Health-related quality of life and its influencing factors in patients with primary cutaneous B-cell lymphomas: A multicentric study in 100 patients.

BACKGROUND: Primary cutaneous B-cell lymphomas (CBCL) are a group of rare malignant skin diseases that represent approximately 20%-30% of all primary cutaneous lymphomas (PCL). Previous studies revealed impaired health-related quality of life (HRQoL) in patients diagnosed with primary cutaneous T-cell lymphoma (CTCL). Currently, only small-sized studies investigated HRQoL in CBCL patients and lacked detailed analysis of respective subtypes. OBJECTIVES: This study aims to investigate HRQoL in CBCL patients to identify independent factors of HRQoL impairment in CBCL patients. METHODS: One hundred CBCL patients were recruited from eight German PCL centres in this multicentric, cross-sectional study from 2021 to 2022. The patients completed the dermatologic HRQoL questionnaire Skindex-29 and an investigator-designed 'CBCL-Questionnaire' with additional questions on HRQoL and clinical characteristics. RESULTS: The Skindex-29 revealed that HRQoL in CBCL patients is impaired on a mild to moderate level. The multiple regression analysis identified parameters like worries about dying, feeling prejudiced/discriminated and impairment of daily activities to be independently associated with impairment of HRQoL. Highest scores for HRQoL impairment were found in patients with primary cutaneous follicle centre lymphoma while on rituximab treatment and in patients with primary cutaneous marginal zone lymphoma while on watchful waiting. CONCLUSIONS: HRQoL is impaired in CBCL patients, even though, in the face of indolent disease course and favourable prognosis in the majority of cases. Of note, our investigator-designed tool identified worries about dying, feeling prejudiced/discriminated, and the type of treatment to have a negative impact on patients' HRQoL. Our study highlights the importance of a thorough patient-doctor communication to capture overall disease burden because generic HRQoL tools might lack of disease-specific items.

[Atypical fibroxanthoma and pleomorphic dermal sarcoma]. / Atypisches Fibroxanthom und pleomorphes dermales Sarkom.

Atypical fibroxanthoma (AFX) or undifferentiated pleomorphic sarcoma (UPS) is a rare malignant neoplastic disease of the skin. At the beginning of the 1960s AFX was described as an independent entity and superficial variant of malignant fibrous histiocytoma (MFH). Since then, many controversies on the classification have arisen mainly because in many cases dedifferentiated neoplasms from other origins were falsely diagnosed as AFX. A relevant deep expansion, the invasion of nerves and vessels or the presence of tumor necrosis are described as being typical for UPS; however, in the first-line they represent risk factors for recurrence. In view of the clinical and histological features it is meaningful to consider AFX and UPS as one disease. In recent years many studies on the molecular pathological background have attempted to make a better classification of the neoplasm, without being able to so far name a certain specific histopathological or molecular pathological characteristic. The AFX/UPS is still in essence a morphological and immunohistochemical diagnosis by exclusion.

[Malignant collision tumor of the skin : Melanoma, squamous cell carcinoma and basal cell carcinoma]. / Maligner Kollisionstumor der Haut : Melanom, kutanes Plattenepithelkarzinom und Basalzellkarzinom.

We present the case of a woman in her eighties with a collision tumor composed of a malignant melanoma, a squamous cell carcinoma and a basal cell carcinoma. The simultaneous growth of histogenetically different, spatially not separate, malignant tumors of the skin is rare. The classification is difficult and sometimes confusing, especially regarding the terminology used in the literature. The correct classification of such tumors has a high significance for the clinical daily routine.

[Tinea barbae profunda due to Trichophyton mentagrophytes : Case report and review]. / Tinea barbae profunda durch Trichophyton mentagrophytes : Patientenbeschreibung und Übersicht.

Tinea barbae is a rare dermatomycocis, by definition follicular bound in the beard area of adult men. Manifestation usually starts with erythema accompanied by desquamation. Deeper distribution along terminal hairs leads to folliculitis with formation of pustules and nodes as well as abscesses; fixed adherent yellowish crusts may appear. Frequently there is locoregional swelling of the lymph nodes and occasionally a deterioration of general condition with (sub)febrile temperatures. Often this leads to the initial suspected diagnosis of a bacterial folliculitis barbae or impetigo contagiosa. Tinea barbae is mostly induced by species of the genus Trichophyton (T.). The pathogens are diverse and are mostly zoophilic, sometimes anthropophilic and rarely geophilic dermatophytes. With the help of a specific anamnesis and diagnostic procedure, including mycological examinations, histology and molecular detection of dermatophytes via polymerase chain reaction (PCR), tinea barbae-in our patient induced by T. mentagrophytes-can be rapidly diagnosed. Early initiation and adequate treatment duration lead to restitutio ad integrum.

[Smooth muscle hamartoma in volar skin]. / Glattmuskelhamartom in volarer Haut.

We report the case of a 12-year-old girl with a smooth muscle hamartoma of the right index finger. Smooth muscle hamartoma (SMH) is a congenital, relatively common disorder typically with predominance of autochthonal arrector pili muscles. An SMH can also rarely originate from smooth muscles of vessels in palmoplantar skin with the absence of pilosebaceous units. Because of overlapping histological features, the possibility of Becker's nevus being identical or associated with SMH has often been suspected by some authors.

Knockout of cyclophilin D in Ppif⁻/⁻ mice increases stability of brain mitochondria against Ca²âº stress.

The mitochondrial peptidyl prolyl isomerase cyclophilin D (CypD) activates permeability transition (PT). To study the role of CypD in this process we compared the functions of brain mitochondria isolated from wild type (BMWT) and CypD knockout (Ppif(-/-)) mice (BMKO) with and without CypD inhibitor Cyclosporin A (CsA) under normal and Ca(2+) stress conditions. Our data demonstrate that BMKO are characterized by higher rates of glutamate/malate-dependent oxidative phosphorylation, higher membrane potential and higher resistance to detrimental Ca(2+) effects than BMWT. Under the elevated Ca(2+) and correspondingly decreased membrane potential the dose response in BMKO shifts to higher Ca(2+) concentrations as compared to BMWT. However, significantly high Ca(2+) levels result in complete loss of membrane potential in BMKO, too. CsA diminishes the loss of membrane potential in BMWT but has no protecting effect in BMKO. The results are in line with the assumption that PT is regulated by CypD under the control of matrix Ca(2+). Due to missing of CypD the BMKO can favor PT only at high Ca(2+) concentrations. It is concluded that CypD sensitizes the brain mitochondria to PT, and its inhibition by CsA or CypD absence improves the complex I-related mitochondrial function and increases mitochondria stability against Ca(2+) stress.

Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease.

BACKGROUND: Histopathological diagnosis including selection of lesions, the determination of the best point of time for biopsy and workup is not trivial in cutaneous graft-versus-host disease (GvHD). OBJECTIVES: To develop interdisciplinary recommendations on performing, the laboratory work up and reporting of the results of skin biopsies in patients with suspected cutaneous GvHD. METHODS: A working group consisting of dermatopathologists, dermatologists, transplant-physicians and transplant-pathologists prepared recommendations for performing skin biopsies, laboratory workup and evaluation of tissue samples, and reporting of the results in patients with cutaneous GvHD. After achieving a consensus within the working group, a survey that comprised the core issues of the recommendations was electronically sent out to 72 alloHSCT centres within Germany, Austria, and Switzerland and their Departments of Pathology. The answers were discussed in a Consensus Conference and final recommendations were established. RESULTS: Twenty-five centres responded to the clinical and 17 centres to the histopathological survey. Questions addressed to the clinicians comprised the indication for skin biopsy in chronic GvHD (cGvHD) and acute GvHD (aGvHD) and the appropriate point of time for skin biopsy. Eighty-eight per cent agreed that the skin biopsy is generally indicated in patients with suspected cGvHD lacking diagnostic features. In contrast, with suspected aGvHD, only 62% of respondents felt that skin biopsy was necessary even if GvHD had not been confirmed in another organ. Although restricted due to the fact that immunosuppression is often applied in an emergency setting most centres supported skin biopsies before initiation of topical or systemic immunosuppression. The majority of pathologists agreed that in non-sclerotic GvHD a punch biopsy is adequate, whereas in sclerotic GvHD a scalpel biopsy is preferred. CONCLUSION: While a consensus on the need for biopsies in cGvHD was reached the value of skin biopsies in aGvHD and subsequent biopsies during therapy requires further evaluation.

Histopathological diagnosis of graft-versus-host disease of the skin: an interobserver comparison.

BACKGROUND: Histopathology is an important tool in diagnosing cutaneous graft-versus-host disease (GvHD). Minimum diagnostic criteria for active chronic GvHD have recently been defined. However, they are not specific and their interpretation is dependent on observer judgement. AIMS OF THE STUDY: i) to explore interobserver variability in the interpretation of histopathological changes in GvHD, and ii) to analyse the impact of detailed clinical data on histopathological diagnosis of GvHD. METHODS: Histopathological slides from 15 skin biopsies of GvHD and from dermatoses with histopathologically similar appearance were sent in two phases to four dermatopathologists experienced in cutaneous GvHD in France, Germany, Italy and Switzerland (first round of 'blind' review followed by a second round with complete clinical information provided). RESULTS: Interface dermatitis, especially vacuolar alteration, was the most inconsistently evaluated, particularly in cases with minor alterations. Interestingly, for vacuolar alteration and apoptotic keratinocytes, interobserver variability was lower in the adnexal epithelia than in the interfollicular epidermis. Complete clinical information resulted in increased diagnostic confidence and greater concordance on the final diagnosis, rising from 53% (first round, k = 0.345, fair agreement) to 80% (second round, k = 0.529, moderate agreement). The percentage of correct diagnoses increased from 33.3% to 80%. CONCLUSION: For the diagnosis of GvHD, histopathological analysis is of importance, but, for correct diagnosis, the correlation of pathological findings with clinical results is crucial. In cases of minor alteration, histopathologists should focus on the interpretation of vacuolar changes and apoptotic keratinocytes, possibly on the adnexal epithelia.

[Delayed-type cutaneous drug reactions. Pathogenesis, clinical features and histology]. / Kutane Arzneimittelreaktionen vom Spättyp. Pathogenese, Klinik und Histologie.

BACKGROUND: Cutaneous reactions to drugs can be subdivided in different ways. In addition to the standard classification according to the etiopathogenesis there are also classifications based predominantly on morphological criteria. The majority of drug-related cutaneous adverse reactions are immunological reactions which are collectively classified under the term hypersensitivity. These reactions are based on drug-specific immunoglobulin E (IgE) or cell-mediated mechanisms, not on the mechanism of action of the drug and are unpredictable. Delayed type reactions to drugs are forms of type IV T-cell mediated hypersensitivity. A prerequisite is a stable association of a pharmaceutical substance with a protein so that hapten-protein conjugates can be produced. The most common clinical symptom is maculopapular (morbilliform) drug-related exanthema. This article also examines lichen planus like drug reaction and drug-induced (hematogenic) allergic contact dermatitis in more detail. DIAGNOSTICS: The diagnostics are never trivial but also include the differentiation from viral exanthema and initial phases of severe cutaneous adverse reactions, such as toxic epidermal necrolysis. In addition to the morphological classification, the final diagnosis encompasses the interpretation of histopathological alterations in the skin biopsy, analysis of patient medication history, laboratory results and inclusion of data from the literature. Patch tests can also have additional diagnostic benefits. In vitro tests which involve the cellular incubation of the drug responsible should be reserved for specialized laboratories. A prerequisite for successful treatment is immediate termination of the drug responsible. THERAPY AND PROGNOSIS: Therapy is symptomatic with topical and also short-term systemic steroids and antihistamines. The prognosis is very good.

Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial.

AIM: ImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAFV600-mutated melanoma. METHODS: In this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed. RESULTS: Of 185 patients enroled between November 2016 and December 2019, 135 were randomly assigned after the run-in period (Arm A, n = 69; Arm B, n = 66). Median PFS1 was significantly longer in Arm A versus Arm B (13.9 versus 5.9months; hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.37-0.84; PStratified=0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69-2.16; PStratified=0.389); 2-year OS was higher in Arm B versus Arm A (67%; 95%CI, 53-78 versus 58%; 95%CI, 45-70). Grade 3/4 AEs occurred in 55% of patients in Arm A and 64% in Arm B; treatment-related AEs led to discontinuation of any drug in 7% and 9% of patients, respectively. CONCLUSION: In patients with BRAFV600-mutated advanced melanoma who achieve tumour control with TT, early switch at 3months to atezolizumab led to rapid loss of tumour control but provided a numerical OS benefit at 2years compared with continued TT.

Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with lupus erythematosus: a descriptive study of 17 cases from a national registry and review of the literature.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions with high morbidity and mortality. Some expressions of lupus erythematosus (LE) may cause enormous difficulties in differentiating them from SJS and TEN by showing large areas of sheet-like epidermal necrosis. OBJECTIVE: To evaluate clinically and histopathologically probable or definite cases of SJS/TEN with a history of systemic or other LE [(S)LE]. METHODS: This was a retrospective analysis of validated cases of SJS/TEN with a history of (S)LE, based on a large population-based national registry. RESULTS: Among 1366 patients with SJS/TEN, 17 with a sufficiently documented history of (S)LE and representative histological material could be identified, suggesting a considerable over-representation of LE in patients with SJS/TEN. Eight of these showed clinically and/or histopathologically some LE-characteristic features interfering with the diagnosis of SJS/TEN. Differentiation could be elaborated on clinical and histopathological grounds: four patients were classified as SJS/TEN with a preceding (S)LE exacerbation and/or LE-typical histopathological features, and four as 'TEN-like' (S)LE. CONCLUSION: Most patients with SJS/TEN and a history of (S)LE demonstrate clinical and histopathological properties allowing clear differentiation. However, occasionally acute cutaneous manifestations of (S)LE and SJS/TEN can be phenotypically similar, caused by extensive epidermal necrosis. Although no feature by itself is conclusive, a combination of recent (S)LE exacerbation, evident photodistribution, annular lesions and absent or only mild focal erosive mucosal involvement may favour LE over SJS/TEN clinically. Histopathologically, in particular, junctional vacuolar alteration, and the presence of solitary necrotic keratinocytes at lower epidermal levels, combined with moderate to dense periadnexal and perivascular lymphocytic infiltrates with a variable presence of melanophages, and mucin point to a LE-related origin.

[Diagnostics and exclusion of hereditary angioedema : a standarized approach for the practice]. / Diagnostik und Ausschluss des hereditären Angioödems : Ein standardisierter Ansatz für die Praxis.

The differentiation between mast cell mediator-mediated and bradykinin-mediated forms of angioedema can be difficult. Bradykinin-mediated hereditary angioedema is a rare autosomal dominant hereditary disease which is characterized by recurrent edema attacks of varying magnitude. The edema occurs in the skin and mucous membranes and can be temporarily disfiguring, very painful and life-threatening by attacks in the laryngeal region. Because of the multitude of differential diagnoses, a final diagnosis is only achieved after an average duration of more than 10 years. The anamnestic and laboratory diagnostic algorithm presented here is designed to assist a simpler differentiation of the various forms of angioedema and to reach the correct diagnosis more quickly.

[Erythema annulare centrifugum. A clinical reaction pattern]. / Erythema anulare centrifugum. Ein klinisches Reaktionsmuster.

Erythema annulare centrifugum (EAC) is a clinical reaction pattern and not a specific clinicohistologic entity. The clinical and histologic differential diagnosis of EAC should take at least three main disease groups into consideration, which are often classified under this disorder: (tumid) lupus erythematosus, spongiotic dermatitides, and pseudolymphomas.

New concepts on erythema annulare centrifugum: a clinical reaction pattern that does not represent a specific clinicopathological entity.

BACKGROUND: Erythema annulare centrifugum (EAC) is considered an inflammatory skin disease with unknown aetiology. In most textbooks it is assigned to the incoherent conglomeration of figurate or gyrate erythemas. OBJECTIVES: To re-evaluate a large cohort of patients with EAC and to assess the evidence for infection with Borrelia. METHODS: We retrospectively investigated 90 cases with the diagnosis of EAC. Haematoxylin and eosin sections were re-examined and diagnoses were specified; these were then confirmed by clinicopathological correlation. Infection with Borrelia was assessed by focus-floating microscopy and by a Borrelia-specific polymerase chain reaction (PCR). RESULTS: Besides a miscellaneous group of annular disorders at times confused with EAC such as urticaria, leucocytoclastic vasculitis and psoriasis (20 of 90; 22%), EAC appeared to serve as a collective term for three main clinicopathological reaction patterns: (i) (tumid) lupus erythematosus (29 of 90; 32%), (ii) spongiotic dermatitides (25 of 90; 28%) and (iii) pseudolymphoma (16 of 90; 18%). In 13 of 16 (81%) cases with a pseudolymphomatous reaction pattern spirochaetes stained positive but were negative in other reaction patterns of EAC as well as in negative controls. These findings were confirmed by a Borrelia-specific PCR which was positive in two of three (67%) of these pseudolymphomatous EAC cases but was negative in all other variants of EAC (none of five) as well as 20 controls. CONCLUSIONS: We conclude that 'EAC' is a clinical reaction pattern that does not represent a specific clinicopathological entity and should lead to consideration of mainly lupus erythematosus, dermatitis and, in some cases, cutaneous Lyme disease.

Lymphocytic infiltration of the skin (Jessner-Kanof) but not reticular erythematous mucinosis occasionally represents clinical manifestations of Borrelia-associated pseudolymphoma.

BACKGROUND: Lymphocytic infiltration of the skin (LIS) and reticular erythematous mucinosis (REM) are characterized histologically by an inflammatory cutaneous lymphocytic infiltrate similar to the histological appearance of pseudolymphoma. OBJECTIVES: To re-evaluate a large cohort of patients with the clinical and/or histological diagnosis or differential diagnosis of LIS and REM and to assess the evidence for infection with Borrelia. METHODS: Sixty-nine cases of LIS and 34 cases of REM were retrospectively investigated. Haematoxylin and eosin sections were re-examined, and histological diagnoses were specified and confirmed by clinicopathological correlation. Evidence for Borrelia infection was assessed by immunohistochemistry and focus-floating microscopy (FFM). RESULTS: LIS appeared to serve as a collective term for two main clinicopathological reaction patterns: (i) (tumid) lupus erythematosus (LE) (32 of 69, 46%) and (ii) pseudolymphoma (31 of 69, 45%). Other diagnoses (five of 69, 7%) included polymorphic light eruption, arthropod bite reaction, spongiotic dermatitis, drug eruption and urticaria. Spirochaetes were detected by FFM in 24 of 31 (77%) cases with a pseudolymphomatous reaction, while all nonpseudolymphomatous reactions were negative. Of the cases initially considered as REM, 21 of 34 (62%) were classified as LE, four of 34 (12%) as pseudolymphoma (three of four positive for Borrelia), and five of 34 (15%) as other diagnoses (folliculitis, morphoea, seborrhoeic dermatitis, prurigo and arthropod bite reaction). The diagnosis of Borrelia-associated pseudolymphoma was made significantly more often in those cases where LIS was considered as initial differential diagnosis than REM (P < 0.05). CONCLUSIONS: LIS and REM seem to represent clinicopathological reaction patterns. Our results confirm that, after accurate clinicopathological correlation, most cases of both conditions constitute hidden variants of LE. Furthermore, LIS, in contrast to REM, frequently comprises pseudolymphomatous reactions including borrelial lymphocytoma.