Lives of Skin Lesions in Monkeypox: Histomorphological, Immunohistochemical, and Clinical Correlations in a Small Case Series.

Monkeypox (mpox), a former rare viral zoonosis, has increasingly made it into the public eye since the major outbreak that started in May 2022. Mpox presents with skin lesions that change over time and go through different stages (macular, papular, pustular, and early and late ulceration). In this study, we evaluated skin biopsies of all stages. Therefore, five biopsies from four patients were analyzed histologically, immunohistochemically with anti-Vaccinia virus antibodies, and electron-microscopically. Notably, the early macular stage only showed subtle viropathic changes; it did not express of Orthopoxvirus proteins in immunohistochemistry and therefore can easily be missed histologically. In later stages, immunohistochemistry with anti-Vaccinia virus antibodies might be useful to distinguish mpox from differential diagnoses such as herpes virus infections. In the ulcerative stages, the identified occlusive vasculopathic changes could be an explanation for the severe pain of the lesions reported by some patients. Despite the small number of samples examined, our analysis suggests that the histological findings of mpox are highly dependent on the stage of the biopsied lesion. Therefore, knowledge of all different stages of histology is necessary to reliably diagnose mpox histologically, especially when molecular testing is not available.

Hyperpigmented Mycosis Fungoides Masquerading as Longstanding Lichen Planus Pigmentosus: A Diagnostic Pitfall.

BACKGROUND: Mycosis fungoides (MF) is a rare primary cutaneous T-cell lymphoma, accounting for 50%-60% of all cutaneous T-cell lymphoma cases. It has a prevalence of approximately 5-6 cases per 1 million people annually and a higher incidence in dark-skinned populations. CASE PRESENTATION: We report a case of hyperpigmented MF in a 72-year-old dark-skinned man with a 5-year history of progressive, widespread poikilodermatous patches and thin plaques on the back and bilateral legs. The patient had been treated for lichen planus pigmentosus for 5 years without significant response to therapy. ASSESSMENT: Multiple biopsies revealed a band-like lymphoid infiltrate in the dermis, accompanied by intraepidermal lymphocytes, some of which had larger hyperchromatic nuclei. CD4 + T lymphocytes were predominant over CD8 + T-positive cells located along the epidermis, dermoepidermal junction, and in the dermis. DIAGNOSIS: A diagnosis of hyperpigmented MF was made based on the clinical, histopathological, and immunohistochemical findings. CONCLUSION: This case report highlights the importance of considering hyperpigmented MF as a differential diagnosis in patients with longstanding lichen planus pigmentosus, particularly when there is a lack of response to therapy.

Disseminierte papulöse Variante des Morbus Dowling-Degos: Histopathologische Merkmale bei POGLUT1-Mutation.

Der Morbus Dowling-Degos ist eine seltene, benigne Genodermatose. Charakteristisch sind lentiginöse Hyperpigmentierungen sowie rotbraune Papeln und Plaques. Häufig sind die Beugeseiten und Intertrigines betroffen, das klinische Bild kann jedoch variieren. Verantwortlich für die klinische Ausprägung sind Mutationen in unterschiedlichen Genen. Während Mutationen im Keratin 5 (KRT5)-Gen ein retikuläres Verteilungsmuster begünstigen, führen Mutationen im POGLUT1-Gen zu einem disseminierten, papulösen klinischen Bild. Die akantholytische Variante des Morbus Dowling-Degos wird historisch als Morbus Galli-Galli bezeichnet, unsere Falluntersuchung zeigt jedoch, dass die histopathologischen Veränderungen auch innerhalb eines Patienten variieren können. Bisher gibt es kein einheitliches Therapiekonzept. Keratolytische Maßnahmen stehen im Vordergrund, mit unterschiedlich gutem Ansprechen. Neue Therapieansätze mit Hilfe der Lasertechnologie scheinen eine vielversprechende Behandlungsoption zu sein.

Klinisch-pathologische Merkmale und histologische Tumorreste in Reexzisionspräparaten unvollständig resezierter Basalzellkarzinome.

HINTERGRUND UND ZIELSETZUNG: Die chirurgische Exzision ist die bedeutendste Therapiemodalität zur Versorgung von Basalzellkarzinomen (BCC). Oft kommt es zu einer unvollständigen Exzision, die eine Reexzision nach sich zieht. Allerdings enthalten Reexzisionspräparate häufig keine Tumorreste, weswegen die Reexzision im Nachhinein überflüssig ist. Ziel unserer Studie ist die Identifikation von klinisch-pathologischen Merkmalen, die mit dem Vorhandensein von histologischen Tumorresten in Reexzisionspräparaten assoziiert sind. PATIENTEN UND METHODEN: 255 unvollständig resezierte BCC von 222 Patienten wurden in diese Fall-Kontroll-Beobachtungsstudie eingeschlossen. Acht klinisch-pathologische Merkmale wurden in einer binären logistischen Regressionsanalyse mit dem Vorhandensein oder Nichtvorhandensein von histologischen Tumorresten in Reexzisionspräparaten korreliert. ERGEBNISSE: Ein höheres Alter bei der ersten Exzision und ein BCC in der Rezidiv-Hochrisikozone erwiesen sich als unabhängige Risikofaktoren für das Vorhandensein von histologischen Tumorresten in Reexzisionspräparaten. SCHLUSSFOLGERUNGEN: Die Ergebnisse unserer Studie zeigen, dass eine Reexzision von unvollständig resezierten BCC in der oben genannten Subpopulation definitiv notwendig ist. Für die Nachbehandlung unvollständig resezierter BCC, die sich in der Rezidiv-Niedrigrisikozone jüngerer Patienten befinden, können jedoch auch weniger invasive Therapien wie Imiquimod in Betracht gezogen werden.

Clinicopathological features and histological tumor residues in re-excision specimens of incompletely resected basal cell carcinomas.

BACKGROUND AND OBJECTIVE: Surgical excision is the primary mode of treating basal cell carcinoma (BCC). Incomplete excision is a common phenomenon usually dealt with by re-excision. However, re-excision specimens often do not contain any tumor residues, rendering the procedure superfluous in hindsight. Our study objective is the identification of clinicopathological features associated with the presence of histological tumor residues in re-excision specimens. PATIENTS AND METHODS: 222 patients with a total of 255 incompletely resected BCCs were enrolled in this observational case-control study. Eight clinicopathological features were correlated in a binary logistic regression analysis to the presence or absence of histological tumor residues in re-excision specimens. RESULTS: Advanced age at first excision and a BCC in the high-risk zone for recurrence were found to be independent risk factors for the presence of histological tumor residues in re-excision specimens. CONCLUSIONS: Our study results indicate a clear need for re-excision of incompletely resected BCCs in the aforementioned subpopulation. However, less invasive therapies such as imiquimod may be considered for the follow-up treatment of incompletely resected BCCs located in the low-risk zone for recurrence in younger patients.

Disseminated papular variant of Dowling-Degos disease: Histopathological features in POGLUT1 mutation.

Dowling-Degos disease is a rare benign genodermatosis. It is characterized by lentiginous hyperpigmentation and reddish-brown papules and plaques. The flexor sides and intertrigines are often affected, but the clinical appearance may vary. Mutations in different genes are responsible for the clinical manifestation. While mutations in the keratin 5 (KRT5) gene favor a reticular distribution pattern, mutations in the POGLUT1 gene lead to a disseminated, papular clinical picture. Acantholytic variants of Dowling-Degos disease have historically been referred to as Galli-Galli disease, but our case study shows that the histopathological changes can vary even within a single patient. To date, no standardized therapy concept exists. The main focus is on keratolytic measures, with varying response. New therapeutic approaches using laser technology appear to be a promising treatment option.

Podoconiosis: Clinical spectrum and microscopic presentations.

BACKGROUND: Podoconiosis is a skin Neglected Tropical Disease (skin NTD) that causes lymphoedema, and affects barefooted subsistence farmers in some tropical countries. The clinical presentation and histopathologic correlates of podoconiosis have been understudied. Here, we systematically document the clinical and histopathologic spectrum of podoconiosis. METHODS: This is a cross-sectional study in Durbete, Ethiopia from February 2018 to October 2019. Dermatologists performed a patient history, physical examination, filariasis test strip, and skin biopsy for histopathologic examination. The results were summarised and a descriptive statistical analysis and Wilcoxon rank sum test with continuity correction was done. RESULTS: We recruited 289 patients for the study, 178 (61.6%) had stage 1 or 2 podoconiosis, and 111(38.4%) stage 3 to 5 podoconiosis. 188 (64.1%) had a family history of podoconiosis. In 251 (86.9%) patients, both legs were affected by podoconiosis and in 38 (13.1%) only one leg was affected. 220 (77.5%) patients had warty lesions, 114 (39.4%) had nodules. The median number of episodes of Acute Dermato-Lymphangio-Adenitis (ADLA) reported by the patients in the last three months was 2 (interquartile range (IQR) 1-4). Increased episodes of ADLA were significantly associated with stage 3-5 podoconiosis (P = 0.002), while burning pain in the feet was more common in stage 1 or 2 podoconiosis. Stage 3-5 disease was histopathologically characterised by epidermal and dermal thickening, verrucous acanthosis, inflammatory cell infiltrates (predominantly lymphoplasmacytic), dilated and ectatic and a reduced number of lymphatic vessels, eccrine ductal hyperplasia, and sclerosis such as thickened collagen bundles. CONCLUSION: We provide a detailed description of the different clinical patterns, associated clinical findings and the histopathologic spectrum of podoconiosis at different stages of the disease. Our observations should serve as a guide to classifying patients with podoconiosis for prognostic assessment and treatment decision.

Diagnosis of Lyme Borreliosis With a Novel, Seminested Real-Time Polymerase Chain Reaction Targeting the 5S-23S Intergenic Spacer Region: Clinical Features, Histopathology, and Immunophenotype in 44 Patients.

ABSTRACT: Lyme borreliosis (LB) is the most common tick-borne infection in Europe and North America. Polymerase chain reaction (PCR) is an important tool to confirm the diagnosis, but not always successful, especially when organisms are sparse. We developed a novel, seminested real-time PCR assay [target: 5S-23S intergenic spacer region (IGS)] and compared it with 3 well-established conventional PCR assays (IGS/OspA/real-time IGS) on 596 formalin-fixed, paraffin-embedded routine skin biopsies. The seminested real-time assay identified 46 cases of borreliosis while 25, 27, and 38 were identified by the 3 other assays, respectively (P 0.01, P 0.02, and P 0.42; significance P < 0.05). Clinicopathologic and immunophenotypic analysis of PCR-positive cases revealed 38 erythema migrans (EM), 6 Borrelia lymphocytomas, and 2 acrodermatitis chronica atrophicans (ACA). In the 44 PCR-confirmed cases, plasma cells were present in only a third of EM cases. By contrast, CD123-positive plasmacytoid dendritic cells were common (74%) and therefore are unlikely to be helpful in the differential diagnosis between EM and tumid lupus erythematosus. A loss of CD34 in a third of all LB specimens limits its diagnostic value in the differential diagnosis with morphea. Interstitial macrophages were common in cutaneous LB (42/43) forming interstitial granulomas in a third of all cases, and 3/38 EM, 3/6 Borrelia lymphocytomas, and 1/2 ACA were only identified by the new seminested real-time assay, suggesting that it is especially helpful in confirming the diagnosis of Borrelia lymphocytoma.

A Deep Learning Approach for Histopathological Diagnosis of Onychomycosis: Not Inferior to Analogue Diagnosis by Histopathologists.

Onychomycosis is common. Diagnosis can be confirmed by various methods; a commonly used method is the histological examination of nail clippings. A deep learning system was developed and its diagnostic accuracy compared with that of human experts. A dataset with annotations for fungal elements was used to train an artificial intelligence (AI) model. In a second dataset (n=199) the diagnostic accuracy of the AI was compared with that of dermatopathologists. The results show a non-inferiority of the deep learning system to that of analogue diagnosis (non-inferiority margin 5%) with respect to specificity and the area under the receiver operating characteristic curve (AUC). The AI achieved an AUC of 0.981. One limitation of this system is the need for a large number of training images. The AI had difficulty recognizing spores and confused serum or aggregated bacteria with fungal elements. Use of this deep learning system in dermatopathology routine might help to diagnose onychomycosis more efficiently.

Psoriasis on the Leg: Site-specific Histopathological and Immuno-histochemical Features and Diagnostic Difficulties.

The histopathology of psoriasis can lack classical features on certain anatomical sites. The aim of this study was to detail the histopathology and immunophenotype of psoriasis on the legs, in order to differentiate it from other inflammatory dermatoses, such as stasis dermatitis. The histopathology of psoriasis on the legs was retrospectively compared with psoriasis on the trunk and stasis dermatitis. Statistically, psoriasis on the legs was significantly less likely to show typical histological criteria of psoriasis, such as regular hyperplasia, suprapapillary thinning, and "kissing vessels". The most valuable criteria to distinguish psoriasis on the legs from stasis dermatitis were the presence of neutrophils in the cornified layer and staggered parakeratosis. In addition, an immunohistochemical panel (Ki-67, Bcl-2alpha, S100A7, CD3, MPO, CK10, CK16) revealed that staining with Ki-67 and MPO could be diagnostically useful. Since the cornified layer contains important histopathological clues to differentiate psoriasis on the legs from stasis dermatitis, clinicians should refrain from unnecessary rubbing during disinfection before taking a biopsy.

Histopathological Spectrum and Immunophenotypic Characterization of Symmetrical Drug-Related Intertriginous and Flexural Exanthema.

INTRODUCTION: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a clinically very well-defined drug eruption, but the histopathological findings are still considered to be nonspecific. OBJECTIVES: To characterize the histopathological and immunophenotypical features of SDRIFE. MATERIAL AND METHODS: We performed a retrospective study that identified 11 biopsies from 9 patients with SDRIFE. The histopathological features were analyzed in conjunction with the immunohistochemical findings. RESULTS: The most common histopathological feature was basal cell vacuolization, which was often associated with necrotic keratinocytes and focal spongiosis. TIA1+ T cells and neutrophils were frequently detected in the epidermis and at the dermoepidermal junction. The dermal inflammatory infiltrate was mixed, consisting of CD3+ T cells, macrophages, granulocytes, low numbers of CD20+ B cells, and plasma cells. A combination of histopathological patterns was observed in 5 cases. The most frequent combined histopathological patterns were interface dermatitis, spongiotic dermatitis, and psoriasiform dermatitis. Other histopathological patterns found in different combinations were pustular dermatitis, perivascular and interstitial neutrophilic dermatitis, and interstitial granulomatous dermatitis. In the other 4 cases, a single histopathological pattern predominated, such as psoriasiform dermatitis, vacuolar interface dermatitis of erythema multiforme-like type, or superficial and deep perivascular and interstitial dermatitis with eosinophils and neutrophils. CONCLUSIONS: SDRIFE is characterized histologically by a vacuolar interface dermatitis induced by cytotoxic T lymphocytes and neutrophilic granulocytes. This pattern may be obscured by accompanying spongiotic, psoriasiform, or pustular features combined with a mixed superficial and sometimes deep dermal infiltrate.

[Lichen planus: fundamentals, clinical variants, histological features, and differential diagnosis]. / Lichen (ruber) planus: Grundlagen, klinische Varianten, histologische Besonderheiten und Differenzialdiagnostik.

Lichen planus (LP) is a relatively common inflammatory skin disease in dermatological practice. The typical presentation of LP is usually diagnosed clinically. Less common variants such as LP inversus, atrophic LP, the palmoplantar manifestation or childhood LP may pose diagnostic difficulties so that a biopsy is taken to confirm the diagnosis. Differentiation from LP-like drug eruption may be challenging and biologicals have to be considered as triggers. Etiology and pathogenesis of LP are discussed based on recent literature. Finally, an overview of therapeutic options for different variants of the condition includes most recent approaches to treatment.

[New aspects in the histopathology of infectious skin diseases]. / Neue Aspekte zur Histopathologie bei Hautinfektionen.

BACKGROUND: An infectious pathogenesis should always be considered in inflammatory infiltrates in the skin. While some organisms can be recognized on hematoxylin-eosin staining (e.g. yeasts, leishmania), histochemical and immunohistochemical stainings are available for others. OBJECTIVES: If no organisms are seen in a section, the diagnosis of an infection cannot be made with surety, but the pattern of the inflammatory infiltrate can still be suggestive of an infectious process. New or little-known reaction patterns and difficulties in differential diagnosis will be demonstrated. MATERIALS AND METHODS: Selective literature review and analysis of individual cases. RESULTS: Studies using molecular techniques to identify organisms in biopsy specimens have helped to better characterize the histomorphological spectrum of skin infiltrates in infectious skin diseases. Apart from unusual herpes simplex and varicella zoster infections, the histopathology of coxsackie virus and measles exanthem, borreliosis, syphilis, and of cutaneous leishmaniasis is demonstrated. For numerous organisms, molecular tests have been established that can be used on the formalin-fixed, paraffin-embedded material. CONCLUSIONS: Selected skin infections demonstrate the broad histomorphological spectrum of skin infiltrates induced by infectious organisms. It is important for histopathologists to know which reaction pattern requires them to alert the clinician to necessary ancillary diagnostics (culture, serology) and when to consider molecular diagnostics to be performed on the biopsy specimen.

Promyelocytic Differentiation in Infiltrates of Prurigo Pigmentosa: An Analogy to Histiocytoid Sweet Syndrome.

Prurigo pigmentosa (PP) is a rare inflammatory dermatosis of unknown etiology. Young women are affected most commonly. Clinically, heavily itchy papules erupt mainly on the trunk healing with residual reticulate pigmentation. Histopathologic descriptions of PP are somewhat controversial. First, PP was reported as lichenoid-interface dermatitis, and later, neutrophils were recognized as the characteristic feature, and the variation in histopathologic patterns was interpreted as a time-dependent phenomenon. Immunohistochemical studies on PP are rare. Biopsies of 5 patients with clinically typical PP were examined histopathologically, and infiltrates were characterized immunohistochemically: myeloperoxidase, CD11c, CD68, CD4, CD8, tryptase, and langerin. In all cases, myeloperoxidase-positive cells with band forms of nuclei and with histiocytoid cytomorphology were identified. They were seen in the epidermis (4/5) and in the dermal infiltrate (5/5). On staining with CD11c, myeloid dendritic cells could be demonstrated in the infiltrate (5/5). In conclusion, myeloid progenitor cells are part of the infiltrate in PP, and they may sometimes be more numerous than mature neutrophils, akin to the situation in histiocytoid Sweet syndrome. This supports the classification of PP as a "neutrophilic dermatosis." In biopsies of suspected PP in which mature neutrophils are sparse, the section should be searched for neutrophilic band forms and histiocytoid promyelocytic cells. Immunohistochemical staining with myeloperoxidase helps to identify such cells and may enable a diagnosis of PP even when mature neutrophils are few.

Cytologic Grading of Cutaneous Sebaceous Neoplasms: Does it Help to Differentiate Benign From Malignant?

Both architectural and cytologic characteristics are used to distinguish benign from malignant sebaceous neoplasms; however, specific cytopathologic features of sebocytes have not been well defined. The authors assessed architectural and cytological features of 63 sebaceous neoplasms [15 sebaceous hyperplasias, 12 sebaceomas, 16 sebaceous adenomas (SA), 14 sebaceous carcinomas (SC), and 6 ocular sebaceous carcinoma (OSC)] to investigate whether cytological grading may facilitate classification of lesions. Among other criteria, nuclear pleomorphism (size, nucleolar appearance, membrane irregularity, crowding, mitoses, and chromatin pattern) was assessed and 3 theoretical nuclear grades established. Immunohistochemistry for CK10, p16, adipophilin and ki67 was performed on 7 cases of each type of tumor. Most sebaceous neoplasms, except OSC, showed a bland architectural silhouette. However, SA, SC, and OSC revealed larger nuclei (≥14 µm in ≥50% of cases), evident to multiple nucleoli, membrane irregularity, coarse to clumped chromatin, and nuclear grade ≥2 (latter in ≥56% of cases); by contrast, sebaceous hyperplasia and sebaceomas showed smaller nuclei (≤10 µm in ≥50% of cases), smooth borders, inconspicuous nucleoli, fine chromatin, and grade 1 nuclei (latter in 100% of cases). In the setting of a well-circumscribed architecture, cytologic features gain importance in the classification of sebaceous neoplasms. Interestingly, cytologic similarities found in SA and SC may indicate a close relationship of both neoplasms.

Histopathology of Hand-Foot-Mouth Disease in Adults and Criteria for Differentiation From Erythema Multiforme.

BACKGROUND: Hand-foot-mouth disease (HFMD) is a common contagious viral infection usually affecting infants and children. Recently, literature on HFMD in adults is increasing. It has been reported that adults often present with unusual exanthems with similarities to erythema multiforme (EM). No study has so far compared the histologic features of HFMD with those of EM. METHODS: Histopathologic features in 7 biopsies of 6 adult patients with HFMD are compared with biopsies from 9 patients with EM to identify the best criteria for differentiation. RESULTS: HFMD and EM both have a perivascular lymphocytic infiltrate together with epidermal necrosis, spongiosis, ballooning, and reticular alteration. However, large numbers of neutrophils in parakeratosis (P < 0.05), in the viable epidermis (P < 001), or neutrophils forming intraepidermal collections (P < 0.05) are significantly more common in HFMD. In HFMD, necrotic keratinocytes are emphasized in the upper third of the epidermis (P < 0.05), whereas the lower third is typically involved more in EM. Neutrophils are significantly more common and more numerous in the dermal infiltrate of HFMD compared with EM (P < 0.01) Extravasated erythrocytes in the epidermis are more common and more numerous in HFMD (P < 0.05). CONCLUSIONS: Lesions of EM and HFMD can be differentiated based on the amount of neutrophils in the epidermis and in the dermal infiltrate, which are significantly more numerous in HFMD. In addition, necrosis is emphasized in the upper part of the epidermis in HFMD and in the lower part of it in EM.

Histomorphology and Immunophenotype of Eczematous Skin Lesions Revisited-Skin Biopsies Are Not Reliable in Differentiating Allergic Contact Dermatitis, Irritant Contact Dermatitis, and Atopic Dermatitis.

Lesions of allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), and atopic dermatitis (AD) share similar clinical features and thus, their diagnosis can be challenging. The aim of this study was to reassess histopathology and immunophenotyping properties to distinguish between ACD, ICD, and AD. Charts of patients with eczema, who had undergone complete routine diagnostic workup (skin biopsies, patch tests, skin prick tests, and respectively or serum IgE levels), were reviewed. Thirty-five skin biopsy specimens of 28 patients (mean age 64 ± 15 years; ♀ = 13 ♂ = 15) with clear diagnosis of ACD (n = 15), ICD (n = 6), or AD (n = 14) were analyzed. Histomorphological and immunohistochemical (CD3, CD4, CD8, CD11c, CD34, CD123, S100, and IL-17) parameters were evaluated using Kruskal-Wallis test, Wilcoxon test, Fisher exact test, and decision tree analysis. Eosinophils were statistically significant (P = 0.0184), more often observed in AD than in ACD or ICD. No other statistically significant differences were found with regard to epidermal patterns, patterns of dermal infiltrates, or immunophenotyping. Using predictive modeling approaches, dermal eosinophils were found to be associated with AD, necrotic epidermal keratinocytes with ICD, and a focal type of parakeratosis with ACD. As an additional finding, pseudo-Pautrier microabscesses, which were present in the skin of 2 AD and 2 ACD patients, contained myeloid dendritic cells (CD11c). Differentiation of ACD, ICD, and AD should be based on clinical features and results of allergy tests. Histopathology does not reliably differentiate between ACD, ICD, and AD, but helps to exclude psoriasis, tinea, or T-cell lymphoma.

Induction of Desmoplastic Trichoepithelioma in a Dermatofibroma.

Induction of follicular germinative structures above a dermatofibroma (DF) is a common finding. Rarely, induction of a trichoblastoma in a DF has been observed. Here, we report the case of a desmoplastic trichoepithelioma induced by a DF. The lesion with clinical and histological appearance of a DF situated on the left dorsal foot showed an associated adnexal proliferation that fulfilled histopathological criteria of desmoplastic trichoepithelioma. Immunohistochemistry (Ber-EP4, Bcl-2, CK17, CK20, CK7, EMA, and Ki67) helped to confirm the diagnosis and to exclude possible differential diagnoses.