Felix von Bärensprung-A Review of His Life and Work on the Occasion of His 200th Birthday.

ABSTRACT: Felix von Bärensprung was a pioneer of dermatopathology. His monograph of 1848, "Contributions to the Anatomy and Pathology of the Human Skin," was one of the first publications on that subject. Von Bärensprung also described and named erythrasma, elucidated the pathogenesis of herpes zoster, contributed a comprehensive review of the history of dermatology in an unfinished textbook of skin diseases, and was coauthor, together with Ferdinand Hebra of Vienna, of one of the most influential clinical atlases in the history of dermatology. The 200th anniversary of his birthday in 2022 provides an occasion for reminding of one of the leading dermatologists of the mid 19th century.

Histopathological features of human mpox: Report of two cases and review of the literature.

Human monkeypox is an emerging zoonosis with epidemic potential. Although it usually causes a mild disease, some patients are at risk for complications, including death. In face of the current outbreak of monkeypox in non-endemic areas, awareness is paramount to diagnose it timely, prompting an early break of the transmission chain. Histopathologic findings in vesiculopustular lesions of monkeypox are distinctive, consisting of ballooning and reticular degeneration of keratinocytes, necrosis, especially of the upper portions of the epithelium, multinucleation of keratinocytes, nuclear enlargement showing a "basophilic halo" around a "ground glass" eosinophilic center, the orthopoxvirus-specific cytoplasmic eosinophilic Guarnieri-type inclusions (in the pustular stage especially), and a dense mixed inflammatory cell infiltrate with prominent neutrophil exocytosis. The diagnosis of human monkeypox requires a high index of suspicion. In correlation with clinical information, histopathological findings allow for a presumptive diagnosis of monkeypox if polymerase chain reaction testing is not available. Both clinicians and pathologists can optimize diagnostic sensitivity, respectively, by considering the epidemiological context, sampling pustular lesions and providing data for clinicopathological correlation, and by intentionally searching the tell-tale eosinophilic inclusions in genital, anal and oral lesions with reticular and ballooning degenerescence.

The Emperor's New Clothes: A Critique of the Current WHO Classification of Malignant Melanoma.

The World Health Organization's classification of skin tumors of 2018 presents melanoma as a loose assembly of independent biologic entities, each of which is characterized by a distinctive constellation of clinical, histopathologic, and molecular findings that evolve through different pathways of lesional progression from a benign to an intermediate and, ultimately, malignant tumor. The alleged pathways, however, are based on vague correlations and fail to take into account the common occurrence of lesions that cannot be assigned to either of them. Moreover, there is no such thing as a lesional progression. The evolvement of neoplasms is always a clonal and, therefore, initially focal event. In the majority of melanomas, there is no evidence of a juxtaposition of a benign, intermediate, and malignant portion. Occasionally, a melanoma may develop within the confines of a melanocytic nevus, but a nevus cannot transform into melanoma. The concept of lesional progression merely serves to handle problems of differential diagnosis because it obscures and, in fact, denies the difference between benign and malignant neoplasms. In the current classification of the World Health Organization, every lesion is said to bear some risk of malignant progression, intermediate categories are recognized for all alleged pathways, and no distinction is made between "high-grade dysplasia" and melanoma in situ. Differentiation between benign and malignant neoplasms of melanocytes may be difficult, but the concept of lesional progression does not address those problems; it merely offers evasions under the disguise of diagnoses.

Joseph von Gerlach-A Reminder of One of the Pioneers of Histochemistry on the Occasion of His 200th Birthday.

Joseph von Gerlach was an eminent German anatomist and pioneer of histology. He devised various techniques to assess the fine structure of tissues, most notably a procedure of staining histologic sections that marked the beginning of routine staining in histology. Gerlach was also one of the pioneers of microphotography.

Angiogenesis in Ocular and Extraocular Sebaceous Carcinoma.

To shed more light on the pathogenesis of sebaceous carcinoma, we analysed the expression of proteins related to angiogenesis in 18 ocular and 22 extraocular sebaceous carcinomas using a broad panel of immunohistochemical markers. To quantify the expression of D2-40, vascular endothelial growth factor, vascular endothelial growth factor receptor-2 and -3, we calculated a quantification score by considering the percentage of positive tumour cells (0=0%, 1=up to 1%, 2=2-10%, 3=11-50%, and 4=>50%) in relation to the staining intensity (0=negative, 1=low, 2=medium, and 3=strong). Additionally, lymphatic microvessel density in the D2-40 stained sections was counted. Vascular endothelial growth factor receptor-3 (quantification score 9.42 ± 2.94) was significantly more strongly expressed than vascular endothelial growth factor receptor-2 (quantification score 2.15 ± 2.42, p < 0.001). Furthermore, epidermal vascular endothelial growth factor expression was negatively correlated with the intratumoural lymphatic vessel density, and the ratio of small lymphatics to large lymphatics was much higher in intratumoural tissue than in paratumoural tissue and in intraindividual control tissue, suggesting a lymphangiogenetic potential of sebaceous carcinoma.

"Personalized Excision" of Malignant Melanoma-Need for a Paradigm Shift in the Beginning Era of Personalized Medicine.

The premises on which guidelines for the excision of primary cutaneous melanoma are based are illogical and fail to take into account peculiarities of the individual lesion. The horizontal margins of excision continue to be adjusted to the vertical thickness of the neoplasm, and recommended clinical margins do not reflect the histopathologic borders of melanoma. Micrographically controlled surgery has become accepted for acral melanomas and melanomas of the face and neck but not for melanomas on the trunk, arms, and legs, although the latter tend to be more sharply confined. Extending margins of excision for the purpose of removing inapparent metastases is fallacious because the latter are rare, their localization cannot be foretold, and satellite metastases are usually associated with distant metastases, so that patients do not profit from early removal of cutaneous lesions. The only meaningful objective of excision is complete removal of the primary melanoma. The success of excision must be controlled histopathologically. Because of limitations of the method, a histopathologic safety margin should be observed that must depend on the characteristics of the individual lesion. In sharply confined melanomas, a histopathologic margin of at least 1 mm is sufficient. In the case of poor demarcation, with solitary atypical melanocytes extending far beyond the bulk of the lesion, a broader histopathologic safety margin is advisable. Special caution should be exercised in the presence of regression and for desmoplastic melanomas, acral melanomas, and melanomas on the face and scalp. Instead of wide and deep excisions with standardized margins, "personalized excisions" are required for primary cutaneous melanoma. The concept of clinical safety margins is a relic of former times that has no place in modern medicine.

Screening for malignant melanoma-a critical assessment in historical perspective.

Screening for melanoma has been advocated for many years because early detection and excision have been regarded as the most important measure to lower mortality from that neoplasm. In the past decade, concern has been raised by epidemiologists that screening might result in excision chiefly of "inconsequential cancer," i.e., melanomas that would never have progressed into life-threatening tumors, a phenomenon referred to by the misleading term "overdiagnosis." Without any firm evidence, that speculation has been embraced worldwide, and incipient melanomas have been trivialized. At the same time, efforts at early detection of melanoma have continued and have resulted in biopsy of pigmented lesions at a progressively earlier stage, such as lesions with a diameter of only 2, 3, or 4 mm. Those tiny lesions often lack sufficient criteria for clinical and histopathologic diagnosis, the result being true overdiagnoses, i.e., misdiagnoses of melanocytic nevi as melanoma. This is especially true if available criteria for histopathologic diagnosis are diminuished even further by incomplete excision of lesions. The reliability of histopathologic diagnosis is far higher in excisional biopsies of lesions that were given some more time to develop changes that make them recognizable. Biopsy of pigmented lesions with a diameter of 6 mm has been found to result in a far higher yield of melanomas. In addition to better clinical judgment, slight postponement of biopsies bears the promise of substantial improvement of the reliability of histopathologic diagnosis, and of alleviating true overdiagnoses.

Regressing basal-cell carcinoma masquerading as benign lichenoid keratosis.

BACKGROUND: Benign lichenoid keratosis (BLK, LPLK) is often misdiagnosed clinically as superficial basal-cell carcinoma (BCC), especially when occurring on the trunk. However, BCCs undergoing regression may be associated with a lichenoid interface dermatitis that may be misinterpreted as BLK in histopathologic sections. METHODS: In order to assess the frequency of remnants of BCC in lesions interpreted as BLK, we performed step sections on 100 lesions from the trunk of male patients that had been diagnosed as BLK. RESULTS: Deeper sections revealed remnants of superficial BCC in five and remnants of a melanocytic nevus in two specimens. In the original sections of cases in which a BCC showed up, crusts tended to be more common, whereas vacuolar changes at the dermo-epidermal junction and melanophages in the papillary dermis tended to be less common and less pronounced. CONCLUSIONS: Lesions from the trunk submitted as BCC and presenting histopathologically as a lichenoid interface dermatitis are not always BLKs. Although no confident recommendations can be given on the basis of this limited study, deeper sections may be warranted if lesions are crusted and/or associated with only minimal vacuolar changes at the dermo-epidermal junction and no or few melanophages in the papillary dermis.

Frequent detection of human polyomavirus 6 in keratoacanthomas.

BACKGROUND: The recent discovery of the Merkel cell polyomavirus and its consistent association with Merkel cell carcinoma has drawn attention to the numerous recently discovered polyomaviruses and their possible involvement in the etiopathogenesis of non-melanoma skin cancer (NMSC). Data on the recently discovered human polyomavirus 6 (HPyV6) and its role in NMSC are sparse and in part controversial. METHODS: In the present study we tested a large number (n = 299) of NMSC specimens for the presence of human polyomavirus 6 (HPyV6) by DNA PCR and HPyV6 fluorescence in situ hybridization (FISH). In detail, 59 keratoacanthomas (KA), 109 basal cell carcinomas (BCC), 86 squamous cell carcinomas (SCC) and 45 trichoblastomas (TB) were tested for the presence of HPyV6. RESULTS: HPyV6 DNA PCR and subsequent sequence analysis revealed that 25 KAs (42.3 %), 23 BCCs (21.1 %), 8 SCCs (9.3 %) and 10 TBs (22.2 %) were HPyV6 positive. The presence of HPyV6 DNA was visualized and validated on the single cell level within the histomorphological context by HPyV6 fluorescence in situ hybridization. CONCLUSIONS: The high frequency of HPyV6 DNA in 42.3 % of KA possibly points to a role for HPyV6 in the etiopathogenesis of KAs. Although the detection rate of HPyV6 DNA in BCCs and TBs is within the previously reported detection range in normal skin, it does not exclude a possible role for HPyV6 in the carcinogenesis in a significant subset of these skin tumors.

Forward to the Past-Oncology Between Underdiagnosis and Overtreatment.

Efforts at early detection of cancer have resulted in a sharp increase of overdiagnoses, ie, benign lesions being misinterpreted as malignant ones. Clinical overdiagnoses usually prompt a biopsy to be performed. The number of biopsies has risen dramatically, and the average time and diligence devoted to them have decreased. Biopsy specimens are often extremely small and sometimes crushed, leading to great difficulties in the assessment of histopathologic findings. In their fear not to overlook a malignant lesion, histopathologists confronted with an equivocal lesion tend to err on the malignant side, the results being histopathologic overdiagnoses and overtreatment. Epidemiologists have tried to counter those problems by cautioning against cancer screening and by inaugurating a change in nomenclature: the term "cancer" has been reserved for lesions likely to result in death, whereas earlier stages of the same process are referred to by different names emphasizing their ostensible innocuousness, and any diagnosis of a malignant neoplasm that does not produce symptoms or kill the patient is qualified as "overdiagnosis." In contrast to those suggestions that ignore biologic entities and sacrifice the foundations of morphologic diagnosis, measures are discussed that may help to overcome the problem of overdiagnosis and overtreatment in more substantial fashion.

William Boog Leishman-A Brief Reminder of His Life and Work on the Occasion of His 150th Birthday.

William Boog Leishman was born 150 years ago. Although his description of "small round or oval bodies" in a smear from the spleen pulp of a soldier who had died of kala-azar was not the first one of Leishmania and although Leishman did not make the diagnosis of kala-azar and misinterpreted the microorganisms to be trypanosomes, his article became the springboard for a series of studies that, within a few months, established Leishmania as a previously unknown genus of protozoa and led to appreciation of the clinical spectrum of kala-azar and the relationship between cutaneous and visceral leishmaniasis.

Hypertrophic lichen sclerosus sine sclerosis: clues to histopathologic diagnosis when presenting as psoriasiform lichenoid dermatitis.

BACKGROUND: The histopathologic diagnosis of lichen sclerosus (LS) is usually facilitated by a subepidermal zone of sclerosis. In the absence of sclerosis, LS mostly presents itself as a psoriasiform lichenoid dermatitis that may be difficult to distinguish from other diseases. OBJECTIVE: We sought to assess histopathologic findings that allow recognition of LS in the absence of sclerosis. METHODS: We studied 28 criteria in 100 biopsy specimens of LS from genital or perianal skin, including 55 cases with marked sclerosis, 16 cases with mild sclerosis confined to foci of the papillary dermis and 29 cases without sclerosis. Fifteen cases each of the early plaque stage of mycosis fungoides, lichen planus and lichen simplex chronicus were studied for comparison. RESULTS: Some histopathologic hallmarks of LS were seen chiefly in sclerotic lesions and, therefore, did not contribute to the diagnosis of difficult cases, such as dissolution of elastic fibers. Others were seen rarely in non-sclerotic lesions but might be helpful in individual cases, including follicular hyperkeratosis and thickening of the basement membrane. Findings that were more common and may be utilized as clues to the histopathologic diagnosis of non-sclerotic LS include tiny foci of homogenized tissue in dermal papillae, marked fibrosis with thickening of the papillary dermis, marked thickening of individual collagen fibers, lymphocytes aligned in rows between those fibers, necrotic keratinocytes, often with preserved pyknotic nuclei, in all reaches of the epidermis, including the cornified layer, clustering of necrotic keratinocytes above elongated dermal papillae and vertical columns of parakeratosis with distinct dyskeratotic parakeratotic cells. CONCLUSION: In the absence of sclerosis, histopathologic diagnosis of LS depends on findings that are less distinctive. Nonetheless, a constellation of those findings allows a specific diagnosis to be made.

Phase 1 clinical study with Bioneedles, a delivery platform for biopharmaceuticals.

Vaccination campaigns using syringes, needles, vials and refrigeration have a heavy logistic burden. A vaccination platform that circumvents these problems would improve the quality of vaccination campaigns by faster and safer vaccination of populations anywhere. A clinical phase I study in eighteen volunteers has been carried out, using biodegradable mini-implants (Bioneedles™), made of a polymer based on starch, allowing for high speed vaccination of thermostable vaccines and omitting the use of syringes, needles, vials and refrigeration. Clinical and histological assessment demonstrated excellent local tissue tolerance for the Bioneedle polymer. Histological findings were those of normal tissue restitution without evidence for infection, allergic or granulomatous response, or scar formation. The Bioneedle polymer was mostly degraded within hours, remnants of it being cleared by macrophages. The technique of subcutaneous insertion of Bioneedles with a kinetic energy of 0.33 Joule and higher is 100% effective and pain free. All volunteers graded global tolerance of Bioneedles as "very good" or "good". Bioneedles offer a safe, effective and very fast alternative vaccination platform.

Confusion-specimen mix-up in dermatopathology and measures to prevent and detect it.

Maintaining patient identity throughout the biopsy pathway is critical for the practice of dermatology and dermatopathology. From the biopsy procedure to the acquisition of the pathology report, a specimen may pass through the hands of more than twenty individuals in several workplaces. The risk of a mix-up is considerable and may account for more serious mistakes than diagnostic errors. To prevent specimen mix-up, work processes should be standardized and automated wherever possible, e.g., by strict order in the operating room and in the laboratory and by adoption of a bar code system to identify specimens and corresponding request forms. Mutual control of clinicians, technicians, histopathologists, and secretaries, both simultaneously and downstream, is essential to detect errors. The most vulnerable steps of the biopsy pathway, namely, labeling of specimens and request forms and accessioning of biopsy specimens in the laboratory, should be carried out by two persons simultaneously. In preceding work steps, clues must be provided that allow a mix-up to be detected later on, such as information about clinical diagnosis, biopsy technique, and biopsy site by the clinician, and a sketch of the specimen by the technician grossing it. Awareness of the danger of specimen mix-up is essential for preventing and detecting it. The awareness can be heightened by documentation of any error in the biopsy pathway. In case of suspicion, a mix-up of specimens from different patients can be confirmed by DNA analysis.

Josef jadassohn--an appreciation on the occasion of his 150th birthday.

Josef Jadassohn was a pioneering dermatologist who influenced the development of his specialty in many ways. He introduced the patch test for detection of hypersensitivity reactions, gave original descriptions of several entities, such as nevus sebaceous, granulosis rubra nasi, and pachyonychia congenita, and edited the Handbuch der Haut- und Geschlechtskrankheiten, the most comprehensive textbook of dermatology ever published. Moreover, Jadassohn left a phalanx of distinguished students, including Felix Lewandowsky, Wilhelm Lutz, Max Jessner, Hans Biberstein, Hermann Pinkus, and Marion B. Sulzberger.