A Low-Risk HPV-Associated Well-Differentiated Squamous Cell Carcinoma of the Cervix with Low-Grade Squamous Intraepithelial Lesion Morphology: Clinical and Pathologic Diagnostic Difficulties and Review of the Literature.

Approximately 95% of cervical squamous cell carcinomas are associated with high-risk HPV, with a small number of HPV-independent tumors. However, low-risk HPV types have also been detected in rare cervical squamous cell carcinomas. Low-grade squamous intraepithelial lesion-related changes are a rare morphologic finding in cervical squamous cell carcinoma. We present the case of a 30-yr-old woman who presented with pelvic pain and foul-smelling vaginal discharge showing an exophytic lesion protruding from the cervix. Repeated superficial biopsies showed a low-grade squamous intraepithelial lesion (LSIL) characterized by binucleation and koilocytosis. Chromogenic in-situ hybridization revealed the presence of HPV6/11. The absence of high-risk HPV was confirmed by PCR. After following the patient for nine months without intervention, type III hysterectomy and bilateral pelvic paraaortic lymphadenectomy were performed. Microscopic examination showed well-differentiated squamous cell carcinoma with solid epithelial islands and extensive eosinophilic cytoplasm without pleomorphism. HPV 6 and 11 were also detected with chromogenic in-situ hybridization. Neoplasm invaded the full-thickness of the cervical wall and infiltrated the vagina, parametrium, the proximal ureter and bladder. The patient who received chemoradiotherapy is disease-free at 36 months follow-up. Low-risk HPV-related well-differentiated invasive squamous lesions exist, and such lesions could be a diagnostic pitfall for gynecologists and pathologists; in these cases, radiologic-pathologic correlation and radiologic guided biopsy are mandatory.

Spatial UMAP and Image Cytometry for Topographic Immuno-oncology Biomarker Discovery.

Multiplex immunofluorescence (mIF) can detail spatial relationships and complex cell phenotypes in the tumor microenvironment (TME). However, the analysis and visualization of mIF data can be complex and time-consuming. Here, we used tumor specimens from 93 patients with metastatic melanoma to develop and validate a mIF data analysis pipeline using established flow cytometry workflows (image cytometry). Unlike flow cytometry, spatial information from the TME was conserved at single-cell resolution. A spatial uniform manifold approximation and projection (UMAP) was constructed using the image cytometry output. Spatial UMAP subtraction analysis (survivors vs. nonsurvivors at 5 years) was used to identify topographic and coexpression signatures with positive or negative prognostic impact. Cell densities and proportions identified by image cytometry showed strong correlations when compared with those obtained using gold-standard, digital pathology software (R2 > 0.8). The associated spatial UMAP highlighted "immune neighborhoods" and associated topographic immunoactive protein expression patterns. We found that PD-L1 and PD-1 expression intensity was spatially encoded-the highest PD-L1 expression intensity was observed on CD163+ cells in neighborhoods with high CD8+ cell density, and the highest PD-1 expression intensity was observed on CD8+ cells in neighborhoods with dense arrangements of tumor cells. Spatial UMAP subtraction analysis revealed numerous spatial clusters associated with clinical outcome. The variables represented in the key clusters from the unsupervised UMAP analysis were validated using established, supervised approaches. In conclusion, image cytometry and the spatial UMAPs presented herein are powerful tools for the visualization and interpretation of single-cell, spatially resolved mIF data and associated topographic biomarker development.

Acquired Leukonychia of the Distal Nail Plate: A Morphologic and Proteomic Analysis.

Leukonychia, or whitening of the nail plate, is a common disease that was first described in 1919. Leukonychia is classified as acquired or congenital and may be due to abnormality of the nail bed (pseudoleukonychia) or nail plate (true leukonychia). The distal whitened area of the nail plate was clipped from a 31-year-old woman with striated leukonychia and a 32-year-old man and 34-year-old woman with punctate leukonychia. Routine hematoxylin and eosin staining of all clipped samples was performed. A piece of nail with leukonychia and a normal nail from case 2 were sent to the Mayo Clinic for mass spectrometric analysis. On hematoxylin and eosin examination, all leukonychia samples showed odd-appearing eosinophilic linear parakeratinization in the mid-segment of the nail plate. Mass spectrometric analysis of case 2 revealed serum proteins (albumin, serotransferrin IgG, gamma chain, IgG lambda chain, and haptoglobulin) and hair proteins that were not found in the keratin content of the normal nail (keratin type Ha1 and cuticular keratin Ha4). This is the first description of odd-appearing linear parakeratosis and the first proteomic analysis showing abnormal protein content in acquired leukonychia.

Urine nerve growth factor (NGF) level, bladder nerve staining and symptom/problem scores in patients with interstitial cystitis.

BACKGROUND: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a challenging disease, affecting thousands of people all around the world, especially women. Although there have been numerous theories regarding IC/BPS etiology, the physiopathology of the disease still remains unclear and there is a lack of certain treatment. OBJECTIVES: The aim of the study was to assess the role of nerve fibers and nerve growth factor (NGF) in the etiopathogenesis of IC/BPS symptoms by demonstrating if there is a correlation between urine NGF levels, amount of peripheral nerves in bladder mucosa and symptom severity. MATERIAL AND METHODS: A prospective clinical study was conducted with 15 IC/BPS patients and 18 controls. Urine NGF levels were measured by enzyme-linked immunosorbent assay (ELISA). Bladder punch biopsies were obtained from 15 IC/BPS patients and 9 controls. Immunohistochemistry was performed for S-100 to highlight peripheral nerve twigs in bladder mucosa. The O'Leary-Sant Interstitial Cystitis Symptom and Problem Index (OSICSPI) was used to assess symptom severity and effects of the disease on the patients' life. RESULTS: NGF normalized to urine creatinine (NGF/Cr) levels in IC/BPS patients were significantly higher than in controls, 0.34 ±0.22 and 0.09 ±0.08 pg/mL: mg/dL, respectively (p < 0.001). The mean symptom score in IC patients was 12.27 ±2.4 (median: 12) and the mean problem score was 10.9 ±2.3 (median: 12). The mean mucosal nerve (S-100 stained) area in the IC/BPS group was significantly higher than in the controls, 2.53 ±1.90 vs 1.0 ±0.70, respectively (p = 0.018). In correlation analyses, the NGF/Cr level in IC/BPS patients was found significantly correlated with the O'Leary-Sant IC Symptom and Problem Index scores independently (p = 0.001 and p = 0.028, respectively). CONCLUSIONS: NGF seems to be a promising biomarker in IC/BPS. It may help clinicians in diagnoses and patient follow-up. Thus, unnecessary, expensive and invasive tests, interventions and treatments might be avoided.

SATB2 Expression Distinguishes Ovarian Metastases of Colorectal and Appendiceal Origin From Primary Ovarian Tumors of Mucinous or Endometrioid Type.

The primary origin of some ovarian mucinous tumors may be challenging to determine, because some metastases of extraovarian origin may exhibit gross, microscopic, and immunohistochemical features that are shared by some primary ovarian mucinous tumors. Metastases of primary colorectal, appendiceal, gastric, pancreatic, and endocervical adenocarcinomas may simulate primary ovarian mucinous cystadenoma, mucinous borderline tumor, or mucinous adenocarcinoma. Recently, immunohistochemical expression of SATB2, a transcriptional regulator involved in osteoblastic and neuronal differentiation, has been shown to be a highly sensitive marker of normal colorectal epithelium and of colorectal adenocarcinoma. SATB2 expression has not been reported in normal epithelium of the female reproductive tract. Therefore, we hypothesized that SATB2 may be of value in distinguishing ovarian metastases of colorectal adenocarcinoma from primary ovarian mucinous tumors and from primary ovarian endometrioid tumors. Among primary ovarian tumors, SATB2 staining was observed in 0/22 mucinous cystadenomas that lacked a component of mature teratoma, 4/12 mucinous cystadenomas with mature teratoma, 1/60 mucinous borderline tumors, 0/17 mucinous adenocarcinomas, 0/3 endometrioid borderline tumors, and 0/72 endometrioid adenocarcinomas. Among ovarian metastases, SATB2 staining was observed in 24/32 (75%) colorectal adenocarcinomas; 8/10 (80%) low-grade appendiceal mucinous neoplasms; and 4/4 (100%) high-grade appendiceal adenocarcinomas. No SATB2 staining was observed in any ovarian metastasis of pancreatic, gastric, gallbladder, or endocervical origin. Evaluation of primary extraovarian tumors showed the highest incidences of SATB2 staining among primary colorectal adenocarcinomas (71%), primary appendiceal low-grade mucinous neoplasms (100%), and primary appendiceal high-grade adenocarcinomas (100%). Similar to their metastatic counterparts, none of the primary pancreatic or gastric adenocarcinomas showed any SATB2 staining. In a subset of tumors for which CK7, CK20, and CDX2 were available, SATB2 was never positive in any tumor of any origin that was CK7+CK20-CDX2-. Among tumors that coexpressed all 3 markers (CK7+CK20+CDX2+), 6/7 SATB2 tumors were of colorectal or appendiceal origin, and 1/7 was a primary ovarian borderline tumor. We conclude that ovarian tumors with mucinous or endometrioid features that express SATB2 are unlikely to be of primary ovarian origin unless there is a component of mature teratoma in the ovary; instead, attention should be directed to a colorectal or appendiceal origin. SATB2 may be of particular value in ovarian mucinous tumors that are positive for all 3 markers (CK7+CK20+CDX2+), as SATB2 staining strongly implicates a colorectal or appendiceal origin.

Pulsed radiofrequency treatment of piriformis syndrome in a pregnant patient with malignant mesenchymal tumor.

Cancer is frequently seen in women of reproductive age. Diagnosis, management of treatment, and safety of the therapeutic approach are particularly important for these patients. Presently described is pain management in a case of pregnancy with malignant mesenchymal tumor. A 23-year-old woman in 30th gestational week presented with severe pain in right hip and back of the right thigh. Piriformis block successfully decreased pain and was followed by pulsed radiofrequency (PRF) to the piriformis muscle. PRF, as a non-neurodestructive method, is a safe and effective method to treat cancer pain in a pregnant patient.

Renal Carcinoid Tumor Metastatic to the Uvea, Medial Rectus Muscle, and the Contralateral Lacrimal Gland.

Renal carcinoid tumor is an exceedingly rare malignancy. A 57-year-old man with a renal carcinoid tumor discovered after metastasizing to intraocular and bilateral orbital structures is described. The patient presented with a blind painful OS and a right superotemporal subconjunctival mass. Imaging studies revealed a large left intraocular tumor, a mass in the left medial rectus muscle, and right lacrimal gland enlargement. The OS was enucleated, and incisional biopsies were performed from the other 2 lesions. Histopathological studies demonstrated metastatic neuroendocrine tumor with chromogranin and synaptophysin positivity. Systemic work up revealed a right renal mass and multiple hepatic metastatic lesions. Radical nephrectomy was performed, and octreotide, capecitabine, and temozolomide were administered. Removal of the primary tumor and the eye that had no prospect for useful vision and further treatment with octreotide, capecitabine, and temozolomide provided a disease progression-free period of 24 months and allowed the patient to function normally.

Pauci-immune necrotizing crescentic glomerulonephritis with crescentic and full moon extracapillary proliferation: clinico-pathologic correlation and follow-up study.

The prognostic value of the type and extent of extracapillary proliferation (ECP) in pauci-immune necrotizing crescentic glomerulonephitis (PIGN) was evaluated in this study. In 141 PIGN cases, all glomeruli with ECP were grouped according to type (cellular, fibrocellular and fibrous) and extent of the lesions in Bowman's space; (segmental, semicircumferential and circumferential, which might be termed full moon-FM). Cases with cellular and fibrous lesions involving ≥ 50% of glomeruli with ECP were classified as cellular and fibrous groups, respectively, while the remaining cases were classified as fibrocellular. Cases with segmental and circumferential (FM glomerulus) lesions involving ≥ 50% of glomeruli with ECP were classified as ECPI and ECPIII (FM) groups, respectively, while the rest were classified as ECPII. All the cases were classified according to Berden et al. Significant results were only nearly obtained for the FM group, including the need for dialysis. The Cox regression model revealed a 2.6-fold risk for FM cases regarding dialysis requirement. We propose that the percentage of FM glomeruli should be noted in the pathology report, and cases with more than 50% of FM glomeruli (FM group) should be identified in the group with increased risk of dialysis requirement. Our series also suggests that classification according to Berden et al. is of clinical relevance.

Ganglioneuroblastoma of the thoracic spinal cord: a very rare case report.

An eight-month-old male child was admitted with weakness and swelling in the feet. Paraparesis and bilateral lower extremity edema were present in the neurological examination. Thoracic MRI showed an intradural intramedullary mass 61 x 11 mm in size in the T5-T10 levels. Laminotomy between the T5-T10 vertebrae was performed. A mass with smooth borders was separated from most of the neural tissue. In the postoperative MRI, we observed a contrast enhancing area, considered a residual fragment, only 5 x 4 mm in size. Histopathological properties were compatible with the intermixed subtype of ganglioneuroblastoma. Only a limited number of thoracic cord Ganglioneuroblastoma reports have been previously published. Although very rare in children and young adults, ganglioneuroblastoma should be included in the differential diagnosis of thoracic cord tumors. It is difficult to obtain a preoperative diagnosis with clinical features and radiological investigations. Diagnosis depends on histopathological examinations. Curative treatment should be in the form of a complete resection of the tumor. In partially resected cases, adjuvant radiotherapy may become necessary, along with close follow-up.

Indian ink vs tissue marking dye: a quantitative comparison of two widely used macroscopical staining tool.

The evaluation of the surgical margins is a major concern in surgical pathology, and marking of surgical margins with substances such as alcian blue, Tipp-ex, artist's pigments, colored gelatin, starch, erythrocyte layers, etc. was recommended for this purpose; Indian ink and tissue marking dyes are widely used. As there is no systematic study comparing tissue marking dyes and Indian ink as the most common substances used for the purpose, this study was conducted to compare the two. Penetration into the tissue, brightness under the microscope, the spreading area of one drop of dye on tissue paper, the intensity of colors, and unit price were compared for each of the five colors of Rotring's Indian ink and Thermo-Shandon's tissue marking dyes, applied on reduction mammoplasty specimens. Rotring's Indian ink is proved to be just as effective as Thermo-Shandon's tissue marking dye and bares the majority of the characteristics of a perfect staining substance, which are easily applied, quickly fixed, durable and cheap, contain no potential contaminants, be work safe, would not smudge/stain surrounding tissues, and look bright under the microscope without obscuring the view.