Artificial intelligence-based epigenomic, transcriptomic and histologic signatures of tobacco use in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort (n = 257) and an internal cohort (n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients.

Unusual presentation of glioblastoma in the brainstem: a case report of a diffuse pontine glioblastoma multiforme and surgical management.

Diffuse pontine glioblastoma multiforme is a rare subtype of glioblastoma associated with a poor prognosis. In this case report, we present a unique case of diffuse primary pontine glioblastoma multiforme in a patient without any supratentorial lesions. We review the symptoms, treatment options, and case management of patients with infratentorial glioblastoma multiforme and compare these with our patient. Our patient presented with symptoms including progressive diplopia, gait disturbance, and lower extremity weakness. Magnetic resonance imaging revealed a diffuse lesion involving the pons and biopsy revealed only mildly-atypical glial infiltrates. Consequentially, diagnosis was driven by genetic analysis. Due to the location of the tumor, surgery was not considered a viable option. Instead, the patient received radiation therapy along with concomitant and adjuvant temozolomide chemotherapy which has resulted in improvement of symptoms. This case highlights the challenges of managing diffuse primary pontine glioblastoma multiforme and the need for more effective treatment options for this rare subtype of glioblastoma. Despite aggressive treatment, the prognosis for patients with infratentorial glioblastoma multiforme remains poor, with a median survival time of less than a year. Further research is needed to improve our understanding of the biology and optimal management of this disease.

Isocitrate Dehydrogenase Mutations Are Associated with Different Expression and DNA Methylation Patterns of OLIG2 in Adult Gliomas.

Isocitrate dehydrogenase (IDH) mutant gliomas are associated with a better prognosis in comparison to adult IDH wild-type glioma and glioma-CpG island methylator phenotypes. Although OLIG2 is mainly expressed in oligodendrocytes in normal adult brain, it is expressed in both astrocytomas and oligodendrogliomas. Utilizing the clinical, DNA methylation, and RNA-sequencing data from the Cancer Genome Atlas (TCGA) for lower-grade glioma and glioblastoma cohorts, we explored the association between IDH mutation status and OLIG2 expression on transcription, DNA methylation, and gene target levels. Compared to IDH wild-type gliomas, IDH mutant gliomas showed consistently higher expression of OLIG2 transcripts. OLIG2 overexpression is a good surrogate marker for IDH mutation with an AUC of 0.90. At the DNA methylation level, IDH-mutant gliomas showed hyper- and hypomethylation foci upstream of the OLIG2 transcription start site. Underexpressed OLIG2 target genes in IDH mutant glioma were enriched in cell cycle-related pathways. Thus, the differential expression of OLIG2 between IDH mutant and wild-type gliomas reflects involvement in multiple pathways in tumorigenesis.

72-year-old man with right homonymous hemianopia and gait instability.

An elderly man presented with right homonymous hemianopia and gait instability. He was found to have a left occipital ring enhancing lesion that was resected. Neuropathologic examination demonstrated a Cladophialophora bantiana brain abscess (cerebral phaeohyphomycosis).

Hepatic Secondary Syphilis Can Cause a Variety of Histologic Patterns and May Be Negative for Treponeme Immunohistochemistry.

The rate of syphilis in the United States has been increasing steadily in the past decade, but it remains an uncommon diagnosis in tissue biopsies. Most of the pathology literature on hepatic syphilis consists of older series or case reports. This study aimed to systematically characterize the histologic spectrum of hepatic syphilis in a contemporary cohort. Clinicopathologic features of 14 hepatic syphilis cases between 2012 and 2018 were analyzed to characterize the broad spectrum of histologic changes. Thirteen patients were men (age range: 19 to 59 y); 6 had known human immunodeficiency virus, 7 were men known to have sex with men, and no patient had known prior syphilis. Hepatic syphilis was the primary clinical suspicion in only 1 patient. Common symptoms included jaundice, rash, and abdominal pain. Thirteen had elevated transaminases, and 12 had elevated alkaline phosphatase. Pathologic changes were grouped into 5 histologic patterns: biliary-pattern injury (n=5), acute hepatitis (n=4), autoimmune hepatitis-like (n=1), fibroinflammatory mass-forming lesion (n=2), and no particular pattern (n=2). Nearly all showed portal and lobular lymphocytes and plasma cells; 12 had prominent histiocytes/Kupffer cells, 9 had ductular reaction, and 7 had duct inflammation. Occasional focal findings included dropout (n=7), phlebitis (n=7), and loose granulomata (n=5). Treponeme immunohistochemistry was positive in 10 and negative in 4, though treatment was given before biopsy in 3 of those 4. Thirteen patients had rapid plasma reagin testing either before or after biopsy, with 1:64 or higher titer. All patients who received treatment recovered. Hepatic syphilis is rare but likely underrecognized. It exhibits a variety of histologic appearances and therefore should be considered in several hepatic differential diagnoses, especially in men who have sex with men. Kupffer cells, granulomata, and phlebitis may suggest the diagnosis regardless of predominant histologic pattern. Negative treponeme immunohistochemical staining does not exclude the diagnosis, including in untreated patients.

Immunoglobulin G4-related disease of the cavernous sinus with orbit invasion - A case report.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a rare systemic disease of unknown etiology. It is characterized by tissue infiltration caused by IgG4 plasma cells and sclerosing inflammation of various body organs. At present, there are very few reported cases of IgG4-RD invasion of cavernous sinus and the orbit. CASE DESCRIPTION: A 56-year-old female with a history of rheumatoid arthritis was presented with a gradual onset of right oculomotor, abducens, and trigeminal nerve deficits. Four weeks after the onset of symptoms, the patient developed gradual visual deficit. Following this, a trial of steroids was administered to the patient. However, the treatment did not work as expected and patient's condition worsened. She progressed on to suffer complete visual loss in the right eye. Extensive work-up conducted on her turned out to be nondiagnostic. After this, the patient was referred to us for our evaluation. Neuroimaging revealed a right-sided cavernous sinus and orbital apex lesion. Given the lack of diagnosis and response to steroid treatment, we recommended surgical intervention and performed a modified pterional and pretemporal approach with extradural anterior clinoidectomy and transcavernous approach. We performed a lesion biopsy and cavernous sinus decompression, which helped in the partial recovery of visual function. The pathology report was consistent with IgG4-RD. CONCLUSION: IgG4-RD is a rare disease that occurs even less in combination with cavernous sinus and orbit invasion. The rarity of the disease and the diverse presentation of symptoms have sometimes caused delayed diagnosis and intervention. Patients who failed to respond to conservative management and patients in the fibrotic stage of the disease without other organ involvement may benefit from surgical intervention if amenable. Early suspicion, diagnosis, and intervention can facilitate better prognosis.

Striking MRI Changes of Focal Cortical Dysplasia Over Time: A Case Series and Literature Review.

PURPOSE OF REVIEW: Brain MRI findings of focal cortical dysplasia (FCD) can undergo dramatic changes over time, which may be related to long-term epilepsy or a combination of histopathologic changes that necessitate further investigation. RECENT FINDINGS: We describe 2 cases of FCD type IIb that initially displayed inconspicuous findings on MRI, however progressed to obvious signal changes on subsequent MRI 10-17 years later. Pathologic analysis indicates that the interval changes are likely attributed to reactive astrogliosis and diffuse parenchymal rarefaction. A few case reports and case series showing similar MRI changes have been described in the literature, the majority in pediatric patients. The adult cases we present add to the scientific evidence of these changes occurring in the adult population. SUMMARY: Our observations lead to several clinical suggestions, including closer interval follow-up imaging for nonlesional cases, the addition of postprocessing imaging methods, earlier surgical intervention, and meticulous surgical planning.

Sarcina Organisms in the Upper Gastrointestinal Tract: A Report of 3 Cases With Varying Presentations.

Sarcina species are anaerobic gram-positive cocci rarely seen in the upper gastrointestinal tract and associated with delayed gastric emptying. We present 3 cases of Sarcina infection with varying clinical presentations including the first reported case of Sarcina in a patient with eosinophilic esophagitis. Although the pathogenesis of Sarcina is unclear, awareness of the bacteria is important as they can usually only be detected on histopathologic examination of upper gastrointestinal biopsies. Treatment in symptomatic patients may prevent severe complications such as emphysematous gastritis and gastric perforation.

Saksenaea infection masquerading as a brain tumor in an immunocompetent child.

Saksenaea species are a rare cause of mucormycosis, the majority associated with cutaneous and subcutaneous infections resulting from trauma in both immunocompromised and immunocompetent individuals. Unlike other causative agents of mucormycosis, cerebral infections are exceptionally rare. We describe the first case of isolated cerebral infection by Saksenaea in a 4-year-old previously healthy male child who presented with headaches. He had no past medical history other than an episode of febrile seizures. In addition to raising the awareness of an unusual presentation of infection by Saksenaea, this case highlights the importance of pathologic examination for the prompt diagnosis of mucormycosis as well as the specific fungal identification for treatment as Saksenaea spp. may be more susceptible to posaconazole and less susceptible to amphotericin B compared to more common causes of mucormycosis.

Concomitant KRAS and BRAF mutations in colorectal cancer.

BRAF and KRAS are two key oncogenes in the RAS/RAF/MEK/MAP-kinase signaling pathway. While previously considered mutually exclusive, concomitant mutations in both KRAS and BRAF genes have been identified in colorectal cancer (CRC). The clinical outcome of these patients remains undetermined. We present the clinical course of two patients with CRC harboring mutations at codon 12 of KRAS and BRAF non-V600E mutations. More research is needed to determine the clinical-pathological effect of these simultaneous mutations of KRAS and BRAF in CRC on disease course and treatment outcome.

Atypical Presentation of Gelsolin Amyloidosis in a Man of African Descent with a Novel Mutation in the Gelsolin Gene.

BACKGROUND Gelsolin amyloidosis is a very rare systemic disease presenting with a pathognomonic triad of corneal lattice dystrophy, cutis laxa, and polyneuropathy. The disease is mostly restricted to a Finnish population with known mutations (G654A, G654T) in exon 4 of the gelsolin gene. The mutations lead to errors in protein processing and folding, and ultimately leads to deposition of an amyloidogenic fragment in the extracellular space, causing the symptoms of disease. CASE REPORT We present a case of gelsolin amyloidosis in a male of African descent with an atypical clinical presentation including fevers, skin rash, polyneuropathy, and anemia. Gelsolin amyloidosis was diagnosed based on mass spectrometry of tissue samples. Importantly, a novel mutation in the gelsolin gene (C1375G) in exon 10 was found in this patient. His atypical presentation can possibly be attributed to the presence of a novel mutation in the gelsolin gene as the likely underlying cause of the syndrome. PCR primers were used to amplify the gelsolin gene from genomic DNA. Purified PCR products were then shipped to Eton Biosciences (San Diego, CA) for sequencing. CONCLUSIONS This study carries several important lessons relevant to the practice of medicine. First, the differential diagnosis for multisystem disease presentations should always include amyloidosis. Second, despite what has been uncovered about the molecular biology of disease, there is always more that can be discovered. Finally, further work to verify the link between this mutation and the clinical syndrome is still needed, as are effective treatments for this disease.

Primary B-cell lymphoma of the uterine cervix: Presentation in Pap-test slide and cervical biopsy.

This case involved a 69-year-old female who presented with irritative urinary voiding. Imaging studies showed an 18-cm uterine mass centering on the cervix and extending into the bladder. The Pap test slide demonstrated necrotic background and degenerative changes in single and grouped atypical "small round blue cells" with high nuclear/cytoplasm ratio, scant cytoplasm, and hyperchromatic focally cleaved nuclei with occasional nuclear membrane "snout projections." Cervical biopsies showed similar findings. The tumor cells were positive for CD45, CD20, and PAX-5, and negative with epithelial, neuroendocrine, and muscle markers. A Ki-67 immunostain showed a markedly elevated proliferative index and the MUM1 stain was diffusely positive. Molecular study identified clonal immunoglobulin heavy chain gene rearrangement. Owing to its rarity, cervical lymphoma may sometimes be confused with other types of malignant neoplasms or inflammatory processes. Therefore, it is important to recognize the cytological features of cervical lymphomas and be aware of the potential diagnostic pitfalls for timely diagnosis and therapy. Diagn. Cytopathol. 2017;45:235-238. © 2016 Wiley Periodicals, Inc.

Serous Cystadenocarcinoma Arising in Presumed Vitelline Duct Remnant: A Case Report and Implications in the Management of Cancer of Unknown Primary.

Background. Malignant neoplasms arising in Meckel's diverticulum, a vitelline duct remnant, are rare yet well-documented. Case Presentation. A 53-year-old previously healthy female presented with an enlarging midline abdominal wall mass. A computed tomography scan revealed a mass involving the linea alba, bilateral rectus abdominis, and subcutaneous fat. Extensive clinical workup failed to demonstrate other lesions, except local and paratracheal/hilar lymphadenopathy. Histopathologic examination of the resected tumor demonstrated a spectrum of serous neoplasia including serous cystadenoma, papillary serous carcinoma with numerous Psammoma bodies, and a poorly differentiated component. Immunophenotypically, the tumor cells were strongly positive for CK7, CK19, CA19.9, and MUC1 but negative for other lineage markers, findings suggestive of pancreatobiliary type differentiation. The patient died of the disease one year after the initial presentation despite chemotherapy, radiation, and surgery. Conclusion. We present a case of adenocarcinoma arising from the anterior midline abdominal wall, from presumed vitelline duct remnant, with histologic and immunophenotypic features of serous cystadenocarcinoma of pancreatobiliary origin. Though the origin from vitelline duct remnant is difficult to prove in this single case, understanding tumorigenesis of embryonic remnant origin is potentially important to improve the management of cancer of unknown primary.

Post traumatic pulmonary pseudoaneurysm requiring pneumonectomy: a case report.

A 57-year-old male presented with progressive exertional dyspnea, cough, and hemoptysis. He underwent a chest computed tomography (CT) that demonstrated a 27 cm × 20 cm right chest mass that was causing a local mass effect. Pertinent history revealed that the patient had suffered a severe chest trauma from a MVA in 1981. The patient underwent workup including: needle localized biopsy, bronchoscopy and endoscopic biopsy. There was considerable concern for a malignant process and a subsequent right pneumonectomy with en bloc resection of the chest wall and diaphragm was performed. The final pathology concluded the mass to be a large pseudoaneurysm. Pseudoaneurysms after traumas are extremely rare, especially blunt trauma, and should be considered once other etiologies have been excluded.

Percutaneous Sentinel Node Biopsy in Breast Cancer: Results of a Phase 1 Study.

BACKGROUND: While sentinel lymph node dissection (SLND) provides axillary staging, recent trials question the necessity of removing positive nonsentinel axillary lymph nodes (LN) in breast cancer. We sought to determine the technical feasibility of percutaneous core needle biopsy (PNB) of axillary sentinel lymph nodes (SLNs). METHODS: After dual tracer injection, 25 patients underwent intraoperative axillary ultrasound and ultrasound guided per PNB of the axillary LN at the site of radiotracer uptake, followed by standard SLND. The primary outcome measure was successful correlation of PNB with SLN, defined as: (1) similar final pathology in core and SLN and (2) presence of blue staining and/or radiotracer in the core or gross evidence of PNB at the SLN (e.g., transected SLN). RESULTS: Preincision axillary ultrasound identified a LN (mean size 1.15 ± 0.67 cm) at the site of radioactive tracer in 92 % (23 of 25) of cases. Gross evidence of PNB at the SLN was found in 76 % (19 of 25) of cases. Blue staining, radioisotope, and pathology matched in core and SLN specimens in 36 % (9 of 25), 64 % (16 of 25), and 72 % (18 of 25) of cases, respectively. Overall, successful correlation of core biopsy with SLN occurred in 72 % (18 of 25) of cases. CONCLUSIONS: Results of this phase I study demonstrate that PNB of the SLN is technically feasible, but further refinement of technique is warranted to improve correlation of core biopsy to SLND.

Gastrointestinal stromal tumor with an unusual presentation as an enlarged prostate gland: a case report and review of the literature.

We report a case of a 78-year-old male who presented with urinary retention, constipation and an enlarged prostate gland. A transurethral resection of the prostate (TURP) was performed. Pathologic examination revealed a hypercellular-spindled neoplasm with frequent mitoses, nuclear pleomorphism, and multifocal geographic tumoral necrosis. A pathologic diagnosis of gastrointestinal stromal tumor (GIST) was made based on morphologic and immunohistochemical findings, and was later reinforced by molecular study results. This lesion was initially thought to represent a primary prostatic GIST. To the best of our knowledge, there have been only five cases of primary prostatic GISTs. Subsequent imaging studies revealed the mass to be contiguous with the anterior rectal wall, suggesting the possibility of a rectal primary with extension to the prostate gland. The patient was treated with imatinib mesylate, and after twelve months of follow up failed to demonstrate any evidence of progression or metastatic disease. GIST should be considered in cases of prostatic tumors with a spindled or epithelioid morphology, and immunohistochemistry and possible molecular studies are recommended to aid in diagnosis and guide treatment decisions.

Image-guided transoral resection of recurrent parapharyngeal space glial heterotopia.

Intranasal glial heterotopia is an uncommon congenital nasal lesion of neuroectoderm origin. Involvement of the parapharyngeal space is extremely rare. We present a case report of a newborn with life-threatening respiratory distress and feeding difficulty caused by a nasal glial heterotopia in a rare location involving the nasopharynx and parapharyngeal space. Surgical treatment was done in a staged fashion, involving image guidance for recurrence. Other diagnostic and treatment options are reviewed in the light of current literature.

Juvenile xanthogranulomas of the nervous system: A report of two cases and review of the literature.

Juvenile xanthogranulomas (JXG) are uncommon non-Langerhans cell histiocytic proliferations which arise most often in children. While most cases present as solitary cutaneous lesions, occasional cases involve extracutaneous sites. Rare examples of JXGs have been reported involving all levels of the neuroaxis. We present two cases of JXGs involving the nervous system, and review the literature. The first patient was a 14-year-old female with headaches and a mass involving the left trigeminal nerve; pathologic examination showed a JXG. At 11 months follow-up, after administration of systemic chemotherapy, the patient remained stable with residual tumor. The second patient was a 15-year-old female with leg weakness and numbness, who underwent complete surgical resection of a dural JXG. At eight months follow-up, she showed no evidence of tumor, and was able to walk without difficulty. Review of the literature revealed 38 previously published reports of JXGs involving the nervous system. The CNS was involved in the majority (75%) of cases. The clinical characteristics of JXGs arising in the CNS varied significantly from cases in the peripheral nervous system (PNS); CNS tumors occurred in younger patients, more often males, and were more likely to be associated with concurrent cutaneous and extra-nervous systemic lesions. The clinical outcomes were similar for CNS and PNS lesions, with the caveat that all three lethal JXGs occurred in the CNS. The clinical and radiologic presentation of JXGs is nonspecific, thus necessitating biopsy and pathologic examination to arrive at the diagnosis. The pathologic differential diagnosis includes a heterogeneous group of histiocytic proliferations; immunostaining for histiocytic markers CD68, factor XIIIa, and Fascin, and the absence of Birbeck granules and CD1a immunoexpression suggests the diagnosis of JXG. In many cases, total surgical resection is curative. However, some cases will require additional chemotherapy and/or radiotherapy.