Mummified Cells are a Common Finding in Cutaneous Hodgkin Lymphoma and Can Be Used as a Diagnostic Clue.

Specific cutaneous involvement in Hodgkin lymphoma is rare. In cutaneous lesions, the diagnosis is usually based on the recognition of diagnostic Reed-Sternberg cells and its variants. In nodal Hodgkin lymphoma, so-called mummified cells (cells with condensed cytoplasm and pyknotic eosinophilic or basophilic nuclei) are often seen. They are sometimes conspicuous and easy to recognize, thus serving as a clue to the diagnosis. Our objective was to study cases of cutaneous Hodgkin lymphoma to identify the occurrence of mummified cells. We studied 12 patients (4 women and 8 men; age range 23-80 years). In 6 patients, cutaneous and extracutaneous disease was identified almost simultaneously; in 4 patients, lymph node disease preceded cutaneous involvement; and in the remaining 2 patients, the skin lesions were the presenting sign, whereas lymph node involvement occurred later. Histopathological, immunohistochemical, and molecular-genetic studies, including rearrangements for TCR, IgH genes, and PCR for EBV, were performed. Cutaneous biopsy specimens revealed either a multinodular or diffuse infiltrate, included small lymphocytes, eosinophils, plasma cells, and macrophages, but in all cases, diagnostic Reed-Sternberg cells and its variants were identified. Mummified cells were detected in 9 cases, either as occasional scattered mummified cells often requiring a search (6 cases) or being conspicuous, grouped and therefore easily identified (3 cases). Immunohistochemically, in all 7 cases studied, mummified cells were positive for both CD30 and CD15. It is concluded that mummified cells are encountered in a majority of cases of cutaneous Hodgkin lymphoma.

Hemophagocytosis in Cutaneous Autoimmune Disease.

BACKGROUND: The significance of the histological visualization of hemophagocytosis in tissues depends on the context, varying from a nonspecific phenomenon to a characteristic or diagnostic feature for certain disease entities. Hemophagocytosis is also one of the key features of macrophage activation syndrome (MAS) (hemophagocytic syndrome) a potentially life-threatening complication of underlying conditions such as infections, malignancy, and autoimmune disorders. Clinical manifestations of MAS are high fever, pancytopenia, liver dysfunction, and coagulopathy. These clinical symptoms are due to an abnormal activation of the immune system in a strong association with the cytokine milieu. The diagnosis of MAS may be easily missed; it is usually detected in the bone marrow, lymph node, liver, and spleen. Only few reports exist in the literature with histological description of cutaneous hemophagocytosis as a sign for MAS in patients with lymphoma and infection. In this report, the authors present the clinicopathological and immunohistochemical features of 3 patients with cutaneous hemophagocytosis, specifically erythrophagocytosis, associated with autoimmune disease, and discuss the relevance of these findings. OBSERVATION: The authors report 3 patients who developed cutaneous hemophagocytosis during the course of an underlying autoimmune disorder. One patient suffered from dermatomyositis, the other 2 patients from systemic lupus erythematosus, whereby one of them was a 3-month old girl with neonatal lupus erythematosus. The patient with dermatomyositis developed MAS according to the current diagnostic criteria. Although the 2 other patients had an acute flare of their autoimmune disease with histological signs of cutaneous hemophagocytosis, they did not fulfill the complete criteria for a diagnosis of MAS. Histiocyte proliferation and activation with increase of cytokines could be demonstrated by immunohistology. CONCLUSIONS: This report is the first to describe hemophagocytosis in cutaneous biopsies of patients with autoimmune diseases, associated with a complete or incomplete constellation of MAS. Key players in this process are histiocytes/macrophages engaged in phagocytosis of erythrocytes. Hemophagocytosis observed in skin biopsies may be a diagnostic clue for MAS and an indicator for a potentially aggressive course of the underlying disease.

Follicular malignant melanoma: primary follicular or folliculotropic?

Follicular malignant melanoma (FMM) is a rare variant of melanoma arising on sun-damaged skin of elderly patients. It is characterized histopathologically by a prominent involvement of 1 or 2 adjacent hair follicles. The authors report 3 new cases of FMM (M:F = 2:1; age range, 23-67 years; median age, 50 years) located on the scalp, cheek, and upper back. Complete effacement of the hair follicle, replaced by neoplastic melanocytes, was observed in 1 case. The interfollicular epidermis and adventitial dermis were involved in all 3 cases. Our series shows that FMM is not restricted to elderly patients but may arise also in young individuals without association with chronic sun damage. FMM should be distinguished from folliculotropic metastases of melanoma and from atypical melanocytic nevi. Although the histopathological features and the term FMM may suggest a derivation from melanocytes of the hair follicle, the exact origin of neoplastic cells is yet unclear, and at least some of these cases may represent folliculotropic examples of primary epidermal malignant melanoma.

Visualization and treatment of subclinical actinic keratoses with topical imiquimod 5% cream: an observational study.

BACKGROUND: Imiquimod 5% is licensed for the treatment of external genital warts, superficial basal cell carcinoma, and actinic keratosis (AK) and is being used experimentally in various other dermato-oncological conditions. OBJECTIVE: This observational study shall show that nonmelanoma skin cancer can be detected at its earliest subclinical stage by its reaction with imiquimod and can be cleared by finishing the course of treatment. MATERIAL AND METHODS: In this single arm trial 15 patients with chronically sun-exposed skin who had no clinical evidence of AK were treated with 5% imiquimod cream on the face or scalp for 4 weeks three times per week. RESULTS: During treatment, all patients developed multiple areas with mild to moderate inflammatory skin reactions, such as erythema, induration, and scaling. Biopsies obtained from 12 patients prior to treatment revealed no malignancies. However, in cases with more pronounced inflammation during treatment, targeted biopsies indicated very early malignant alterations. CONCLUSION: Topical imiquimod treatment of chronically sun-exposed skin without overt clinical signs of AK is able to detect subclinical actinic keratoses (SAK) and to completely clear the lesions, even before they can be clinically diagnosed as AK. In such patients, imiquimod might be able to prevent the evolution of SCC.

Treatment of actinic keratoses with 5% topical imiquimod: a multicenter prospective observational study from 93 Austrian office-based dermatologists.

BACKGROUND: While randomized, controlled trials have generated information about the safety and efficacy of imiquimod 5% cream in the treatment of actinic keratosis, still very little is known about the challenges and pitfalls of this therapy in the daily clinical routine. OBJECTIVE: To mirror the full picture of the actinic keratosis imiquimod routine therapy, ie, patient profile, in-therapy decisions, tolerability, and satisfaction. METHODS: The present observational, multicenter study included 463 patients from the offices of 93 non-hospital based Austrian dermatologists. Inclusion was solely based on the treatment decision of the dermatologist and the patient's will to participate. There were no specific interventions except suggested time points of visits with pre-defined documentation forms. RESULTS: The typical actinic keratosis patient was a male, aged 74 years, with a disease history of 5.7±5.3 years, who presented with 8.4±8.0 multiple pre-treated lesions at the face. More than 95% of the patients developed therapeutic skin responses (dominated by erythema and crusting), which led to a significant reduction of lesions from baseline to the end of the therapy. Notably, one-third of those patients prone to a second therapeutic course were submitted to another form of treatment. Post-imiquimod therapy comprised of antibiotic creams, topical steroids, and numerous emollients. Patients and dermatologists reported high satisfaction with the therapy including the cosmetic outcome. CONCLUSION: Our data show the high need for experience at the dermatologist side and information at the patient side. Moreover, the method of treatment for imiquimod-related skin reactions definitively asks for standardization. The study was registered at ClinicalTrials.gov (NCT01151956). Decision by ClinicalTrials.gov: Federal University Teaching Hospital, Feldkirch, Austria Protocol Record OBIMQ465-AK-08, Imiquimod and actinic keratoses: an observational study.

Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests.

Cutaneous melanomas are characterized by a range of histological appearances, and several morphological variants have been described. In this study, we report a variant of superficial spreading melanoma that is characterized by large, irregular junctional melanocytic nests. The junctional nests varied in shape and size, showed focal tendency to confluence, and were often surrounded by a cuff of epidermal keratinocytes. The melanocytes comprising the nests showed variable cytological atypia. In most of the cases, scant intraepidermal or junctional single melanocytes were seen, and other well-documented diagnostic criteria for melanoma were lacking, and as a result, histological recognition of these tumors as melanoma was difficult. Some cases were associated with an invasive dermal component or showed evidence of sun damage. To provide supporting evidence for malignancy, we analyzed these tumors for genomic aberrations. Using array comparative genomic hybridization (aCGH), we identified multiple genomic aberrations in all analyzed cases. A similar pattern of genomic aberrations was seen in a control group of bona fide superficial spreading melanomas, suggesting that these 'melanomas composed exclusively or predominantly of large nests' are indeed variants of superficial spreading melanoma. Fluorescence in-situ hybridization (FISH) was positive in 40% of the cases. However, using aCGH, the FISH-negative cases showed multiple genomic aberrations in regions that are not covered by FISH. The low sensitivity of the FISH test can be explained by the fact that FISH only evaluates four genomic loci for aberrations, whereas aCGH surveys the entire genome. In summary, we present histological and molecular genetic evidence for a morphological variant of superficial spreading melanoma. Awareness of the histological features will aid in their correct diagnosis as melanoma, and in difficult cases, judicious application of ancillary tests such as aCGH (rather than FISH) will assist accurate diagnosis.

Evaluation of the ICDP-UEMS Dermatopathology Examination.

A detailed analysis of the results of the international annual International Committee for Dermatopathology-Union Européene des Médecins Specialistes dermatopathology examination was undertaken to identify clues for further improvement. The analysis covered 5 consecutive years (2006-2010) and involved a total of 860 questions (591 common questions and 269 uncommon questions) and 181 participants. It focused on the overall performance of the participants, the performance per part of the examination (theoretical or practical), the performance per format of question (multiple choice or open), the performance per dermatopathological topic, and the performance per professional background (dermatologist or pathologist). The overall performance of the participants was high (on average 75% correct answers in 2006 and 85% correct answers in the subsequent years). In the theoretical part of the examination, the topics of vascular diseases and lichenoid dermatoses scored better than the average of all topics, and the topics of cutaneous lymphoproliferative diseases and melanocytic disorders scored worse. In the first practical part (interpretation of images), dermatologists outperformed pathologists, especially on providing a diagnosis (open question format) of clinical images. In the second practical part (microscopical examination), the topics of vascular diseases, granulomatous diseases, including necrobiotic and degenerative and metabolic diseases scored better than the average of all topics, and the topic of infectious diseases scored worse. The results of this detailed analysis provide an excellent feedback to the examination committee that will be used to consider the adjustment of parts and/or topics of the examination that showed a deviant performance by the participants. In addition, it is recommended to give more attention to the postgraduate education of certain dermatopathological topics, including cutaneous lymphoproliferative diseases, melanocytic disorders, and infectious diseases.

Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition.

The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.

"Standard of reasonable care" in dermatopathology.

Diagnoses in dermatopathology are capable of improvement. Clinical pictures should be evaluated along with skin biopsy specimens whenever possible.

Ancient melanocytic nevus: a simulator of malignant melanoma.

Ancient melanocytic nevus (AN) is an unusual but distinctive melanocytic neoplasm within the spectrum of simulators of malignant melanoma. This report describes 13 patients with AN where a long follow-up information was available. Histopathology is characterized by 2 populations of melanocytes, namely, one with large pleomorphic cells and the other with small melanocytes. A few mitotic figures may be present exceptionally. MIB-1 (Ki67) proliferation marker reveals an overall low nuclear labeling index. Additional important findings are stromal degenerative changes. AN must be especially differentiated from dermal melanoma arising in a nevus.

Joy for morphology: dermatopathology and art.

This work displays the bridging of two fields - namely dermatopathology and art. What is astonishing is that structures one sees through the microscope reveal aesthetic and artistic aspects and sometimes resemble in a startling way the designs of certain artists. Specific examples are illustrated to enhance the joy and appreciation of morphologic images.

Influence of evaluation of clinical pictures on the histopathologic diagnosis of inflammatory skin disorders.

BACKGROUND: Clinical information on histologic referral sheets is usually very limited, and particularly for inflammatory skin disorders, dermatopathologists often ask referring physicians for clinical correlation. OBJECTIVE: In this study we tested the value of clinicopathologic correlation in the histopathologic diagnosis of inflammatory skin disorders. METHODS: One-hundred biopsy specimens were digitalized and stored on 3 DVDs along with the clinical images. All cases were evaluated by 9 independent full-time dermatopathologists, initially without looking at the clinical pictures and subsequently after checking them. All diagnoses were finally compared with the "reference" diagnosis established in Graz, Austria, and the results were statistically analyzed. RESULTS: After evaluation of the clinical images, the number of dermatopathologists making a correct diagnosis was increased in 70 cases, unchanged in 25 cases, and decreased in 5 cases. The total number of correct diagnoses increased from 332 (diagnoses before evaluation of clinical pictures) to 481 (diagnoses after evaluation of clinical pictures), with a 16.6% increase in the total. LIMITATIONS: The computerized setting is different from real-life dermatopathology and physical examination of patients. CONCLUSION: Our study clearly shows that clinical pictures should be added to biopsy request slips of inflammatory skin disorders whenever possible, as they allow a better interpretation of histopathologic findings.

Pseudolymphomatous tumid lupus erythematosus of the oral mucosa.

Oral lesions are frequent complications of systemic lupus erythematosus, but only ulceration is included in the 1982 American College of Rheumatology revised criteria. Because the lack of a uniform classification, a range of ulcerative and keratotic lesions are typically described. In this report we describe a unique progressive irregularly cobblestoned and vegetating plaque of the oral mucosa with clinical and histological features mimicking a cutaneous lymphoma. Despite the papillomatous and extensive nature of the lesions and the dense lymphoid infiltrate with follicle formation suggesting a malignant lymphoproliferative process, the slow progression coupled with a mixed cell infiltrate and polyclonality supported a diagnosis of pseudolymphoma. Recognition of this entity is important to prevent diagnosing them as a malignant lymphoma. As well as with the other mucosal lesions in lupus erythematosus, this pseudolymphomatous variant should be added to the disease spectrum.

HGF-promoted motility in primary human melanocytes depends on CD44v6 regulated via NF-kappa B, Egr-1, and C/EBP-beta.

The regulation of CD44v6, a variant of the CD44 family of glycosylated adhesion molecules, through hepatocyte growth factor (HGF) has implications for motility in primary human melanocytes. We show that exposure of primary human melanocytes to HGF results in an increase of CD44v6 expression. Immunostaining of melanocytic lesions revealed low cytoplasmic positivity of CD44v6 in some nevi but high membranous expression in primary cutaneous melanomas, and cutaneous and lymph node metastases. HGF-dependent CD44v6 regulation in melanocytes is NF-kappaB dependent because BAY 11-7082, an inhibitor of NF-kappaB activation, but not interference with the mitogen-activated protein kinase or phosphatidylinositol 3-kinase cascade, antagonized HGF-induced CD44v6 expression. NF-kappaB-mediated transcriptional regulation of CD44v6 involves the transcription factors Egr-1 and CCAAT enhancer-binding protein-beta (C/EBP-beta). In gel shift assays, the initial binding of p100/p52 NF-kappaB, C/EBP-beta, and Egr-1 to the CD44 promoter experienced reshuffling toward increased affinity of C/EBP-beta after HGF stimulation. A blocking antibody to CD44v6 decreased HGF-induced c-Met phosphorylation as well as enhanced random- and site-directed migration. Our data show that HGF-induced motility in primary human melanocytes depends on c-Met-CD44v6 interaction, and that HGF-enhanced CD44v6 expression is required for motility and transcriptional upregulation of CD44v6, presumably mediated through a complex comprising NF-kappaB/C/EBP-beta and Egr-1.