The PROCLIPI international registry of early-stage mycosis fungoides identifies substantial diagnostic delay in most patients.

BACKGROUND: Survival in mycosis fungoides (MF) is varied and may be poor. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) study is a web-based data collection system for early-stage MF with legal data-sharing agreements permitting international collaboration in a rare cancer with complex pathology. Clinicopathological data must be 100% complete and in-built intelligence in the database system ensures accurate staging. OBJECTIVES: To develop a prognostic index for MF. METHODS: Predefined datasets for clinical, haematological, radiological, immunohistochemical, genotypic, treatment and quality of life are collected at first diagnosis of MF and annually to test against survival. Biobanked tissue samples are recorded within a Federated Biobank for translational studies. RESULTS: In total, 430 patients were enrolled from 29 centres in 15 countries spanning five continents. Altogether, 348 were confirmed as having early-stage MF at central review. The majority had classical MF (81·6%) with a CD4 phenotype (88·2%). Folliculotropic MF was diagnosed in 17·8%. Most presented with stage I (IA: 49·4%; IB: 42·8%), but 7·8% presented with enlarged lymph nodes (stage IIA). A diagnostic delay between first symptom development and initial diagnosis was frequent [85·6%; median delay 36 months (interquartile range 12-90)]. This highlights the difficulties in accurate diagnosis, which includes lack of a singular diagnostic test for MF. CONCLUSIONS: This confirmed early-stage MF cohort is being followed-up to identify prognostic factors, which may allow better management and improve survival by identifying patients at risk of disease progression. This study design is a useful model for collaboration in other rare diseases, especially where pathological diagnosis can be complex.

A Literature Revision in Primary Cutaneous B-cell Lymphoma.

The term "Primary Cutaneous B-Cell Lymphoma" (PCBCL) comprehends a variety of lymphoproliferative disorders characterized by a clonal proliferation of B-cells primarily involving the skin. The absence of evident extra-cutaneous disease must be confirmed after six-month follow-up in order to exclude a nodal non-Hodgkin's lymphoma (NHL) with secondary cutaneous involvement, which may have a completely different clinical behavior and prognosis. In this article, we have summarized the clinico-pathological features of main types of PCBCL and we outline the guidelines for management based on a review of the available literature.

Septic vasculitis and vasculopathy in some infectious emergencies: the perspective of the histopathologist.

Sepsis is a potentially life-threatening complication of an infection where cutaneous lesions often represent one of the early signs. A myriad of microorganisms including bacteria, fungi, yeasts, viruses, protozoas, helminths and algae can be implicated. A broad spectrum of clinical and histopathologic findings can be observed in the skin and the common denominator is a thrombotic vasculopathy. The pathogenesis of cutaneous septic vasculitis (SV)/vasculopathy is complex and includes five main mechanisms: disseminated intravascular coagulation, direct invasion and occlusion of blood vessel walls by microorganisms, hypersensitivity reaction with immune complex deposition into blood vessel walls, embolism from a distant infectious site and vascular effects of toxins. Herein we describe the clinicopathologic findings of some selected cases of SV recently observed in our hospital, including purpura fulminans, necrotizing fasciitis, cutaneous meningococcemia, malignant syphilis and disseminated alternaria infection. Histopathologically, a wide spectrum of histopathologic changes was observed in skin specimens from the various entities, involving the intensity and composition of the inflammatory infiltrate, the degree of vascular changes and the presence of microorganisms, that ranged from a predominant not inflammatory, thrombotic-occlusive vasculopathy in purpura fulminans to leukocytoclastic vasculitis like changes in cutaneous meningococcemia to a dermal angiomatosis-like pattern in disseminated Alternaria infection. The different pathologic presentations may be related to the microorganism involved, the main pathogenetic mechanism that induced the vascular injury and the individual immunologic burden. Early skin biopsy for histopathologic examination and microbiologic culture is a cornerstone in the diagnosis of life-threatening diseases that present with cutaneous septic vasculitis. Ancillary techniques, such as immunohistochemistry and polymerase chain reaction are additional novel and helpful tools to identify pathogens, leading to definite diagnosis in cases with challenging or ambiguous clinical and/or pathologic findings.

From erythema multiforme to toxic epidermal necrolysis. Same spectrum or different diseases?

Erythema multiforme (EM), Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute bullous disorders associated to different prognosis, mainly due to infections and drugs. More in particular EM in more than 90% is caused by infections (especially Herpes virus infection), while, on the other hand SJS and TEN are referable in more than 95% of cases to drugs. Distinction among these three forms is often controversal and still debated. An attempt to distinguish these forms has been possible mainly according to anamnesis, clinical presentation (morphology, involved sites, extension of lesions) and pathogenetic mechanisms, being on the contrary more difficult from an histopathological point of view. Nowadays a clear diagnosis and a distinction from other life-threatening diseases is possible with the integration of all the mentioned aspects. Moreover, this recognition should be as early as possible in order to perform a prognostic evaluation of the case and to start supportive cares and therapies as soon as possible.

Histopathologic spectrum of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): a diagnosis that needs clinico-pathological correlation.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by an heterogeneous group of severe dermatologic manifestations and systemic involvement, due to several groups of medicaments. A series of 9 consecutive cases, observed from 2008 to 2013 in the Department of Dermatology, University of Pavia, is reported, all satisfying the clinical, hematological and systemic diagnostic criteria of DRESS. Clinically, 4 out of 9 patients had an urticarial and papular eruption, 2 an erythema-multiforme-like (EM-like) pattern, 2 erythroderma and 1 had an erythematous and macular reaction. Aim of the study was to describe the histopathologic features of DRESS and to trace a possible correlation between the four clinical recognized types of the syndrome and the histopathological patterns. Predominantly, a superficial perivascular lymphocytic infiltrate, extravasation of erythrocytes, and focal interface changes characterized DRESS cases. Less frequently, histopathology revealed the presence of necrotic keratinocytes; surprisingly, only in 2 cases the presence of rare dermal eosinophils was detected, even if all the patients had significant peripheral eosinophilia. A histopathological diagnosis of DRESS seems per se, according to our data, not feasible, since the main histopathological changes (interface changes, superficial perivascular dermatitis, focal spongiosis, lichenoid infiltrate, rare presence of necrotic keratinocytes) can be interpreted generically as a drug induced dermatitis. The above mentioned histopathological changes, however, when associated with clinical information on cutaneous and systemic involvement of the patient, allow the pathologist or the dermatopathologist to make a diagnosis of DRESS with a reliable margin of certainty.

A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert-Bazin type) mycosis fungoides.

BACKGROUND: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma; in its classical presentation it evolves slowly, but it can have an aggressive course in a subset of patients. OBJECTIVES: To investigate the impact of epigenetic mechanisms on the progression of early stage MF. METHODS: We analysed DNA methylation at 12 different loci and long interspersed nucleotide elements-1 (LINE-1), as a surrogate marker of global methylation, on tissue samples from 41 patients with stage I MF followed up for at least 12 years or until disease progression. The methylation profiles were also analysed in two T-cell lymphoma cell lines and correlated with gene expression. RESULTS: The selected loci were methylated in a tumour-specific manner; concomitant hypermethylation of at least four loci was more frequent in cases progressing within 1-3 and 3-6 years than in late-progressive or non-progressive cases. LINE-1 methylation was significantly lower in rapidly progressive MF at 3 years (61%, P < 0·001) than in those at 12 years (67%). PPARG, SOCS1 and NEUROG1 methylation showed remarkable differences among the prognostic groups, but only PPARG was a significant predictor of disease progression within 6 years, after adjustment for patients' age or gender. Strikingly, a methylation profile similar to progressive cases was found in highly proliferative Sézary-derived HUT78 cells but not in MF-derived HUT102 cells. Exposure to a DNA demethylating agent restored sensitivity to apoptosis and cell cycle arrest. CONCLUSIONS: Epigenetic silencing of specific biomarkers can predict the risk of disease progression in early-stage MF, providing insights into its pathogenesis, prognosis and therapy.

Favourable prognostic role of regression of primary melanoma in AJCC stage I-II patients.

BACKGROUND: The prognostic significance of regression in primary melanoma has been debated over the past few years. Once it was considered to be a negative prognostic factor, as it may have prevented proper melanoma thickness measurement, therefore affecting the staging of the tumours. For this reason, it was considered to be an indication for sentinel lymph node biopsy (SLNB) in melanoma < 1 mm. OBJECTIVES: To ascertain the utility of SLNB in thin melanoma and to clarify the role of regression in disease-free survival (DFS) and overall survival (OS) in our series. METHODS: We analysed data collected from 1693 consecutive patients with AJCC (American Joint Committee on Cancer) stage I-II melanoma. RESULTS: Globally, SLNB was performed in 656 out of 1693 patients. Regression was present in 349 patients and 223 of them were characterized by thin lesions. SLNB was performed in 104 cases of thin melanoma with regression. The majority of regional lymph node metastases were observed in patients who did not undergo SLNB (89 out of 132). Among the remaining 43 'false negative' patients only three showed regression in the primary. Using the Cox multivariate model, histological regression maintained a significant protective role [hazard ratio (HR) 0·62, P = 0·012 for DFS; HR 0·43, P = 0·008 for OS] when corrected for the principal histopathological and clinical features, despite SLNB. CONCLUSIONS: We confirmed that regression alone should not be a reason to perform SLNB in thin melanoma and, on the contrary, it can be considered a favourable prognostic factor in patients with AJCC stage I-II melanoma.

How to make a specific diagnosis of panniculitis on clinical grounds alone: an integrated pathway of general criteria and specific findings.

A clinical approach to the vexing problem of diagnosis of panniculitis is traced in this paper, in order to obtain from the clinical findings, history and laboratory data of the patient useful, detailed and precise information, essential to address dermatologists to a specific clinical diagnosis of panniculitis. This approach is created in the same way as when a dermatologist faces any other dermatological disease, be it inflammatory or neoplastic. A common behavior in case of panniculitis is in fact just to take an adequate biopsy and wait for the pathologist report. This is indeed a limitation both for the dermatologist and above all for the pathologist, who is in tremendous need for detailed clinical information before signing his report. The most common types of panniculitides, taking into account their main clinical diagnostic criteria, will be considered. In particular, Erythema Nodosum, Panniculitides in Sarcoidosis, Pancreatic Panniculitis, Lupus Panniculitis, Erythema Induratum/Nodular Vasculitis and Weber-Christian Panniculitis/Rothman-Makai Pannicultis will be analyzed. Every chapter will consider general criteria (epidemiology, age and gender, distribution of the lesions, laboratory findings) and specific findings (characteristics of the lesions, i.e. redness, pain, tenderness, evolution, ulceration, sites of involvement) as well as comorbidities and systemic signs and symptoms. Detailed analysis of the general criteria integrated with the specific findings will allow the clinicians to reach a clinical diagnosis with a high degree of confidence.

The role of skin biopsy in diagnosis of panniculitides.

Several factors hamper the clinical and histologic diagnosis of panniculitis. Clinically the patients tend to present with erythematous subcutaneous nodules with quite a monotonous appearance, without additional symptoms. Histopathologically, as the subcutaneous fat responds to a variety of insults in a limited number of forms, there are sometimes subtle pathologic differences among the conditions. Although the biopsy plays a critical role in the diagnostic process of a panniculitis, a series of prerequisites must be met in order to obtain as much information as possible from this procedure. If the biopsy is inadequate, i.e., does not include sufficient subcutaneous fat or the site of sampling site/biopsy timing is wrong, histopathologic assessment is limited and the correct diagnosis may be delayed and further sampling may be required. This article introduces the reader to the field of panniculitides under the histopathologic perspective through a brief description of the normal histology of subcutaneous fat. I also includes the definition of the types of fat necrosis, role of biopsy of panniculitis and its rules and pitfalls, up to a microscopic approach of a slide.

Post-surgical lipophagic panniculitis: a specific model of traumatic panniculitis and new histopathological findings.

Aim of this work was to define the histopathological features of post-surgical panniculitis. Dermal and hypodermal changes will be analyzed in detail, to understand the cascade of events that characterize the tissue response to surgical trauma. Cutaneous re-excision specimens of cases of basal cell carcinoma, squamous cell carcinoma, and melanoma consecutively seen from January 1, 2011 to June 30, 2011 at the Department of Dermatology, University of Pavia, were included in this study. Only the cases in which the first surgical procedure included the subcutaneous fat, were considered. In addition, the time elapsed from the first surgical procedure and the re-excision had to be included in a period of time from one to three months. All the specimens were stained with hematoxylin and eosin. Thirty cutaneous re-excision specimens were studied. Histopathologic examination revealed changes of epidermis, ranging from slight atrophy to moderate hyperplasia. In two cases focal ulceration was seen, with transfollicular elimination of foreign body material. The main dermal changes observed were the: 1) scar with well defined vertical orientation along the dermal suture line; 2) rounded cicatricial areas with radial branching septa of scarring tissue; 3) foreign body granuloma formation; 4) alignment of hystiocytes at the dermo-hypodermal border; 5) traumatic neuromas. The subcutaneous fat changes included: 1) lobular panniculitis with consistent presence of foam cells; 2) striking anisocytosis with pseudocystic degeneration and necrosis of adipocytes; 3) eritrocyte extravasation, mainly at the dermo-hypodermal border; 4) deep seated phlebitis. Post-surgical panniculitis is a lobular foam cell panniculitis characterized by simultaneous dermal and hypodermal changes, expression of the multi-faceted tissue response to a surgical trauma. This type of peculiar lipophagic response puts post-surgical panniculitis into the wider chapter of lipophage tissue response seen in atherosclerosis, glomerulosclerosis and some infectious models such as Mycobacterium tuberculosis and Chlamydia pneumoniae infections. Furthermore it may be seen as a reliable and convenient model for laboratory investigation on foam cell tissue response.

Luetic lymphadenopathy despite negative serology.

Laboratory tests can be misleading for the diagnosis of syphilis and false-negative results are possible, but it is rare for both treponemal and non-treponemal tests to prove negative in different stages of the disease. We report on a case of luetic lymphadenopathy, diagnosed by histological examination and supported by immunohistochemical staining for Treponema pallidum, in the absence of skin lesions and positive serology. This case reminds us of how syphilis may present in many different clinical forms and that it should not be excluded only on the basis of negative serological tests. This patient's negative serology was probably due to inadequate initial antibiotic therapy. Given the current widespread use of antibiotics, greater consideration is warranted of the extent to which serological test results are modified by non-specific antibiotic therapies.

Aquagenic (pseudo) keratoderma: a clinical series with new pathological insights.

BACKGROUND: Aquagenic keratoderma is an uncommon condition that occurs after brief water exposure. An association with cystic fibrosis has been suggested. Histopathology is considered to be nonspecific. OBJECTIVES: To describe the microscopic findings in seven of 12 new patients and compare the histopathological results of the lesions which appeared on the palmar skin after immersion into water with normal skin. PATIENTS AND METHODS: Nine female and three male patients (mean age 27 years) were collected prospectively and evaluated for common demographic, clinical and histopathological features. RESULTS: Lesions were located on only the palms in seven patients; the soles were involved in two patients; and one patient had involvement of the dorsal aspect of the hands. One patient had a similar family history. None of the patients reported associated conditions. Genetic studies revealed heterozygosis for mutation in the cystic fibrosis gene in two patients. The most specific histopathological findings were: orthohyperkeratosis with increased thickness and abnormal staining of the stratum corneum; dilated acrosyringia and dermal eccrine ducts with hyperplasia of eccrine glands, clear cell change and vacuolation; increased capillaries around and adjacent to the eccrine glands. A skin biopsy taken after restoration of normal skin with drying revealed a normal stratum corneum with a physiological uniform stain and normal thickness without further evidence of dilation of acrosyringia or dermal eccrine ducts. Incipient dilation of the secretory and ductal structures was also observed in a transitional area between the involved and the clinically normal skin of the palms. CONCLUSIONS: Aquagenic keratoderma may be associated with a heterozygous mutation in the cystic fibrosis gene. Although the diagnosis is a clinical one, histopathology is useful and may reveal some characteristic diagnostic clues. Aquagenic pseudokeratoderma seems to be a more appropriate term to name it.