Cutaneous Lymphadenoma Is a Distinct Trichoblastoma-like Lymphoepithelial Tumor With Diffuse Androgen Receptor Immunoreactivity, Notch1 Ligand in Reed-Sternberg-like Cells, and Common EGFR Somatic Mutations.

The term "cutaneous lymphadenoma" was coined in this journal for an unusual lymphoepithelial cutaneous adnexal neoplasm, possibly with immature pilosebaceous differentiation. Some authors further proposed that cutaneous lymphadenoma was an adamantinoid trichoblastoma. However, although a hair follicle differentiation is widely accepted, the fact that this is a lymphoepithelial tumor is not appropriately explained by the trichoblastoma hypothesis. Our goal was to further clarify the phenotypic and genotypic features of cutaneous lymphadenoma in a series of 11 cases. Histologically, a lobular architecture surrounded by a dense fibrous stroma was present in all cases. The lobules were composed of epithelial cells admixtured with small lymphocytes and isolated or clustered large Reed-Sternberg-like (RS-L) cells. The epithelial cells were diffusely positive for the hair follicle stem cell markers CK15, PHLDA1, and for androgen receptor. No immunostaining for markers of sebaceous differentiation was found. Intraepithelial lymphocytes were predominantly CD3+, CD4+, FoxP3+ T cells. RS-L cells showed both strong Jagged-1 and Notch1 cytoplasmic immunostaining. Androgen-regulated NKX3.1 nuclear immunostaining was present in a subset of large intralobular cells in all cases. Double immunostaining showed coexpression of NKX3.1 and CD30 in a subset of RS-L cells. No immunostaining for lymphocytic or epithelial markers was present in RS-L cells. EGFR, PIK3CA, and FGFR3 somatic mutations were found by next-generation sequencing in 56% of the cases. We consider that cutaneous lymphadenoma is a distinct benign lymphoepithelial tumor with androgen receptor and hair follicle bulge stem cell marker expression, RS-L cell-derived Notch1 ligand, and common EGFR gene mutations.

Non-invasive optical biopsy by multiphoton microscopy identifies the live morphology of common melanocytic nevi.

Multiphoton microscopy (MPM) is a promising non-invasive imaging tool for discriminating benign nevi from melanoma. In this study, we establish a MPM morphologic catalogue of common nevi, information that will be critical in devising strategies to distinguish them from nevi that are evolving to melanoma that may present with more subtle signs of malignancy. Thirty common melanocytic nevi were imaged in vivo using MPM. Quantitative parameters that can distinguish between different types of nevi were developed and confirmed by examining the histology of eleven of the imaged nevi. MPM features of nevi examined included cytologic morphology of melanocytes in the epidermis and dermis, the size and distribution of nevomelanocytes both within and around nests, the size of rete ridges, and the presence of immune cells in the dermis. Distinguishing features include cytological morphology, the size of nevomelanocytes, the size of nevomelanocyte nests, and the distribution of nevomelanocytes. Notably, these distinguishing characteristics were not easily appreciated in fixed tissues, highlighting essential differences in the morphology of live skin. Taken together, this work provides a morphologic compendium of normal nevi, information that will be critical in future studies directed at identifying melanocytic nevi that are evolving to melanoma.

Meningioma-like Tumor of the Skin Revisited: A Distinct CD34+ Dermal Tumor With an Expanded Histologic Spectrum.

The term meningioma-like tumor of the skin (MLTS) was coined in 1993 to designate a particular whorled spindle cell superficial cutaneous tumor. No additional confirmed cases of this entity have been reported to date. Some authors have speculated that these cases might be cellular neurothekeomas. In order to delineate the histologic spectrum and the immunophenotype of this unusual tumor, we studied 5 cases, 2 previously unreported and the 3 original cases. The immunohistochemical findings of case 5, however, were limited to those from the original study. Clinically, the tumor presented as a reddish papule, plaque, or nodule, located in the extremities or trunk. The patient often referred to a recent growth of a longstanding lesion. Histologically, the characteristic whorled spindle and stellate dendritic cell population, commonly in a perivascular arrangement, and variable myxoid component, were consistently found in all cases. A prominent microvasculature was also a constant finding. The presence of large deciduoid cells was conspicuous in one case. A reticular pattern of multivacuolated cells giving a chordoma-like appearance was evident in another case. Tumor cells were diffusely positive for CD34 in all 4 cases studied, and negative for S-100, EMA, NKI-C3, CD68, and smooth muscle markers. No complete loss of retinoblastoma protein was found. No brachyury immunostaining was found in the case with chordoid features. No EWSR1 or NAB2-STAT6 gene fusions were found. From these findings, we demonstrate that MLTS is a distinct CD34 spindle cell benign dermal tumor, unrelated to cellular neurothekeoma, and exhibiting myxoid, deciduoid, or chordoma-like features.

A randomized, double-blind, placebo-controlled phase II clinical trial of lovastatin for various endpoints of melanoma pathobiology.

On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed.

Atypical cellular unguioblastic fibroma-A rare case with more atypical histological features than previously reported.

We herein present the clinicopathological features of an atypical cellular unguioblastic fibroma, a rare onychomatrical tumor, in an adult woman of Southeast Asian origin. The tumor displayed both diffuse hypercellularity and atypia in the mesenchymal component and the presence of large multinucleated cells with a ring-/floret-like arrangement of irregular and hyperchromatic nuclei. The mesenchymal cells displayed a patchy weak positive immunereactivity for CD34 (including atypical and wreath-like multinucleated cells) and for CD10 but were negative for low molecular weight cytokeratins, epithelial membrane antigen, CD68, factor XIIIa, smooth muscle actin, desmin, and HMB-45. The proliferative index as measured immunohistochemically (Mib-1/Ki-67) was 5%. The extent of these atypical histological features has not previously been described. One-year follow-up has been uneventful.

Bortezomib-induced histiocytoid Sweet syndrome.

Bortezomib, a proteasome inhibitor approved for the treatment of multiple myeloma, has been reported to be associated with Sweet syndrome. However, careful review of the histopathology of the first reported case and our case revealed similar histologic and immunohistochemical findings (a mononuclear dermal infiltrate) and not the usual neutrophilic infiltrate of Sweet syndrome. We suggest that the dermatitis induced by bortezomib is best classified as "histiocytoid Sweet syndrome."

Acantholytic dyskeratotic acanthoma: a variant of a benign keratosis.

Acantholytic acanthoma was originally described as a solitary lesion displaying histologic features of acantholysis without dyskeratosis. Solitary, non-genital lesions displaying confluent acantholysis and dyskeratosis have not been well described in the literature, clinically or histologically. We screened cases at our institution over a 6-month period and found 28 such lesions. Lesions were most often found on the trunk as a solitary papule, for which the clinical diagnosis was often basal cell carcinoma. There was a slight female predominance. Confluent acantholysis and dyskeratosis is a histologic pattern that may present as a solitary keratosis.

Changes of epidermodysplasia verruciformis in benign skin lesions: the EV acanthoma.

Foci of histological changes of epidermodysplasia verruciformis (EV) were noted in five benign skin lesions. These skin lesions included an intradermal nevus, a pigmented seborrheic keratosis, an isolated papule on the forearm, a perianal lesion, and an acantholytic acanthoma. Because the changes resembled true EV so strongly despite the absence of clinical EV in these patients, we searched for EV-human papilloma virus (HPV) types in these skin lesions. Polymerase chain reaction (PCR) analysis on the formalin-fixed, paraffin-embedded blocks was performed. As a positive control, we included tissue from two HIV-positive patients with clinical EV proven by biopsy. Studies were also performed on five other archived biopsies that did not show changes of EV on multiple tissue sections. A nested PCR method detected EV-HPV types in three of the five benign skin lesions showing EV changes as well as in the positive controls. EV changes and EV-HPV can be found incidentally on biopsy in the absence of clinical EV; when such changes are the major histopathological finding in an isolated skin lesion, the lesion should be termed an EV acanthoma.

Papillated Bowen disease, a distinct variant.

Bowen disease usually presents as an irregular, asymptomatic, scaly or crusted erythematous plaque that can occur anywhere on the skin. An unusual clinicopathologic variant is described which presents as a well-circumscribed, papillated, exophytic and endophytic, sometimes keratotic lesion. This papillated variant of Bowen disease exhibits keratinocytes with prominent perinuclear halos suggestive of koilocytic change associated with human papillomavirus (HPV) infections. Classic Bowen disease has been associated in previous studies with a variety of HPV types, especially types 16, 18, and 31. Twenty-six patients with papillated Bowen disease were evaluated. The patients included 15 males and 11 females, ranging in age from 33 to 87 years old. Fifty-four percent (14) of the lesions involved the head and neck, 8% (2) involved the trunk, and the remaining 38% (10) involved extremities (including 3 lesions from the hands). Lesions were examined using in situ hybridization with widely screening genomic probes for HPV types 6, 11, 16, 18, 30, 31, 33, 35, 45, 51, and 52. None of the specimens contained HPV DNA from the more common oncogenic HPV types. Given the striking histologic appearance of these lesions, however, this does not exclude HPV infection detectable by more sensitive screening methods such as polymerase chain reaction. Papillated Bowen disease is distinct from other variants, including the verrucous-hyperkeratotic type.

Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification--part two.

Cutaneous squamous cell carcinoma (SCC) includes many subtypes with widely varying clinical behaviors, ranging from indolent to aggressive tumors with significant metastatic potential. However, the tendency for pathologists and clinicians alike is to refer to all squamoid neoplasms as generic SCC. No definitive, comprehensive clinicopathological system dividing cutaneous SCCs into categories based upon their aggressiveness has yet been promulgated. Therefore, we have proposed the following based upon the malignant potential of SCC variants, separating them into categories of low (< or = 2% metastatic rate), intermediate (3-10%), high (greater than 10%), and indeterminate behavior. Low-risk SCCs include SCC arising in actinic keratosis, HPV-associated SCC, tricholemmal carcinoma, and spindle cell SCC (unassociated with radiation). Intermediate-risk SCCs include adenoid (acantholytic) SCC, intraepidermal epithelioma with invasion, and lymphoepithelioma-like carcinoma of the skin. High-risk subtypes include de novo SCC, SCC arising in association with predisposing factors (radiation, burn scars, and immunosuppression), invasive Bowen's disease, adenosquamous carcinoma, and malignant proliferating pilar tumors. The indeterminate category includes signet ring cell SCC, follicular SCC, papillary SCC, SCC arising in adnexal cysts, squamoid eccrine ductal carcinoma, and clear-cell SCC. Subclassification of SCC into these risk-based categories, along with enumeration of other factors including tumor size, differentiation, depth of invasion, and perineural invasion will provide prognostically relevant information and facilitate the most optimal treatment for patients.

Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification. Part one.

Cutaneous squamous cell carcinoma (SCC) includes many subtypes with widely varying clinical behaviors, ranging from indolent to aggressive tumors with significant metastatic potential. However, the tendency for pathologists and clinicians alike is to refer to all squamoid neoplasms as generic SCC. No definitive, comprehensive clinicopathological system dividing cutaneous SCCs into categories based upon their aggressiveness has yet been promulgated. Therefore, we have proposed the following based upon the malignant potential of SCC variants, separating them into categories of low (< or = 2% metastatic rate), intermediate (3-10%), high (greater than 10%), and indeterminate behavior. Low-risk SCCs include SCC arising in actinic keratosis, HPV-associated SCC, tricholemmal carcinoma, and spindle cell SCC (unassociated with radiation). Intermediate-risk SCCs include adenoid (acantholytic) SCC, intraepidermal epithelioma with invasion, and lymphoepithelioma-like carcinoma of the skin. High-risk subtypes include de novo SCC, SCC arising in association with predisposing factors (radiation, burn scars, and immunosuppression), invasive Bowen's disease, adenosquamous carcinoma, and malignant proliferating pilar tumors. The indeterminate category includes signet ring cell SCC, follicular SCC, papillary SCC, SCC arising in adnexal cysts, squamoid eccrine ductal carcinoma, and clear-cell SCC. Subclassification of SCC into these risk-based categories, along with enumeration of other factors including tumor size, differentiation, depth of invasion, and perineural invasion will provide prognostically relevant information and facilitate the most optimal treatment for patients.

Evaluation of single versus multiple cryogen spray cooling spurts on in vitro model human skin.

Many commercially available dermatologic lasers utilize cryogen spray cooling for epidermal protection. A previous tissue culture study demonstrated that single cryogen spurts (SCS) of 80 ms or less were unlikely to cause cryo-injury in light-skinned individuals. More recently, multiple cryogen spurts (MCS) have been incorporated into commercial devices, but the effects of MCS have not been evaluated. The aim was to study an in vitro tissue culture model and the epidermal and dermal effects of SCS vs patterns of shorter MCS with the same preset total cryogen delivery time (Deltat(c)) and provide an explanation for noted differences. Four different spurt patterns were evaluated: SCS: one 40-ms cryogen spurt; MCS2: two 20-ms cryogen spurts; MCS4: four 10-ms cryogen spurts; MCS8: eight 5-ms cryogen spurts. Actual Deltat(c) and total cooling time (Deltat(Total)) were measured for each spurt pattern. RAFT tissue culture specimens were exposed to cryogen spurt patterns and biopsies were taken immediately and at days 3 and 7. Actual Deltat(c) was increased while Deltat(Total) remained relatively constant as the preset Deltat(c) of 40 ms was delivered as shorter MCS. Progressively more epidermal damage was noted with exposure to the MCS patterns. No dermal injury was noted with either SCS or MCS. For a constant preset Deltat(c) of 40 ms, delivering cryogen in patterns of shorter MCS increased the actual Deltat(c) and consequently the observed epidermal cryo-injury as compared to an SCS.

Primary cutaneous myxofibrosarcoma mimicking pleomorphic hyalinizing angiectatic tumor (PHAT): a potential diagnostic pitfall.

Myxofibrosarcoma (MFS) is one of the most common sarcomas of adults, and includes lesions ranging from low to high grade based on increasing cellularity, nuclear pleomorphism, and mitotic activity. We present an unusual case of MFS, which initially showed features of a pleomorphic hyalinizing angiectatic tumor (PHAT), a rare soft-tissue tumor considered benign in the WHO classification. The initial lesion showed a subcutaneous proliferation of spindled to polygonal eosinophilic cells with striking cellular pleomorphism, set in a myxoid to sclerotic stroma with prominent hyalinized and angiectatic vasculature, classic characteristics of PHAT. Rare mitotic figures were identified. The preliminary diagnosis of PHAT was confirmed by a consultant expert soft-tissue pathologist. Four months after the initial surgery, local recurrence was noted. The recurrent tumor demonstrated findings of a high-grade MFS, with a diffuse and cellular proliferation of atypical spindle cells set in a prominent myxoid stroma. Multiple mitoses, including atypical ones, were present. In light of these findings, the original specimen was reexamined and the initial diagnosis was amended to MFS. MFS may mimic or be confused with several benign soft-tissue lesions. Cases mimicking PHAT have not been previously reported. We describe a unique case of a high-grade MFS that initially showed characteristic features of a PHAT, to illuminate the fact that MFS may rarely arise in, or have areas that masquerade as, PHAT. It is also conceivable, although speculative, that at least some cases of PHAT, currently considered a benign tumor by the WHO, may actually represent or evolve into a unique form of MFS of low malignant potential.

Metaplastic breast carcinoma histologically mimicking cutaneous spindle cell squamous cell carcinoma.

Squamous cell carcinoma is one of the most common primary cutaneous carcinomas but on rare occasion, metastatic squamous cell carcinoma from a distant site or solid organ can present as a cutaneous lesion. Most metastases occur as dermal nodules or involve the dermal lymphatics, but when they are intimately associated with the epidermis, distinguishing the lesion as primary or metastatic may be extremely difficult and usually requires a clinical history or high index of suspicion. A 71-year-old woman presented with multiple eruptive nodules over her chest, flank, and back. Histologically the lesions appeared to be arising from the surface epithelium and consisted of atypical, predominantly spindle cells, some of which streamed off of the epidermis. Following the initial evaluation, a history of breast carcinoma with subsequent radiation therapy and ultimate mastectomy was obtained, and the original breast biopsy and mastectomy material was reviewed. After performing additional studies, it became clear that the origin of the carcinomas was metastatic from an underlying metaplastic breast carcinoma.

Exogenous and endogenous cutaneous anomalies and curiosities.

Exogenous and endogenous substances can produce some interesting cutaneous abnormalities. Exogenous lesions are externally introduced materials or foreign bodies. Endogenous lesions are substances that result from tissue host response to an injury or physical insult. There may be an overlap of these endogenous and exogenous lesions such that externally introduced materials can lead to peculiar tissue reactions. Pathologists should be aware of these anomalies as many of them can simulate neoplasms (ie, Monsel's reaction, polyvinylpyrrolidone disease, silica reaction) and inflammatory (ie, paraffinoma) and infectious processes (ie, Drysol(R) reaction and Lycopodium granuloma). The most interesting and important entities within each of these categories are presented with essential clinical and pathologic descriptions.