, with PIK3CA-activating mutation reported in 1 case. We analyzed 5 porocarcinomas by next-generation sequencing using the DNA component of the Oncomine Comprehensive Assay, which provides data on copy number changes and mutational events in 126 cancer-relevant genes through multiplex polymerase chain reaction. We detected an average of 3.3 high-confidence nonsynonymous mutations per tumor (range, 1-6), including a spectrum of oncogenic activation and tumor suppressor inactivation events. Tumor suppressor mutations included TP53 (4/5, 80%), RB1 (3/5, 60%), ATM (2/5, 40%), ARID1A (1/5, 20%), and CDKN2A (1/5, 20%). In 4 (80%) of 5 tumors, at least 1 potential oncogenic driver was identified. Activating HRAS mutations were detected in 2 (40%) of 5, including G13D and Q61L hotspot mutations. Mutations of EGFR were identified in 2 (40%) of 5; these mutations have been previously reported in cancer but did not affect classic activation hotspot sites. EGFR and HRAS mutations were mutually exclusive. HRAS mutations were detected by targeted sequencing in a minority of benign eccrine poromas (2/17; 11.7%), suggesting that HRAS activation may rarely be an early event in sweat gland neoplasia. Together, our data suggest roles for HRAS and EGFR as drivers in a subset of poroma and porocarcinoma. TP53 and RB1 inactivation events are also likely to contribute to tumorigenesis. These findings suggest that porocarcinomas display diversity with respect to oncogenic drivers, which may have implications for targeted therapy in metastatic or unresectable cases.

Expression of the p40 isoform of p63 has high specificity for cutaneous sarcomatoid squamous cell carcinoma.

Cutaneous spindle cell malignancies such as sarcomatoid squamous cell carcinoma (SCC), leiomyosarcoma, desmoplastic melanoma (DM) and atypical fibroxanthoma (AFX) may be morphologically indistinguishable, yet accurate diagnosis is important for appropriate clinical management. The distinction among these entities relies on immunohistochemical evaluation for epidermal, muscle or melanocytic differentiation. Epidermal differentiation markers include cytokeratins and p63. p63 is expressed as two distinct isoforms, ΔNp63 (p40) and TAp63. p40 positivity is highly specific for pulmonary SCC and head and neck sarcomatoid SCC. We examined the utility of p40 vs. p63 immunostaining in the differentiation of a variety of cutaneous spindle cell malignancies, including sarcomatoid SCC (n = 27), AFX (n = 34) and DM (n = 10). p40 was less sensitive than p63 for detecting sarcomatoid SCC (56% and 81%, respectively). p63 and p40 were comparably specific for sarcomatoid SCC relative to AFX, with only rare weak staining of tumor cells for p63 and/or p40 in a minority of AFX cases, including one case with approximately 10% of cells staining weakly for p40. All cases of DM were negative for p40 and p63. Our results support continued use of p63 for diagnosis of cutaneous sarcomatoid SCC because of greater sensitivity relative to p40.

A Synthetic Biology Approach to Understanding Biological Oscillations: Developing a Genetic Oscillator for Escherichia coli

Our goals are to construct a simple genetic clock that will stably oscillate in Escherichia coli and to identify the design principles and parameters responsible for oscillations. We previously described a simple genetic circuit of linked activator and repressor operons that produced damped oscillations. Here, we altered the repression of the activator operon and identified an oscillator that produces improved oscillations over our initial system. We also explored mathematical models of the oscillator. Toy models were used to investigate the behaviors that may be obtained from our clock circuitry. Depending on parameters, the circuitry produced a wide array of oscillatory systems, including sinusoidal and relaxation oscillators. We also attempted to explicitly model all known interactions that affect the oscillator, producing a 32-dimensional ODE model. This model can produce results similar to those obtained in experiments, and we have begun attempts to fit experimental data to the model.

Atypical umbilical naevi: histopathological analysis of 20 cases†

Melanocytic naevi on the umbilicus have been described as a form of flexural naevi, with the most common feature being a ‘nested and dyshesive pattern’. We have encountered a distinct group of umbilical naevi with more significant atypia and prominent fibrosis, not reported previously. This study aimed to characterize these naevi more clearly.