Null T-cell phenotype mycosis fungoides with aberrant CD20 and CD56 expression: A diagnostic dilemma.

Mycosis fungoides (MF) represents the most common type of primary cutaneous T-cell lymphoma. Recognition of MF variants with divergent immunophenotypes is important for accurate diagnosis and appropriate management, as they can be confused with other lymphoma subtypes. We present a case of a 49-year-old male previously diagnosed with a cutaneous lymphoproliferative disorder with an unusual NK/T-cell phenotype. He presented with a 10-year history of pelvic girdle rash involving the right hip and upper thigh. The lesions were characterized as atrophic patches concentrated in sun-protected areas and involving 10% of the body surface area. Shave biopsies revealed an atypical epidermotropic infiltrate composed of hyperchromatic small to medium-sized lymphocytes with perinuclear halos and "tagging" along the dermal-epidermal junction. The immunophenotype was unusual in that the neoplastic lymphocytes showed complete loss of pan T-cell antigens along with expression of CD56, cytotoxic markers, and weak CD20. All other B-cell markers were negative. The combination of clinical findings, in addition to the histopathologic and immunophenotypic profile, were diagnostic of null T-cell phenotype MF with aberrant expression of CD56 and CD20. Null T-cell phenotype MF is very uncommon, can be diagnostically challenging, and can mislead the diagnosis of aggressive lymphoma subtypes.

A Severe Presentation of Plasma Cell Cheilitis.

Plasma cell cheilitis (PCC) is an uncommon condition characterized by mature plasma cell infiltration of the dermis of the mucosal lip. The condition often presents as a red-brown patch or plaque on the lower lip in older individuals that can progress to erosions and edema. Diagnosis can be delayed because clinical findings are nonspecific and can mimic neoplastic, infectious, and inflammatory conditions. We describe a patient with PCC who presented to our institution via teledermatology. Findings were equivocal on 2 early biopsies until the presentation evolved to dramatic ulceration and necrosis, which prompted a third biopsy that was diagnostic for PCC. Empiric therapy with a class I topical corticosteroid was successful.

Clinical validity of a gene expression signature in diagnostically uncertain neoplasms.

Aim: Evaluate the accuracy of a 23-gene expression signature in differentiating benign nevi from melanoma by comparing test results with clinical outcomes. Materials & methods: Seven dermatopathologists blinded to gene expression test results and clinical outcomes examined 181 lesions to identify diagnostically uncertain cases. Participants independently recorded diagnoses and responses to questions quantifying diagnostic certainty. Test accuracy was determined through comparison with clinical outcomes (sensitivity and percent negative agreement). Results: Overall, 125 cases fulfilled criteria for diagnostic uncertainty (69.1%; 95% CI: 61.8-75.7%). Test sensitivity and percent negative agreement in these cases were 90.4% (95% CI: 79.0-96.8%) and 95.5% (95% CI: 87.3-99.1%), respectively. Conclusion: The 23-gene expression signature has high diagnostic accuracy in diagnostically uncertain cases when evaluated against clinical outcomes.

Immunohistochemistry utilization in the diagnosis of melanoma.

BACKGROUND: The use of immunohistochemical (IHC) stains in dermatopathology is commonplace; however, little is known regarding utilization trends in melanoma diagnosis. Current Medicare local coverage determinations (LCDs) state that most pigmented lesions, including melanoma, can be diagnosed using H&E alone. METHODS: Histopathology reports for all biopsy-proven melanomas excised between January 1, 2017 and June 30, 2018, at a single dermatology clinic, were identified with the following parameters abstracted: laboratory/dermatopathologist rendering the diagnosis, whether IHC was performed, type/number of stains utilized, presence/depth of invasion, and melanoma subtype. The association of characteristics with IHC utilization was evaluated using χ2 test for categorical variables. RESULTS: Three hundred and fifty six eligible melanomas were identified. IHC was employed in 228 (64%) of the diagnoses. Invasive melanoma was diagnosed in 199 cases (55.9%) while 157 (44.1%) were identified as melanoma in situ (MIS). Of the 228 that utilized IHC, 117 were performed on invasive melanoma (58.8%) and 111 were performed on MIS (70.7%). CONCLUSION: Our findings suggest a higher IHC usage for the diagnosis of melanoma than previously reported. Existing LCDs regarding IHC utilization in melanoma do not reflect the current state of practice. Further investigation regarding IHC utilization and the development of appropriate-use criteria for melanoma IHC is necessary.

Loss of TP63 Promotes the Metastasis of Head and Neck Squamous Cell Carcinoma by Activating MAPK and STAT3 Signaling.

TP63 is frequently amplified or overexpressed in primary head and neck squamous cell carcinomas (HNSCC). Nevertheless, the role of TP63 in the initiation and progression of HNSCCs is not known. Using archival HNSCC tissue sections, we found that TP63 expression is often downregulated in late-stage human HNSCCs. To establish a causal link between TP63 loss and HNSCC tumorigenesis, we developed a genetically engineered mouse model in which Trp63 (the mouse homolog of human TP63) was ablated from head and neck epithelia. Upon exposure of the mice to a chemical carcinogen, we found that Trp63 ablation accelerated HNSCC initiation and progression. To determine whether these findings are relevant for human HNSCCs, we generated TP63 knockdown HNSCC cell lines. These cells were implanted into the tongue of athymic nude mice to generate orthotopic xenografts. We found that loss of TP63 promoted HNSCC progression and metastasis. Furthermore, we determined that tumor metastasis is dependent on MAPK activation in TP63 knockdown HNSCCs. The significance of these findings is underscored by our finding that pharmacologic inhibition of MAPK activity by trametinib drastically impaired HNSCC metastasis mediated by TP63 loss. In conclusion, our data provide novel mechanistic insights into the role of TP63 loss in HNSCC initiation and progression, and provide a rationale for the development of new therapeutic approaches specifically targeting TP63-dependent tumor pathways. IMPLICATIONS: Our findings uncover a novel functional role for TP63 loss in HNSCC metastasis and identify MAPK signaling as a potential therapeutic target for treating HNSCCs with low TP63 expression.

The difficulty in interpreting gene expression profiling in BAP-negative melanocytic tumors.

BACKGROUND: BAP-negative melanocytic tumors were unrecognized in the medical literature until 2011. While the clinical significance of these tumors is poorly understood, there is concern such lesions represent processes in transition, and malignant degeneration is a concern. We investigated use of a 23-gene expression profiling (23-GEP) test for distinction from melanoma with the aim of better characterizing the biologic potential of such tumors. METHODS: Twenty BAP-negative melanocytic tumors, subjected to 23-GEP (Myriad Genetic Laboratories, Inc. [Salt Lake City, Utah]) testing, were retrospectively analyzed. RESULTS: Tumors exhibited varying degrees of atypia and aberrant immunohistochemical profiles. 23-GEP testing revealed a "malignant" genetic signature in four cases, a "benign" signature in 15 cases, and an "indeterminate" signature in one case. Array-based comparative genomic hybridization (aCGH) testing was performed for two cases with a "malignant" 23-GEP signature, but the aCGH result conflicted with 23-GEP, and supported benignity. Conversely, in one case with a "benign" 23-GEP result, aCGH testing supported assessment as melanoma. Moreover, evolving melanoma could not be wholly excluded by histopathological analysis in 2 "benign" cases. CONCLUSIONS: BAP-negative melanocytic tumors remain a diagnostic dilemma for dermatopathologists. A widely marketed 23-GEP test may not be useful in distinguishing these tumors from spitzoid melanoma, at least in comparison to aCGH technology.

Detection of Genetic Aberrations in the Assessment and Prognosis of Melanoma.

The assessment of melanoma by light microscopy with hematoxylin-eosin staining remains an often subjective process. However, there are additional diagnostic measures that may be of utility, such as immunohistochemical staining and genetic evaluation. Adjunctive genetic assessment to augment the diagnosis of melanoma includes comparative genomic hybridization or fluorescent in situ hybridization to assess for gains or losses in genetic material, or gene expression profiling in some form, to ascertain the expression of genes associated with malignancy. Although these techniques may bolster the dermatopathologic assessment of melanoma, none of them, at the present time, are singularly diagnostic. Additional developments in the genetic assessment and prognostication of melanoma are anticipated.

Integrating Skin Cancer-Related Technologies into Clinical Practice.

Early diagnosis and treatment of melanoma improve survival. New technologies are emerging that may augment the diagnosis, assessment, and management of melanoma but penetrance into everyday practice is low. In the current health care climate, greater emphasis will be placed on the incorporation of technology for clinically suspicious pigmented lesions to facilitate better, more cost-effective management.

Fulminant Mycosis Fungoides with Tissue Eosinophilia: A Unique Presentation of Two Cases with Acro-Periorbital Ulceration and An Aggressive Clinical Course.

We describe two unique cases of fulminant mycosis fungoides with remarkably similar and aggressive clinical courses resulting in death. Both cases demonstrated ulcerated palmar and periorbital plaques and marked tissue eosinophilia, which was confirmed by T-cell receptor γ chain gene rearrangement studies to display identical monoclonality at temporally and anatomically distinct sites. Dense eosinophilic infiltrates on biopsy led to misdiagnosis of inflammatory dermatoses in both instances. While mycosis fungoides may be challenging to diagnose histologically, the presence of eosinophils in progressive disease may herald a poor prognosis and should not exclude the diagnosis.

Histopathologic Distinguishing Features Between Lupus and Lichenoid Keratosis on the Face.

BACKGROUND: The occurrence of lichenoid keratosis (LK) on the face is not well characterized, and the histopathologic distinction between LK and lupus erythematosus (LE) occurring on the face is often indeterminate. The authors aimed to describe differences between LE and LK occurring on the face by hematoxylin and eosin alone. METHODS: Cases of LK and LE were obtained using computer-driven queries. Clinical correlation was obtained for each lupus case. Other diagnoses were excluded for the LK cases. Hematoxylin and eosin-stained sections were reviewed. RESULTS: Forty-five cases of LK and 30 cases of LE occurring on the face were identified. Shared features included follicular involvement, epidermal atrophy, pigment incontinence, paucity of eosinophils, and basket-weave orthokeratosis. Major differences between LK and LE, respectively, included perivascular inflammation (11%, 90%), high Civatte bodies (44%, 7%), solar elastosis (84%, 33%), a predominate pattern of cell-poor vacuolar interface dermatitis (7%, 73%), compact follicular plugging (11%, 50%), hemorrhage (22%, 70%), mucin (0%, 77%), hypergranulosis (44%, 17%), and edema (7%, 60%). A predominate pattern of band-like lichenoid interface was seen more commonly in LK as compared with LE (93% vs. 27%). CONCLUSIONS: The authors established the occurrence of LK on the face and identified features to help distinguish LK from LE. Follicular involvement, basket-weave orthokeratosis, pigment incontinence, paucity of eosinophils, and epidermal atrophy were not reliable distinguishing features. Perivascular inflammation, cell-poor vacuolar interface, compact follicular plugging, mucin, hemorrhage, and edema favored LE. High Civatte bodies, band-like lichenoid interface, and solar elastosis favored LK.

Immunohistochemical analysis of KBA.62 in 18 neurothekeomas: a potential marker for differentiating neurothekeoma, but a marker that may lead to confusion with melanocytic tumors.

BACKGROUND: Neurothekeoma represents a neoplasm of uncertain histogenesis that often occurs on the head and neck of younger individuals. Distinguishing neurothekeoma from other tumors, particularly malignancies such as melanoma, can be difficult given the variable presence of nuclear atypia, mitoses and extension into fat or skeletal muscle. KBA.62 represents an anti-melanoma monoclonal antibody that marks approximately 93% of melanomas. This study sought to evaluate KBA.62 expression in neurothekeomas, both as means of affirming the diagnosis and as a potential confounding factor in excluding a melanocytic process. METHODS: Eighteen neurothekeomas from 17 patients were analyzed by light microscopy and immunohistochemistry. Immunohistochemistry was performed with KBA.62, S100 and CD10 antibodies. The diagnosis of neurothekeoma was confirmed by at least two dermatopathologists. RESULTS: All cases showed similar light microscopic and immunohistochemical features. With the exception of two cases, cells expressed CD10 and exhibited morphologic features consistent with neurothekeoma. All 18 cases were S100 immunonegative. The epithelioid cells of all neurothekeomas were KBA.62 immunopositive, including both of two neurothekeomas occurring in the same patient. CONCLUSIONS: In this study 100% of neurothekeomas tested were KBA.62 positive, admittedly to varying degrees, suggesting the utility of this reagent as being supportive of the diagnosis of neurothekeoma.

Evaluation of imatinib mesylate as a possible treatment for nephrogenic systemic fibrosis in a rat model.

INTRODUCTION: The purpose of the study was to evaluate the efficacy of imatinib mesylate in the treatment of nephrogenic systemic fibrosis (NSF) in a rat model administered high-dose gadodiamide, erythropoietin (Epo) and intravenous iron (IV iron). MATERIALS AND METHODS: The local committee for animal research approved this study. Four groups of six Hannover-Wistar rats were studied. Group A received normal saline; Group B, IV iron and Epo; Group C, gadodiamide, IV iron and Epo; and Group D, gadodiamide, IV iron, Epo and imatinib. Gadodiamide was administered at 10 mmol/kg of body weight for 5 consecutive days. Imatinib was administered at 50 mg/kg starting 3 days before gadodiamide injections and was continued for 50 days afterwards. Biopsies were taken 3 and 7 weeks after gadodiamide injection, and dermal histology was analyzed as well as gadolinium deposition as measured by inductively coupled plasma mass spectrometry. Additionally, rats treated with gadodiamide were observed for a total of 16 weeks. For comparison of cellularity, a linear mixed-effects model was used, and for metal deposition, an analysis of variance was used, which was corrected with a Tamhane correction for unequal variances. RESULTS: Rats treated with gadodiamide in addition to IV iron and Epo (group C) had worse skin lesions on histology (P<.001) compared to control animals (groups A and B). Treatment with imatinib resulted in decreased cellularity (group D vs C, P<.001), although there was no difference in the amount of deposited gadolinium (P>.5). Histology at 16 weeks demonstrated increased fibrosis and dermal calcifications, consistent with the clinical presentation of NSF. CONCLUSIONS: The administration of imatinib to rats treated with high-dose gadodiamide resulted in decreased lesion severity.

Medicolegal aspects of prescribing dermatological medications in pregnancy.

Medications are commonly used during pregnancy; in fact, female patients take an average of 2.9 medications during pregnancy. Due to this high prevalence, malpractice litigation poses a high legal risk to dermatologists who prescribe medications to female patients who are or may become pregnant. This article introduces the medicolegal risks involved in prescribing dermatological medications to a pregnant patient and discusses ways for a dermatologist to mitigate those risks. International safety classification systems are reviewed, and potential high risk dermatologic medications prescribed in acne, psoriasis, atopic dermatitis, and connective tissue disease are discussed. In addition, the article summarizes resources available to patients as well as the important elements for dermatologists to include when documenting their discussion with the patient in the medical record.

Teledermatology, teledermatopathology, interstate dermatopathology and the law.

The expansion of telemedicine nationwide has resulted in many states adopting specific telemedicine regulations to avoid the issue of requiring a full medical license to practice telemedicine. How these laws and regulations relate to the practice of telepathology and teledermatology has not been well delineated. It is important to understand these regulations to avoid potential judicial penalties arising from non-compliance. This article aims to outline state-specific telemedicine regulations and penalties.

Medicolegal issues with regard to melanoma and pigmented lesions in dermatopathology.

Understanding malpractice risk and practicing risk management strategies results in better care and a less stressful environment of practice. Errors in diagnosis are most commonly related to melanoma and neoplasms of the skin. To offset the threat of malpractice litigation, malpractice data can be used to focus safety efforts on common diagnostic errors. Recognition of sources of error in the analysis of pigmented lesions by dermatopathologists, and the development of new immunohistochemical or genotypic techniques for the recognition and distinction of malignant disease from benign pigmented lesions, will also provide important improvements in care and diagnosis in the future.

Levamisole-induced Wegener's granulomatosis following contaminated cocaine abuse.

A 44-year-old woman with a medical history of chronic pain syndrome presented with a 3-day history of a painful "rash" that started on her face and spread to her legs. Further history revealed that she recently started a new medication, varenicline, 7 weeks prior to admission and had a long-standing history of intranasal cocaine use. Review of systems was significant for rhinitis, nasal congestion, joint pain, and a febrile episode 2 days prior to admission. Physical examination revealed centrally violaceous, tender, stellate, and retiform purpuric patches and plaques on her extremities, nasal dorsum, and cheeks. Approximately 1.0-centimeter tender purpuric nodules were noted on her bilateral second proximal interphalangeal joints. She was afebrile. Initial laboratory data revealed a mild leukopenia, normal serum urea nitrogen and creatinine without hematuria, and an elevated erythrocyte sedimentation rate. Further analysis showed a normal complement level, negative antinuclear antibody, human immunodeficiency virus, rapid plasma reagin, and hepatitis panel. Trace cryoglobenemia and a positive anti-streptolysin O were noted, along with a positive antineutrophil cytoplasmic antibody (c-ANCA) (> 8.0 U) and perinuclear antineutrophil cytoplasmic antibodies, or p-ANCA (1.5 U). The hypercoagulable workup was negative. A skin biopsy taken from the left thigh was consistent with leukocytoclastic vasculitis. After several weeks of high-dose oral prednisone taper, the patient's symptoms improved, but flared upon discontinuation. On follow-up, she admitted to frequent relapses of cocaine abuse and had developed tender purpuric plaques on her nose, ears, and extremities, some with ulcerations (Figure 1 and Figure 2). She also had significant edema and joint pain that limited her ambulation. Further evaluation revealed normal chest x-ray results; however, computed tomography of her sinuses demonstrated thickened maxillary sinuses consistent with subacute/ chronic sinusitis. She also developed hematuria. Mass spectrometry analysis ofhair and urine samples tested positive for cocaine and levamisole. A presumptive diagnosis of levamisole-induced Wegener's vasculitis was made. She was restarted on high-dose prednisone and methotrexate with improvement and advised to discontinue cocaine use, so as to avoid exposure to both substances.