Perineural Infiltration: A Comprehensive Review of Diagnostic, Prognostic, and Therapeutic Implications.

ABSTRACT: Perineural infiltration refers to a neoplastic cell involvement in, around, and through the nerves. It is considered as one of the neoplastic dissemination pathways. Thus, its identification is crucial to establish the prognosis of some malignant skin neoplasms, such as squamous cell carcinoma, and explains the locally aggressive behavior of cutaneous neoplasms, such as microcystic adnexal carcinoma. We have conducted a review of malignant and benign skin tumors in which perineural infiltration has been described, and we also discuss some histopathological findings that may simulate perineural infiltration.

Bowen Disease Within a Circumscribed Palmar Hypokeratosis.

ABSTRACT: Circumscribed palmar or plantar hypokeratosis is a focal disorder of keratinization that consists of a reduction in the thickness of the corneal layer of the epidermis of palms or soles. Although it is considered a benign entity, the thinning of the stratum corneum facilitates ultraviolet damage in the affected skin, which may result in an increased risk of developing focal epidermal dysplasia. Other factors, such as immunosuppression in transplanted patients, may play a role as well. We present a case of circumscribed palmar or plantar hypokeratosis with features of Bowen disease limited to the hypokeratotic epidermis.

Analysis of the metabolic proteome of lung adenocarcinomas by reverse-phase protein arrays (RPPA) emphasizes mitochondria as targets for therapy.

Lung cancer is the leading cause of cancer-related death worldwide despite the success of therapies targeting oncogenic drivers and immune-checkpoint inhibitors. Although metabolic enzymes offer additional targets for therapy, the precise metabolic proteome of lung adenocarcinomas is unknown, hampering its clinical translation. Herein, we used Reverse Phase Protein Arrays to quantify the changes in enzymes of glycolysis, oxidation of pyruvate, fatty acid metabolism, oxidative phosphorylation, antioxidant response and protein oxidative damage in 128 tumors and paired non-tumor adjacent tissue of lung adenocarcinomas to profile the proteome of metabolism. Steady-state levels of mitochondrial proteins of fatty acid oxidation, oxidative phosphorylation and of the antioxidant response are independent predictors of survival and/or of disease recurrence in lung adenocarcinoma patients. Next, we addressed the mechanisms by which the overexpression of ATPase Inhibitory Factor 1, the physiological inhibitor of oxidative phosphorylation, which is an independent predictor of disease recurrence, prevents metastatic disease. We highlight that IF1 overexpression promotes a more vulnerable and less invasive phenotype in lung adenocarcinoma cells. Finally, and as proof of concept, the therapeutic potential of targeting fatty acid assimilation or oxidation in combination with an inhibitor of oxidative phosphorylation was studied in mice bearing lung adenocarcinomas. The results revealed that this therapeutic approach significantly extended the lifespan and provided better welfare to mice than cisplatin treatments, supporting mitochondrial activities as targets of therapy in lung adenocarcinoma patients.

Histopathology of Dermatologic Complications of Tattoos.

ABSTRACT: Tattoos are characterized by the introduction of exogenous pigments into the dermis. Tattoos usually serve cosmetic purposes, although they may have other causes, such as traumatic pigment implants in accidents or medical-related tattoos in the context of radiotherapy. Dermatologic adverse reactions are relatively uncommon, and they include infections, immune-mediated reactions, cutaneous lesions secondary to the Koebner phenomenon, exacerbation of preexisting dermatosis, benign and malignant neoplasms, and a miscellaneous group of dermatologic conditions that may appear in a preexisting tattoo. The aim of this study is to review the types of histopathologic reactions that may appear in a preexisting permanent tattoo.

Ki-67 immunoexpression and radiological assessment of necrosis improves accuracy of conventional and modified core biopsy systems in predicting the final grade assigned to adult-soft tissue sarcomas. An international collaborative study.

Based on the French Federation Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, this study assesses the accuracy of conventional and modified core biopsy (CB) systems in predicting the final grade (low vs high) assigned to the resected specimen. Substituting Ki-67 immunoexpression for mitotic count, and radiological for histological assessment of necrosis, we used two modified FNCLCC CB grading systems: (1) Ki-67 immunoexpression alone, and (2) Ki-67 plus radiological assessment of necrosis. We graded 199 soft tissue sarcomas (STS) from nine centers, and compared the results for the conventional (obtained from local histopathology reports) and modified CB systems with the final FNCLCC grading of the corresponding resected specimens. Due to insufficient sample quality or lack of available radiologic data, five cases were not evaluated for Ki67 or radiological assessment of necrosis. The conventional FNCLCC CB grading system accurately identified 109 of the 130 high-grade cases (83.8%). The CB grading matched the final FNCLCC grading (low vs high) in 175 (87.9%) of the 199 resected tumors; overestimating the final grade in three cases and underestimating in 21 cases. Modified system 1 (Ki-67) accurately identified 117 of the 130 high-grade cases (90.0%). The CB grading matched the final FNCLCC grading (low vs high) in 175 (89.7%) of the 195 evaluated cases; overestimating seven and underestimating 13 cases. Modified system 2 (Ki-67 plus radiological necrosis) accurately identified 120 of the 130 high-grade cases (92.3%). This last matched the final FNCLCC grading (low vs high) in 177 (91.2%) of the 194 evaluated cases; overestimating seven and underestimating 10 cases. Modified system 2 obtained highest area under ROC curves, although not statistically significant. Underestimated CB grades did not correlate with histological subtypes, although many of the discrepant cases were myxoid tumors (myxofibrosarcomas or myxoid liposarcomas), leiomyosarcomas or undifferentiated pleomorphic/spindle cell sarcomas. Using modified FNCLCC CB grading systems to replace conventional mitotic count and histologic assessment of necrosis may improve the distinction between low and high-grade STS on CB. Our study confirms that classifying grade 1 as low grade and grades 2 and 3 as high grade improves correlation between CB and final grade by up to 21%, irrespective of CB system used. A higher than expected Ki-67 score in a low-grade sarcoma diagnosed on CB should raise concern that a higher-grade component may not have been sampled. Furthermore, correlation of all clinicopathological and radiological findings at multidisciplinary meetings is essential to assess the histological grade on CB as accurately as possible.

Immunophenotypic Differences in Tumor-Infiltrating Lymphocytes and Neovascularization Between Primary Cutaneous Melanoma With and Without Metastasis: An Immunohistochemical Study of 80 Cases.

ABSTRACT: The prognostic implications of the immunophenotype of the tumor-infiltrating lymphocytes (TILs) in primary cutaneous melanoma are well known. In recent years, the study of this immunophenotype has also resulted in immunotherapeutic consequences. The aims of this study were to characterize the subpopulations of TILs in primary cutaneous melanoma, in cases with and without metastasis, as well as the neovascularization associated with the primary neoplasm, and its influence on the development of metastasis. To this end, the immunophenotype of TILs and the neovascularization of 80 patients with primary cutaneous melanoma (40 each with metastatic and non-metastatic melanoma) were analyzed by immunohistochemistry for CD3, CD4, CD8, FOXP3, PD-1, CD31, and D2-40 antibodies. We found that higher frequencies of TILs with brisk pattern, and CD4+, CD8+, and CD20+ cells in TILs, and a lower frequency of CD31+ vessels were histopathological features associated with better prognosis in primary cutaneous melanoma. Our results support the notion that the immunohistochemical study of TILs and neovascularization in primary cutaneous melanoma may be helpful tools for identifying patients at increased risk of metastasis development.

Frequent activating PIK3CA mutations in sporadic angiolipoma.

BACKGROUND: Angiolipoma (AL) is considered as a lipoma variant that is characterized by the combination of mature adipocytes and capillary blood vessels diffusely distributed within the tumor. With the exception of recurrent PRKD2 mutations of uncertain pathogenetic significance, the genetic abnormalities of ALs are unknown, in the absence of any of the specific chromosomal aberrations described in other lipoma variants. METHODS: Formalin-fixed and paraffin-embedded blocks of 13 conventional ALs and 5 cellular ALs from 17 individuals were retrieved and analyzed for mutations in exons 9 and 20 of PIK3CA by polymerase chain reaction and Sanger sequencing. RESULTS: Activating PIK3CA mutations were identified in 14 tumors (78%). All PIK3CA-mutated samples carried the same exon 9 mutation, c.1634A>C (p.E545A). No mutation was detected in exon 20 of PIK3CA. No significant difference between PIK3CA-mutated and wild-type samples appeared to exist based on age, gender, and location of the tumor. All 5 cellular ALs carried the p.E545A PIK3CA mutation. CONCLUSION: The high frequency of the p.E545A PIK3CA mutation in both conventional and cellular ALs suggests that activation of the PI3K/AKT pathway plays a key role in AL pathogenesis and reinforces the concept that cellular AL should be regarded as a variant of AL.

Sonography of solitary fibrofolliculoma with histologic correlation.

We present a case of 15-year old male with solitary fibrofolliculoma on the ear and we demonstrate the use of ultrasound in outlining the features of this rare benign skin tumor with histological correlation. Fibrofolliculoma can be associated with a rare syndrome known as Birt-Hogg-Dubé which affects the skin, lungs and kidneys.

Combination of Congenital and Deep Penetrating Nevus by Acquisition of ß-Catenin Activation.

Deep penetrating nevus (DPN) is an intradermal, sometimes compound benign melanocytic lesion, which involves the reticular dermis, occasionally reaching the subcutis, which can raise concern for melanoma both clinically and histologically. Recently, it has been genetically defined by the combination of MAPK activating and ß-catenin activating mutations. We sought to investigate genetic alterations in 2 cases of combined nevi of congenital melanocytic and DPN. Case 1 was a 16-year-old woman with a pigmented lesion on the trunk since birth, which was completely excised. Histopathological examination revealed a combined congenital nevus with a DPN. Comparative genomic hybridization showed no major genetic alterations, except for gain of 6q11.1 and point mutation of B-RAF V600E. Case 2 was a 62-year-old woman with a congenital pigmented lesion on the back. The lesion was diagnosed as a combined nevus of congenital and DPN. Comparative genomic hybridization showed no genetic alterations, and the NRAS Q61K was detected in both components. DPN is in most cases part of a combined nevus. Our cases showed strong and uniform nuclear expression of ß-catenin and cyclin D1 in the DPN component suggesting the evolution of the congenital nevus to the DPN clone by acquiring ß-catenin activating mutation.

Influence of Serum Vitamin D Level in the Response of Actinic Keratosis to Photodynamic Therapy with Methylaminolevulinate.

In mouse models of squamous cell carcinoma, pre-treatment with calcitriol prior to photodynamic therapy with aminolevulinic acid (ALA) enhances tumor cell death. We have evaluated the association between vitamin D status and the response of actinic keratoses to photodynamic therapy with methylaminolevulinate. Twenty-five patients with actinic keratoses on the head received one session of photodynamic therapy with methylaminolevulinate. Biopsies were taken at baseline and six weeks after treatment. Immuno-histochemical staining was performed for VDR, P53, Ki67 and -catenin. Basal serum 25(OH)D levels were determined. Cases with a positive histological response to treatment had significantly higher serum 25(OH)D levels (26.96 (SD 7.49) ngr/mL) than those without response (18.60 (SE 7.49) ngr/mL) (p = 0.05). Patients with a complete clinical response displayed lower basal VDR expression (35.71% (SD 19.88)) than partial responders (62.78% (SD 16.735)), (p = 0.002). Our results support a relationship between vitamin D status and the response of actinic keratoses to photodynamic therapy with methylaminolevulinate.

Increased Marginal Stiffness Differentiates Infiltrative From Noninfiltrative Cutaneous Basal Cell Carcinomas in the Facial Area: A Prospective Study.

OBJECTIVES: Basal cell carcinoma (BCC) is the most common dermatologic malignant skin cancer. Infiltrative histologic variants are more aggressive and require wider surgical margins or Mohs surgery, in contrast with noninfiltrative variants, which are commonly treated with standard surgical excision. Elastography has not been used to date to differentiate between the histologic variants of BCC. The purpose of this study was to differentiate infiltrative from noninfiltrative BCCs on elastography. METHODS: A total of 31 facial BCCs were studied. Preoperatively, color Doppler ultrasound and strain elastographic examinations of the lesions were performed. The size, intralesional vascularization, and presence of hyperechoic dots were considered relevant B-mode and color Doppler variables. Strain ratios of the tumors were obtained with respect to adjacent healthy tissue. Increased marginal stiffness, which was considered hardness in greater than 50% of the tumor margin, was also blindly evaluated. Histologic confirmation and subtyping (infiltrative or noninfiltrative) were performed in all cases. RESULTS: Infiltrative BCCs did not differ in the size, presence or absence of hyperechoic dots, or vascularization from noninfiltrative BCCs. Strain ratios were similar in both infiltrative and noninfiltrative BCCs (mean ± SD, 1.82 ± 0.879 versus 2.2 ± 1.11). However, infiltrative BCCs had statistically increased marginal stiffness in comparison with noninfiltrative BCCs (88.0% versus 18.8%). Increased marginal stiffness had sensitivity and specificity of 0.89 and 0.82 respectively, with a positive predictive value of 0.67 for infiltrative BCCs and a negative predictive value of 0.95 for noninfiltrative BCCs. CONCLUSIONS: Histologic variants of BCC have different elastographic patterns. These differences may be of help in preoperative assessments of the BCC subtype and specific surgical planning, avoiding unnecessary skin biopsies.

Tissue-specific expression and post-transcriptional regulation of the ATPase inhibitory factor 1 (IF1) in human and mouse tissues.

The ATPase inhibitory factor 1 (IF1) is an intrinsically disordered protein that regulates the activity of the mitochondrial ATP synthase. Phosphorylation of S39 in IF1 prevents it from binding to the enzyme and thus abolishes its inhibitory activity. Dysregulation of IF1 is linked to different human diseases, providing a relevant biomarker of cancer progression. However, the tissue content of IF1 relative to the abundance of the ATP synthase is unknown. In this study, we characterized the tissue-specific expression of IF1 in human and mouse tissues and quantitated the content of IF1 and of ATP synthase. We found relevant differences in IF1 expression between human and mouse tissues and found that in high-energy-demanding tissues, the molar content of IF1 exceeds that of the ATP synthase. In these tissues, a fraction of IF1 is bound to the enzyme, and the other fraction is phosphorylated and hence is unable to bind the enzyme. Post-transcriptional control accounts for most of the regulated expression of IF1, especially in mouse heart, where IF1 mRNA translation is repressed by the leucine-rich pentatricopeptide repeat containing protein. Overall, these findings enlighten the cellular biology of IF1 and pave the way to development of additional models that address its role in pathophysiology.-Esparza-Moltó, P. B., Nuevo-Tapioles, C., Chamorro, M., Nájera, L., Torresano, L., Santacatterina, F., Cuezva, J. M. Tissue-specific expression and post-transcriptional regulation of the ATPase inhibitory factor 1 (IF1) in human and mouse tissues.

Primary Subcutaneous Synovial Sarcoma: First Reported Subcutaneous Case Showing TLE1 Immunoreactivity.

Synovial sarcoma (SS) accounts for 5%-10% of all soft tissue sarcomas. It is a well-defined soft tissue neoplasm with biphasic and monophasic histologic subtypes and unknown histogenesis. It usually occurs in the extremities, especially the thigh-knee region of young adults. Recurrences are frequent and distant metastasis developed in approximately half of the patients. SSs are characterized by a recurrent nonrandom chromosomal translocation, t(X; 18) (p11; q11), which is considered the primary genetic event in more than 90% of cases. Only 4 cases of cutaneous and subcutaneous SSs have been published in the literature so far. We report a case of primary subcutaneous SS in the forearm of a young woman and discuss the histopathologic differential diagnosis with other similar neoplasms. This is the first reported case of primary cutaneous SS showing immunoreactivity for TLE1 in the nuclei of neoplastic cells, supporting the use of this marker for diagnosis of this rare cutaneous neoplasm.

4E-binding protein 1, a cell signaling hallmark in breast cancer that correlates with pathologic grade and prognosis.

PURPOSE: Cell signaling pathways include a complex myriad of interconnected factors from the membrane to the nucleus, such as erbB family receptors and the phosphoinositide-3-kinase/Akt/mTOR and Ras-Raf-ERK cascades, which drive proliferative signals, promote survival, and regulate protein synthesis. EXPERIMENTAL DESIGN: To find pivotal factors in these pathways, which provide prognostic information in malignancies, we studied 103 human breast tumors with an immunohistochemical profile, including total and phosphorylated (p) proteins: human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor, extracellular signal-regulated kinase 1/2, Akt, 4E-binding protein 1 (4EBP1), eukaryotic initiation factor 4E, phosphorylated ribosomal protein S6 kinase 1, phosphorylated ribosomal protein S6, and Ki67. Western blot and reverse lysate protein arrays were also done in a subset of tumors. RESULTS: Significantly, activation of the phosphoinositide-3-kinase/Akt/mTOR cascade was detected in a high proportion of tumors (41.9%). Tumors with HER2 overexpression showed higher p-Akt as compared with negative tumors (P < 0.001). Levels of p-Akt correlated with the downstream molecules, p-4EBP1 (P = 0.001) and p-p70S6K (P = 0.05). Although 81.5% of tumors expressed p-4EBP1, in 16.3% of these tumors, concomitant activation of the upstream factors was not detected. Interestingly, p-4EBP1 was mainly expressed in poorly differentiated tumors (P < 0.001) and correlated with tumor size (P < 0.001), presence of lymph node metastasis (P = 0.002), and locoregional recurrences (P = 0.002). Coexpression of p-4EBP1 and p-eIF4G correlated with a high tumor proliferation rate (P = 0.012). CONCLUSION: In this study, p-4EBP1 was the main factor in signaling pathways that associate with prognosis and grade of malignancy in breast tumors. Moreover, p-4EBP1 was detected in both HER2-positive and HER2-negative tumors. This factor seems to be a channeling point at which different upstream oncogenic alterations converge and transmit their proliferative signal, modulating protein translation.

Psammomatoid ossifying fibromas: immunohistochemical analysis and differential diagnosis with psammomatous meningiomas of craniofacial bones.

OBJECTIVE: To clarify the role of immunohistochemistry in the diagnosis of psammomatoid ossifying fibroma (PSOF), conventional cemento-ossifying fibroma (COF), and psammomatous meningioma (PM) of the craniofacial skeleton. STUDY DESIGN: The histology and immunohistochemistry of 4 PSOFs, 6 COFs, and 7 PMs was studied. Antibodies included EMA, cytokeratins, smooth muscle actin (SMA), desmin, vimentin, CD34, CD10, S-100 protein, and glial fibrillary acidic protein (GFAP). RESULTS: All PSOFs showed multiple round ossicles homogeneously distributed within a fibroblastic stroma. Psammomatous meningiomas had meningothelial features. All tumors, except 1 COF, were positive for EMA. All of them expressed vimentin, and none showed cytokeratins. Staining for SMA and S-100 protein was variable. CD10 was positive in all cases except 2 meningiomas. CD34 and GFAP stained only 1 case of meningioma each. CONCLUSIONS: The diagnosis of PSOF should rest on histologic features. An incorrect diagnosis of meningioma based on the expression of EMA should be avoided.