Colorectal cancer (CRC) is one of the most heterogeneous and deadly diseases, with a global incidence of 1.5 million cases per year. Genomics has revolutionized the clinical management of CRC by enabling comprehensive molecular profiling of cancer. However, a deeper understanding of the molecular factors is needed to identify new prognostic and predictive markers that can assist in designing more effective therapeutic regimens for the improved management of CRC. Recent breakthroughs in single-cell analysis have identified new cell subtypes that play a critical role in tumor progression and could serve as potential therapeutic targets. Spatial analysis of the transcriptome and proteome holds the key to unlocking pathogenic cellular interactions, while liquid biopsy profiling of molecular variables from serum holds great potential for monitoring therapy resistance. Furthermore, gene expression signatures from various pathways have emerged as promising prognostic indicators in colorectal cancer and have the potential to enhance the development of equitable medicine. The advancement of these technologies for identifying new markers, particularly in the domain of predictive and personalized medicine, has the potential to improve the management of patients with CRC. Further investigations utilizing similar methods could uncover molecular subtypes specific to emerging therapies, potentially strengthening the development of personalized medicine for CRC patients.
The WASF3 gene promotes cancer cell invasion and metastasis, and genetic inactivation leads to suppression of metastasis. To identify small molecules that might interfere with WASF3 function, we performed an in silico docking study to the regulatory pocket of WASF3 using the National Cancer Institute (NCI) diversity set VI small molecule library. Compounds that showed the maximum likelihood of interaction with WASF3 were screened for their effect on cell movement in breast and prostate cancer cells, a well-established predictor of invasion and metastasis. Three hit compounds were identified that affected cell movement, and the same compounds also suppressed cell migration and invasion in vitro in both MDA-MB-231 breast cancer cells and Du145 prostate cancer cells. Using a zebrafish metastasis assay, one of these compounds, NSC670283, showed significant suppression of metastasis in vivo while not affecting cell proliferation. NSC670283 showed a consistent effect on suppression of invasion and metastasis, and cellular temperature shift assays provided support for physical interaction with WASF3. In addition, suppression of cell movement and invasion was accompanied by a decrease in actin filament polymerization. The data in this study suggest that these small molecules inhibit cancer cell invasion and metastasis, and to our knowledge, it is the first identification of a small molecule that can potentially inhibit WASF3-directed metastasis, laying the foundation for medicinal chemistry approaches to enhance the potency of the identified compounds.
Mantle cell lymphoma (MCL) is an intermediate-grade B-cell lymphoma, representing 2.8% of all non-Hodgkin lymphomas in the US. It is associated with t(11;14)(q13; q23), which leads to the overexpression of cyclin D1, consequently promoting cell proliferation. MCL usually expresses CD19, CD20, CD43, surface immunoglobulins, FMC7, BCL2, cyclin D1, CD5, and SOX11. Herein is a case of a 67-year-old male, referred to our facility with shortness of breath, anemia (hemoglobin of 5.3 g/dL), thrombocytopenia (12 × 109/L), and leukocytosis (283 × 109/L). A peripheral blood smear showed marked lymphocytosis with blastoid morphology. Morphologic examination of the bone marrow biopsy revealed a diffuse sheet of blastoid cells expressing CD20 and CD10, but without CD5 or cyclin D1. Given these features, a differential diagnosis of diffuse large B-cell lymphoma (DLBCL) with germinal center derivation, high-grade follicular lymphoma, and Burkitt lymphoma was considered, with the latter not favored due to morphology. Additional studies revealed positive SOX11, and fluorescence in situ hybridization (FISH) studies detected t(11;14). These additional studies supported diagnosis of the blastoid variant of MCL. In conclusion, we present a unique and challenging case of MCL without cyclin D1 or CD5, but with an expression of CD10 and SOX11, along with t(11;14). Pathologists should explicitly consider the blastoid variant of MCL when dealing with mature B-cell neoplasms with blastoid morphology in adults, and utilize a broad panel of ancillary studies, including FISH and SOX11.
Adenosquamous Carcinoma is a rare, aggresssive variant of squamous cell carcinoma that may HPV-driven in the oropharynx. Although it is reported to behave similar to HPV-related squamous cell carcinoma, the literature is very limited for this disease. We present a case of early T and N stage HPV + adenosquamous carcinoma of the tonsil that metastasized immediately following surgery and adjuvant therapy despite only having microscopic nodal burden. Circulating tumor DNA (ctDNA) was instrumental in recognizing and salvaging metastatic disease early with radiation.
Carcinoma, Adenosquamous , Carcinoma, Squamous Cell , Neoplasms, Second Primary , Oropharyngeal Neoplasms , Papillomavirus Infections , Humans , Papillomavirus Infections/complications , Papillomavirus Infections/pathology , Papillomaviridae/genetics , Carcinoma, Squamous Cell/pathology , Palatine Tonsil/pathology
Background: A pure ovarian dysgerminoma in a postmenopausal female is a rare phenomenon. Case: A 65-year-old female presented with a large pelvic mass. Following surgical debulking, the patient was diagnosed with FIGO Stage IIB ovarian dysgerminoma. She was treated with three cycles of etoposide and cisplatin and has been disease-free for 12 months. Conclusion: Dysgerminomas in postmenopausal females are uncommon. Gynecologic oncologists should be familiar with the pathological diagnosis and treatment recommendations to achieve optimal outcomes.
Uterine hemangioma (UH) is a rare benign lesion involving the myometrium and cervix. UH often presents as an endometrial polypoid mass that mimics an endometrial polyp. UH is commonly present in women of reproductive age with menorrhagia or pregnancy-associated complications. However, reported cases in postmenopausal women present with postmenopausal bleeding. The bleeding hemangiomatous polyps are treated with hysteroscopic polypectomy. We report the case of a 65-year-old postmenopausal woman with vaginal bleeding severe enough to seek emergency medical care. Transvaginal ultrasonography showed an endometrial thickness of 10.1mm but was otherwise unremarkable. Hysteroscopic examination revealed two endometrial polyps measuring 2.0cm, and 0.5cm. Surgeons had difficulty removing these polyps using usual methods, ultimately resorting to sharp excision. Microscopic examination showed scant endometrium without hyperplasia and a polypoid lesion with numerous CD31 positive capillaries entirely filling the stroma, supporting the diagnosis of capillary hemangioma. The contributing factor to UH in our case was unclear, which opens the door for future investigation of UH in post-menopausal women.
Conventional cytogenetic analysis of products of conception (POC) is of limited utility because of failed cultures, as well as microbial and maternal cell contamination (MCC). Optical genome mapping (OGM) is an emerging technology that has the potential to replace conventional cytogenetic methods. The use of OGM precludes the requirement for culturing (and related microbial contamination). However, a high percentage of MCC impedes a definitive diagnosis, which can be addressed by an additional pre-analytical quality control step that includes histological assessment of H&E stained slides from formalin-fixed paraffin embedded (FFPE) tissue with macro-dissection for chorionic villi to enrich fetal tissue component for single nucleotide polymorphism microarray (SNPM) analysis. To improve the diagnostic yield, an integrated workflow was devised that included MCC characterization of POC tissue, followed by OGM for MCC-negative cases or SNPM with histological assessment for MCC-positive cases. A result was obtained in 93% (29/31) of cases with a diagnostic yield of 45.1% (14/31) with the proposed workflow, compared to 9.6% (3/31) and 6.4% (2/31) with routine workflow, respectively. The integrated workflow with these technologies demonstrates the clinical utility and higher diagnostic yield in evaluating POC specimens.
Fertilization , Polymorphism, Single Nucleotide , Chromosome Mapping/methods , Cytogenetic Analysis/methods , Microarray Analysis/methods
Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal, and systemic hyperinflammatory syndrome with exacerbated and uncontrolled activation of histiocytes and lymphocytes against mature cells. Secondary HLH can occur in association with a myriad of underlying infections or malignancies. Our patient is a 38-year-old male prisoner with poorly controlled diabetes and no known other medical conditions. He was referred to our emergency department with three-week history of worsening malaise, weight loss, fever, bruising, and shortness of breath; imaging showed pneumomediastinum, lung nodule, and adrenal mass. Biopsy of the lung nodule revealed acid-fast bacilli. Furthermore, bone marrow biopsy showed foci of necrosis with associated acid-fast bacilli and hemophagocytosis highlighted by CD163 stain; consequently, secondary HLH was suggested. Hence, lab results were reviewed and found to satisfy five of the eight secondary HLH criteria. Moreover, ferritin was >10,000 ng/ml, which has been suggested to be highly suspicious for HLH. The patient was started on anti-MAC therapy. Unfortunately, the patient's status declined rapidly; he developed multi-organ failure and succumbed to disease. Later, his culture confirmed Mycobacterium tuberculosis. In conclusion, we presented a rare and challenging case of secondary HLH associated with disseminated Mycobacterium tuberculosis. A high index of suspicion is required for early diagnosis and treatment, and pathologists should be aware of Mycobacterium tuberculosis' association with secondary HLH.
Prostatic adenocarcinoma and renal cell carcinoma (RCC) can coexist. However, the incidence of collision metastasis of both prostatic adenocarcinoma and RCC is a rare phenomenon. A 50-year-old non-smoker male with end stage renal disease and a history of prostate adenocarcinoma was noted to have a left renal mass in the upper pole during CT surveillance. With the use of immunohistochemical stains the collision of two distinct malignancies from two different topographical regions was elucidated in a retroperitoneal lymph node. We report the second known case of collision metastasis of RCC and prostatic adenocarcinoma to a retroperitoneal lymph node.
BACKGROUND: The concentration of monoclonal immunoglobulins (Igs) in neoplastic monoclonal gammopathic manifestations is generally measured by densitometric scanning of the monoclonal peaks on gel or by measuring absorbance at 210 nm in capillary electrophoresis (CE). For monoclonal Igs migrating in the beta region, measurement is complicated by the major beta-region proteins, namely, transferrin and C3. METHODS: C3 interference in densitometry was eliminated by heat treatment of serum, and monoclonal Igs were quantified by densitometry of the residual band. The immunochemical measurement of transferrin was converted to its equivalent densitometric quantity. For monoclonal Ig migrating with transferrin, the contribution of the latter was removed by subtracting the converted transferrin concentration from the combined densitometric quantification of the band. With CE, monoclonal Ig was measured by using immunosubtraction (ISUB) to guide demarcation. RESULTS: The results obtained using the C3 depletion and transferrin subtraction method were lower and yet comparable to the results derived from using CE measurement guided by ISUB. As we expected, the results from both methods were lower than those derived from a perpendicular drop measurement of the peak or via nephelometric assay of the involved isotype. DISCUSSION: Accurate measurement of monoclonal Igs is important for the diagnosis and monitoring of monoclonal gammopathic manifestations. Determination of serum free light chain concentration per gram of monoclonal Ig is an essential measure for the diagnosis of light chain-predominant multiple myeloma. The method described herein improves accuracy of measurements for monoclonal Igs migrating in the beta region, without the need for special reagents or equipment.
Immunoglobulin Light Chains , Multiple Myeloma , Antibodies, Monoclonal , Blood Protein Electrophoresis/methods , Electrophoresis, Capillary , Humans , Multiple Myeloma/diagnosis
Heavy chain isotypes of low level monoclonal immunoglobulins are sometimes obscured in serum immunofixation electrophoresis (SIFE) by a heavy background of polyclonal immunoglobulins. However, accurate determination of the heavy chain isotype is essential for a complete diagnosis, as isotype determination of autoantibodies may have relevance in determining therapeutic procedures. Immune subtraction (IS) was employed in a patient with neuropathy and GD1a autoantibody. IS allowed identification of the cognate heavy chain related to a lambda light chain restriction noted on initial SIFE as well as isotype determination of the autoantibody. Antisera specific to individual heavy and light chains were used for depletion of specific immunoglobulin types. Depletion of kappa light chain associated immunoglobulins allowed unequivocal determination of the isotype of lambda light chain-associated low level monoclonal band to be IgG Lambda. Selective depletion of kappa, lambda, gamma and mu heavy chain immunoglobulins was employed to determine IgG Kappa isotype of the auto-antibody.
Ameloblastic fibro-odontoma (AFO) is a relatively rare, benign noninvasive mixed odontogenic neoplasm derived from epithelial and ectomesenchymal elements of the dental tissues. It usually presents with a mean age of 11.5 years and in the posterior segment of the mandible. It is extremely rare in the posterior maxilla. Although the latest WHO edition classified AFO as developing odontoma, here we present a locally aggressive AFO in a 21-year-old male involving the posterior maxilla and sinus with bone destruction. The patient presents with a two-year history of slowly progressive left facial swelling with malodorous drainage. The CT scan revealed a 5.5 x 4.3 cm well-circumscribed expansile mass with mixed attenuation and peripheral calcification occupying the left maxilla and sinus with bone destruction of the hard palate and orbital rim. According to the literature, most of the AFO cases were treated adequately through a conservative approach with just enucleation or surgical curettage. To our knowledge, our case is the first case treated aggressively with left maxillectomy, palatectomy, and reconstruction surgery because of its radiologic findings, which suggested a locally invasive neoplasm. Histologically, the specimen showed a mixture of proliferative epithelial, mesenchymal tissue elements, and variable amounts of mineralized deposits consisting of enamel matrix and dentinoid deposits, and the final diagnosis was AFO. In conclusion, we present a rare case of AFO with an unusual aggressive presentation, age group, and site involved. The radiographic, histopathologic features, and therapeutic approaches of this unusual locally aggressive tumor are presented with the review of relevant literature.
