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.

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.

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.

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.

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.

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.

Hypertrophic lichen sclerosus with dyskeratosis and parakeratosis--a common presentation of vulvar lichen sclerosus not associated with a significant risk of malignancy.

Epithelial hyperplasia, individual necrotic keratocytes, and parakeratosis are common findings in lichen sclerosus. When those changes are prominent, they may pose diagnostic problems, especially because such lesions often show no or only minimal sclerosis. Necrotic keratocytes are often numerous and are found in all reaches of the epidermis, presenting themselves as eosinophilic globules with or without remnants of pyknotic nuclei. Because those changes tend to be accentuated focally above dermal papillae, they often give rise to narrow columns of parakeratosis in the overlying cornified layer. Within those columns, individual necrotic keratocytes with pyknotic nuclei are preserved as distinct dyskeratotic parakeratotic cells. That constellation of findings is fairly characteristic of hypertrophic lichen sclerosus. It was found, at least subtle and focally, in 14 of 70 consecutive biopsy specimens of lichen sclerosus, most of which came from the vulva of elderly women. Although similar cases have been described as differentiated vulvar intraepithelial neoplasia (VIN) in the literature, there was no significant nuclear atypia, no crowding of nuclei, and no significant mitotic activity in any of those lesions. Follow-up of at least 5 years in 8 patients revealed no development of squamous cell carcinoma. Hypertrophic lichen sclerosus with dyskeratosis and parakeratosis seems to be a relatively common presentation of vulvar lichen sclerosus not associated with a significant risk of malignancy.

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.

The 'epidemic' of melanoma between under- and overdiagnosis.

In the past decades, the incidence of melanoma has been reported to rise in epidemic proportions. The chief reason for that pseudo-epidemic is improved criteria for diagnosis that allow melanomas to be recognized far more accurately and at earlier stages. The rising number of melanomas diagnosed has resulted in increased diagnostic scrutiny, more pigmented lesions being biopsied and more melanomas recognized, thus enhancing the 'epidemic' in self-perpetuating fashion. Regression of melanomas may, in part, explain why lesions undetected before did not result in a far higher mortality. Another potential reason for the disparity between increasing incidence of melanoma and relatively steady mortality may be overdiagnosis of melanoma. The latter may be curtailed by establishment of well-defined diagnostic categories, efforts to establish reliable criteria for recognition of those categories, better clinicopathologic correlation, postponement of biopsy of pigmented lesions in the case of irritation and excisional rather than incisional biopsies.

The fallacy of the concept of invasion--critique in historical perspective with implications for diagnosis of early malignant neoplasms.

In recent years, attempts have been made to enhance reproducibility in reporting early cancerous lesions. For this purpose, specific diagnoses in the language of clinical medicine have been substituted by nonspecific designations that encompass benign and malignant processes, such as "squamous intraepithelial lesion" and "melanocytic intraepidermal neoplasia." The propagation of noncommittal terms for all in situ lesions has, in turn, led to a renaissance of the old concept of invasion as a prerequisite for the diagnosis of cancer. Invasion, that is, transgression of the epithelial basement membrane by at least 1 neoplastic cell, is difficult to recognize, can never be excluded, and has little, if any, prognostic significance. Nevertheless, the concept that malignancy requires invasion, deeply rooted in the history of pathology, gave legitimacy to evasive terms that serve to conceal diagnostic difficulties but do not resolve them. The pillars of this concept are based on outdated suppositions of the 19th century that have no place in modern medicine.

Erythema elevatum diutinum - a chronic leukocytoclastic vasculitis microscopically indistinguishable from granuloma faciale?

BACKGROUND: As the sequential inflammatory changes are the same in erythema elevatum diutinum (EED) and granuloma faciale (GF), histopathologic distinction may be difficult. METHODS: All available cases from 1998 to 2009 with the diagnosis of EED and GF were collected and reviewed, both clinically and histopathologically. Nine cases of EED and 41 cases of GF were reviewed in a blinded fashion using a checklist of 26 histopathologic criteria. RESULTS: Only four of the evaluated criteria showed differences between GF and EED. High density of the infiltrate was noted in 97% of cases of GF but only in 56% of cases of EED. Eosinophils were the predominant cell type in 59% of cases of GF but in none of the cases of EED. Plasma cells were more frequent in GF (64%) than in EED (22%), and granulomas were never found in GF but in 22% of EED. A zone of perijunctional sparing (Grenz zone) was observed in about three quarters of the cases in both the groups. CONCLUSIONS: The histopathology of GF and EED is very similar and overlapping. The presence of a Grenz zone and patterned fibrosis does not distinguish the two diseases. However, granulomatous nodules are only seen in EED, and a predominance of eosinophils in the infiltrate favors a diagnosis of GF.

Otto Schrön--an early pioneer in dermatopathology.

Otto Schrön was a German histologist of the mid-19th century who spent most of his life in Italy where he was full professor of pathologic anatomy at the University of Naples. Already as a medical student, he participated in studies by Carl Thiersch that proved the epithelial origin of cancer. Schrön went on to study the histology and histopathology of the skin and was the first to discover desmosomes and the tonofilament system, although he did not recognize the true physiologic role of those structures.

The magic of numbers: malignant melanoma between science and pseudoscience.

In 2009, a new system for staging and classification of malignant melanoma has been proposed by the American Joint Committee on Cancer (AJCC). The AJCC recommends that staging of primary melanoma be based on 3 criteria, namely, thickness, ulceration, and mitotic rate, the latter substituting Clark levels in the previous classification. In melanomas measuring ≤1 mm in thickness, ulceration or finding of single mitotic figure in the dermis defines stage T1b. According to the AJCC, sentinel lymph node dissection should be considered for those melanomas because of a significantly impaired prognosis. As with other prognostic parameters, however, assessment of mitotic rate, with one mitotic figure being the cutoff point, is highly unreliable, and statistics based on such data lack validity. Despite the large database being employed, they may be pseudoscience rather than science.