Cutaneous Malignant Mixed Tumor With Pulmonary Metastasis: A Case Report and Literature Review.

BACKGROUND: Cutaneous malignant mixed tumor (MMT) is a rare sweat gland-derived tumor characterized by admixed malignant epithelial cells and chondromyxoid stroma. Approximately 50 cases have been described in the literature. Metastasis, which may occur in more than one-third of cases, is most common in the lung. METHODS: We summarized the clinicopathologic features of a patient with cutaneous MMT metastatic to the lungs. A literature review of similar cases was completed using Web of Science, Scopus, and PubMed databases. RESULTS: A woman in her 70s presented with an enlarging mass on her left eyebrow; histopathologic examination showed large islands of atypical cells with increased mitotic activity, admixed with necrosis on a background of fibrotic and chondromyxoid stroma. Multiple lung nodules were identified during follow-up. Examination of a pulmonary core needle biopsy specimen was consistent with metastatic cutaneous MMT. Literature review identified 10 cases published between 1980 and 2017. Most primary tumors were large (≥4 cm). Local recurrence was uncommon, and the lung was the only metastatic site in 5 cases. Histopathologically, metastatic tumors were described as more cellular, with diminished stromal tissue compared with the primary lesion. CONCLUSION: This is 1 of the 11 reports of cutaneous MMT with metastasis to the lungs found in the English-language literature published after 1980. Of note, most reports were published before 1990, making this case study one of the few contemporary descriptions of cutaneous MMT with pulmonary metastases. We think that the present case report will increase the awareness of this rare tumor.

Genomic attributes of prostate cancer across primary and metastatic noncastrate and castrate resistant disease states: a next generation sequencing study of 183 patients.

Primary prostatic adenocarcinoma (pPC) undergoes genomic evolution secondary to therapy-related selection pressures as it transitions to metastatic noncastrate (mNC-PC) and castrate resistant (mCR-PC) disease. Next generation sequencing results were evaluated for pPC (n = 97), locally advanced disease (involving urinary bladder/rectum, n = 12), mNC-PC (n = 21), and mCR-PC (n = 54). We identified enrichment of TP53 alterations in high-grade pPC, TP53/RB1 alterations in HGNE disease, and AR alterations in metastatic and castrate resistant disease. Actionable alterations (MSI-H phenotype and HRR genes) were identified in approximately a fifth of all cases. These results help elucidate the landscape of genomic alterations across the clinical spectrum of prostate cancer.

von Hippel-Lindau disease-related neoplasia with an emphasis on renal manifestations.

von Hippel-Lindau (VHL) disease is characterized by biallelic inactivation of the VHL gene leading to abnormal or absent VHL protein function, and constitutive activation of hypoxia-inducible factors (HIF) that leads to pro-tumorigenic signaling. Individuals with VHL disease develop numerous cysts and tumors involving multiple organs including the kidneys, central nervous system, endolymphatic sac, lungs, pancreatobiliary system, adrenal glands, epididymis, and/or broad ligament. On histologic examination, these lesions show morphologic overlap as they are frequently characterized by cells with clear cytoplasm and prominent vascularity. In addition to distinguishing non-renal tumors from metastatic clear cell renal cell carcinoma, understanding site-specific histopathologic and immunophenotypic features of these tumors has several applications. This includes distinguishing VHL-related tumors from those that arise sporadically and lack VHL gene alterations, guiding further genetic workup, and helping distinguish between different genetic predisposition syndromes. In this context, immunohistochemical studies for markers such as paired box 8 (PAX-8), carbonic anhydrase 9 (CA9), and glucose transporter 1 (GLUT-1) have an important role in routine clinical practice and represent cost-effective diagnostic tools. The recent development of targeted therapeutics directed against HIF-mediated signaling represents a significant milestone in the management of VHL disease and highlights the importance of accurately diagnosing and characterizing the wide spectrum of VHL disease-associated lesions.

Identification of amyloidosis of the urinary tract and prostate: Opportunities for early diagnosis & intervention in systemic disease.

OBJECTIVES: To determine the prevalence of different amyloid types and frequency of associated systemic amyloidosis in the urinary tract/prostate. METHODS: We studied Congo red-positive prostate (n = 150) and urinary tract (n = 767) specimens typed by a proteomics-based method between 2008 and 2020. Clinical follow up was available for a subset (urinary tract, n = 111; prostate, n = 17). Amyloid types were correlated with various clinicopathologic features. For patients with clinical follow up, chart review was performed to establish localized versus systemic disease, frequency of initial diagnosis of amyloidosis on urinary tract/prostate specimens, presence of cardiac disease, and death from disease-related complications. RESULTS: The most common amyloid types were AL/AH in urinary tract (479/767, 62 %) and localized ASem1 in prostate (64/150, 43 %). Urinary tract AL/AH amyloid was usually localized, but systemic AL amyloidosis occurred in both sites (urinary tract: 5/71, 7 %; prostate: 2/2, 100 %). ATTR amyloidosis was seen in over a third of cases (urinary tract: 286/767, 37 %; prostate: 55/150, 37 %). Urinary tract/prostate was the site of the initial ATTR amyloidosis diagnosis in 44/48 patients (92 %), and 38/48 (79 %) were subsequently found to have cardiac involvement. Seminal vesicle/ejaculatory duct involvement was pathognomonic for ASem1-type amyloidosis (39/39, 100 %). CONCLUSIONS: Over 40 % of patients had systemic amyloidosis, with urinary tract/prostate often the first site in which amyloid was identified. Since early recognition of systemic amyloidosis is critical for optimal patient outcomes, there should be a low threshold to perform Congo red stain. Proteomics-based amyloid typing is recommended since treatment depends on correctly identifying the amyloid type.

Assessment of PD-L1, TROP2, and nectin-4 expression in penile squamous cell carcinoma.

OBJECTIVES: There is an unmet need for therapeutically relevant biomarkers for advanced penile squamous cell carcinoma (pSCC). Proposed immunohistochemistry (IHC)-based biomarkers include programmed death-ligand 1 (PD-L1), trophoblast cell-surface antigen 2 (TROP2), and nectin-4; however, there is a paucity of data pertaining to these biomarkers. Herein, we investigated the expression of PD-L1, TROP2, and nectin-4 in a well-annotated cohort of pSCCs. METHODS: A single-institution pathology archive was queried for patients who had a partial or total penectomy for pSCC between January 2000 and December 2022. Whole-slide sections were stained with antibodies against PD-L1 (22C3), TROP2, and nectin-4. Expression in tumor cells was quantified using H-scores (0-300). Associations between IHC expression, human papilloma virus (HPV) status, clinicopathologic findings, and outcome parameters were evaluated. RESULTS: This study included 121 patients. For PD-L1, the median combined positive and H-scores were 1 and 0, respectively; 32.7 % of the cases had an H-score>0. Compared to PD-L1-negative tumors, PD-L1-positive tumors had higher pT stage and grade. The median TROP2 and nectin-4 H-scores were 230 and 140, respectively, with high TROP2 and nectin-4, defined by an H-score>200, noted in 80.7 % and 10.9 % of cases, respectively. High-risk HPV-positive cases had higher TROP2 and nectin-4 scores compared to HPV-negative cases. Patients with high TROP2 expression had significantly more disease progression, and patients with high nectin-4 expression had significantly fewer deaths due to disease. CONCLUSIONS: High expression of TROP2 and nectin-4 in pSCC support evaluation of these markers as therapeutic targets pending validation of our findings.

Proteomic and Clinicopathologic Assessment of Penile Amyloidosis: A Single Institutional Review of 12 Cases.

OBJECTIVES: There is a paucity of data on penile amyloidosis. We aimed to assess the frequency of different amyloid types in surgical specimens from the penis involved by amyloidosis and correlate relevant clinicopathologic parameters with proteomic findings. METHODS: Since 2008, our reference laboratory has performed liquid chromatography/tandem mass spectrometry (LC-MS/MS) for amyloid typing. The institutional pathology archive and reference laboratory database were queried to retrospectively identify all penile surgical pathology specimens with LC-MS/MS results between January 1, 2008, and November 23, 2022. Archived H&E-stained and Congo red-stained sections were re-reviewed. RESULTS: Twelve cases of penile amyloidosis were identified, which represented 0.35% (n = 3,456) of penile surgical specimens. AL-type amyloid was most frequent (n = 7), followed by keratin-type amyloid (n = 3) and ATTR (transthyretin)-type amyloid (n = 2). AL-type amyloid cases often showed diffuse dermal/lamina propria deposition, whereas all keratin-type amyloid cases were localized to the superficial dermis. Two cases with keratin-type amyloid had concomitant cutaneous findings (penile intraepithelial neoplasia and condyloma). CONCLUSIONS: This series, the largest to date, demonstrates that penile amyloidosis has a heterogeneous proteomic landscape. To the best of our knowledge, this is the first study describing ATTR (transthyretin)-type penile amyloid.

A chronic wound model to investigate skin cellular senescence.

Wound healing is an essential physiological process for restoring normal skin structure and function post-injury. The role of cellular senescence, an essentially irreversible cell cycle state in response to damaging stimuli, has emerged as a critical mechanism in wound remodeling. Transiently-induced senescence during tissue remodeling has been shown to be beneficial in the acute wound healing phase. In contrast, persistent senescence, as observed in chronic wounds, contributes to delayed closure. Herein we describe a chronic wound murine model and its cellular senescence profile, including the senescence-associated secretory phenotype.

Mass spectrometry-based assessment of prostate cancer-associated crystalloids reveals enrichment for growth and differentiation factor 15.

Intraluminal crystalloids are a common finding within malignant prostatic acini and are infrequently identified within benign glands. The proteomic composition of these crystalloids remains poorly understood and may provide insight regarding prostate cancer pathogenesis. Laser microdissection-assisted liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS) was performed to compare proteomic composition of corpora amylacea within benign acini (n = 9), prostatic adenocarcinoma-associated crystalloids (n = 8), benign (n = 8), and malignant prostatic acini (n = 6). The expression of candidate biomarkers was then measured in urine specimens from patients with (n = 8) and without prostate cancer (n = 10) using ELISA, and immunohistochemistry-based expression in adjacent prostate cancer and benign glands was assessed in 56 whole-slide sections from radical prostatectomy specimens. LMD-LC-MS/MS revealed enrichment for the C-terminal portion of growth and differentiation factor 15 (GDF15) in prostatic crystalloids. Although urinary GDF15 levels were higher in patients with prostatic adenocarcinoma compared to those without (median: 1561.2 versus 1101.3, arbitrary units), this did not meet statistical significance (P = 0.07). Immunohistochemistry for GDF15 revealed occasional positivity in benign glands (median H-score: 30, n = 56), and diffuse positivity in prostatic adenocarcinoma (median H-score: 200, n = 56, P < 0.0001). No significant difference was identified within different prognostic grade groups of prostatic adenocarcinoma, or within malignant glands with large cribriform morphology. Our results show that the C-terminal portion of GDF15 is enriched in prostate cancer-associated crystalloids, and higher GDF15 expression is seen in malignant rather than benign prostatic acini. Improved understanding of the proteomic composition of prostate cancer-associated crystalloids provides the rationale for evaluating GDF15 as a urine-based biomarker of prostate cancer.

Evaluation of an in vivo preclinical model for human middle meningeal artery embolization using the posterior intercostal artery of the swine.

BACKGROUND: Embolization of the middle meningeal artery (MMA) is a promising minimally invasive technique that is gaining traction in the treatment of chronic subdural hematoma. Unfortunately, the human meninges and associated arteries are significantly larger than those of conventional laboratory animals, making the development of a clinically relevant animal model for testing of embolization agents elusive. OBJECTIVE: To introduce the posterior intercostal artery (PIA) model in swine and provide anatomical, angiographic, histological, and procedural data to validate its relevance in modeling the human MMA. METHODS: In human cadaveric specimens, 3D angiograms of the internal maxillary arteries (n=6) were obtained and the dura with MMA were harvested and histologically processed. Angiographic and histologic data of the human MMA were compared with the swine PIA (three animals). Then, embolization of the PIA (n=48 arteries) was conducted with liquid embolization agent (Onyx, Medtronic), and angiographic and histological results were assessed acutely (four animals) and after 30 days (two animals). RESULTS: The human MMA has equivalent diameter, length, branching pattern, 3D trajectory, and wall structure to those of swine PIAs. Each swine has 12 to 14 PIAs (6-7 per side) suitable for acute or chronic embolization, which can be performed with high fidelity using the same devices, agents, and techniques currently used to embolize the MMA. The arterial wall structure and the acute and chronic histological findings in PIAs after embolization are comparable to those of humans. CONCLUSIONS: This PIA model in swine could be used for research and development; objective benchmarking of agents, devices, and techniques; and in the training of neurointerventionalists.

Penile squamous cell carcinoma exclusive to the shaft, with a proposal for a novel staging system.

Penile squamous cell carcinomas (SCC) originating in the shaft are rare. pT1/pT2 categories in the American Joint Committee on Cancer (AJCC) staging manual (8th edition) are poorly defined for SCCs arising in the dorsal shaft as anatomic structures differ between the glans and dorsal shaft (corpus spongiosum vs dartos/Buck's fascia, respectively). We reviewed six penile SCC cases exclusive to the shaft, an unusual presentation, identified amongst 120 patients treated with penectomy. We propose a novel pT staging system for dorsal shaft tumors tailored to its anatomic landmarks, where tumors extending to Buck's fascia are considered pT2 instead of pT1. The mean age at penectomy, average duration of follow-up, and mean depth of invasion were 64 years, 45 months, and 9.8 mm, respectively. Four cases were moderately differentiated, HPV-negative SCCs of the usual type and two cases were HPV-positive basaloid and warty-basaloid carcinomas. Three cases had nodal or distant metastasis at the time of penectomy, and histologic assessment in these cases showed invasion into the Buck's fascia or deeper. According to the current AJCC system, only one of these three cases would be staged as ≥ pT2. In contrast, all three metastatic tumors would be staged as ≥ pT2 in the proposed model. At last follow-up, one patient died of disease-related complications. Based on this limited series, the proposed staging model appears to suggest better patient stratification for pT1/pT2 stages. This model incorporates Buck's fascia, which has been postulated as a pathway of tumor infiltration. Additional studies are needed to validate this model.

Quantitative spatial evaluation of tumor-immune interactions in the immunotherapy setting of metastatic melanoma lymph nodes.

Introduction: Immune cell infiltration into the tumor microenvironment is generally associated with favorable clinical outcomes in solid tumors. However, the dynamic interplay among distinct immune cell subsets within the tumor-immune microenvironment as it relates to clinical responses to immunotherapy remains unresolved. In this study, we applied multiplex immunofluorescence (MxIF) to spatially characterize tumor-immune interactions within the metastatic melanoma lymph node. Methods: Pretreatment, whole lymph node biopsies were evaluated from 25 patients with regionally metastatic melanoma who underwent subsequent anti-PD1 therapy. Cyclic MxIF was applied to quantitatively and spatially assess expression of 45 pathologist-validated antibodies on a single tissue section. Pixel-based single cell segmentation and a supervised classifier approach resolved 10 distinct tumor, stromal and immune cell phenotypes and functional expression of PD1. Results: Single cell analysis across 416 pathologist-annotated tumor core regions of interest yielded 5.5 million cells for spatial evaluation. Cellular composition of tumor and immune cell subsets did not differ in the tumor core with regards to recurrence outcomes (p>0.05) however spatial patterns significantly differed in regional and paracrine neighborhood evaluations. Specifically, a regional community cluster comprised of primarily tumor and dendritic cells was enriched in patients that did not experience recurrence (p=0.009). By an independent spatial approach, cell-centric neighborhood analyses identified an enrichment for dendritic cells in cytotoxic T cell (CTL) and tumor cell-centric neighborhoods in the no recurrence patient response group (p<0.0001). Further evaluation of these neighborhoods identified an enrichment for CTL-dendritic cell interactions in patients that did not experience recurrence (p<0.0001) whereas CTL-macrophage interactions were more prevalent in CTL-centric neighborhoods of patients who experienced recurrence (p<0.0001). Discussion: Overall, this study offers a more comprehensive evaluation of immune infiltrates and spatial-immune signatures in the metastatic tumor-immune microenvironment as it informs recurrence risk following immunotherapy.

Computational tumor stroma reaction evaluation led to novel prognosis-associated fibrosis and molecular signature discoveries in high-grade serous ovarian carcinoma.

Background: As one of the key criteria to differentiate benign vs. malignant tumors in ovarian and other solid cancers, tumor-stroma reaction (TSR) is long observed by pathologists and has been found correlated with patient prognosis. However, paucity of study aims to overcome subjective bias or automate TSR evaluation for enabling association analysis to a large cohort. Materials and methods: Serving as positive and negative sets of TSR studies, H&E slides of primary tumors of high-grade serous ovarian carcinoma (HGSOC) (n = 291) and serous borderline ovarian tumor (SBOT) (n = 15) were digitally scanned. Three pathologist-defined quantification criteria were used to characterize the extents of TSR. Scores for each criterion were annotated (0/1/2 as none-low/intermediate/high) in the training set consisting of 18,265 H&E patches. Serial of deep learning (DL) models were trained to identify tumor vs. stroma regions and predict TSR scores. After cross-validation and independent validations, the trained models were generalized to the entire HGSOC cohort and correlated with clinical characteristics. In a subset of cases tumor transcriptomes were available, gene- and pathway-level association studies were conducted with TSR scores. Results: The trained models accurately identified the tumor stroma tissue regions and predicted TSR scores. Within tumor stroma interface region, TSR fibrosis scores were strongly associated with patient prognosis. Cancer signaling aberrations associated 14 KEGG pathways were also found positively correlated with TSR-fibrosis score. Conclusion: With the aid of DL, TSR evaluation could be generalized to large cohort to enable prognostic association analysis and facilitate discovering novel gene and pathways associated with disease progress.

CDX2 expression in primary skin tumors-case series and review of the literature.

CDX2 expression characterizes tumors of gastrointestinal origin, including those of intestinal-type differentiation. In dermatopathology, CDX2 expression is reported in 4 settings: cutaneous metastases from carcinomas of intestinal origin or differentiation, extramammary Paget's disease associated with an underlying colorectal or urothelial tumor, pilomatricomas and pilomatrical carcinomas, and rare primary cutaneous (adeno)squamous carcinomas with intestinal immunophenotype. Over 4 years (10/2017-10/2021), 252 dermatopathology cases with CDX2 immunostain were reviewed, revealing 46 cases with confirmed positive staining. Among them, 11 cases confirmed as primary nonintestinal type cutaneous carcinoma with definitively positive CDX2 nuclear staining were further studied. All cases demonstrated basaloid morphology with atypia, variable necrosis, and brisk mitotic activity. Cases 1-5 had heterogeneous features that cannot be further classified, including 2 cases with neuroendocrine or pseudoglandular/pseudopapillary features, and 1 case with human papillomavirus high-risk E6/E7 ISH positivity. In cases 6 through 11, the diagnosis of pilomatrical carcinoma was supported morphologically. This study substantiates the association of CDX2 with pilomatrical carcinoma. In addition, CDX2 positivity was observed in a subset of basaloid cutaneous carcinomas of ambiguous classification. However, this finding also raises a diagnostic pitfall in clinical diagnostic specificity of the CDX2 immunostain in skin cancers, which can be observed in rare while heterogeneous subsets of primary cutaneous carcinomas with primitive cytomorphology.

Histopathology of autoimmune bullous dermatoses: what's new?

Autoimmune bullous dermatoses are characterized by the presence of tissue-bound and often circulating pathogenic autoantibodies targeting structural components of the skin and/or mucous membranes. The diagnostic workup for this heterogeneous group of disorders consists of a multi-step process, of which the light microscopic examination is a crucial component. This review is organized following a classification scheme that is based on two main histopathologic features, namely level of intraepithelial split and composition of the inflammatory infiltrate. Overall, we aim to place emphasis on the histopathologic clues that can assist pathologists in differential diagnosis and review the updates in the literature.

Intake of divalent copper and nickel onto natural zeolite from aqueous solutions: a study in mono- and dicomponent systems.

In this study, the noncompetitive and competitive adsorption process of copper (II) and nickel (II) ions on the natural zeolite were examined in simulated wastewater in a batch system with respect to concentration, pH and temperature. Optimum pH values were found as 5,0 for adsorption of copper and nickel ions on the zeolite. The effect of initial concentration and ambient temperature on the yield of adsorption was examined at this pH value. The equilibrium adsorption data of Cu (II) and Ni (II) onto the zeolite were analyzed by the Langmuir's and Freundlich's isotherms, and the experimental metal uptake data fitted well with both isotherm models. In case of the presence of simultaneous multimetal ions in the aqueous phase, the adsorption capacity of the adsorbent is slightly low probably due to the competitive uptake of each metal ion by the adsorbent. For the metal sorption system, the negative Gibbs free energy values show the applicability and spontaneous nature of the metal uptake treatment by the zeolite. The activation energy and enthalpy change of divalent cation adsorption demonstrate that the intake of Cu (II) and Ni (II) onto the zeolite involves not only a chemical adsorption process but also a physical adsorption process.