bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary Bladder Transitional Cell Carcinoma with Chordoid Features-A Rare Entity
Authors: Kozman D , Heneidi S , Ullah A , Ghleilib I , Vemavarapu L , Dykes T
Published: October 2020

Casestudy: Invasive urothelial carcinoma is heterogenous entity and show variant morphologic patterns, of which squamous differentiation is the most common. Other variants have been widely recognized and studied.

Invasive urothelial carcinoma with chordoid features is a rare entity with only 16 reported cases to date in English literature. It has a significant morphologic overlap with other vesical and non-vesical myxoid neoplasms, including extra-skeletal myxoid chondrosarcoma and chordoma, which necessitate an extensive workup to reach an accurate diagnosis.

To the best of our knowledge we report the 17th case of urothelial carcinoma with chordoid features in a 76-year-old male who underwent a cystoprostatectomy and bilateral pelvic lymph node dissection with confirmed diagnosis of high-grade invasive urothelial carcinoma on biopsy. Grossly, bladder showed a 4.2 x 3.4 x 0.6 cm firm white tumor entirely replacing the anterior wall, extending into perivesicular fat, and invading the prostate gland and seminal vesicles.

Microscopically, tumor showed urothelial carcinoma in-situ transitioning into high-grade invasive carcinoma with chordoid features. The tumor characterized by round to elongated epithelial cells and eosinophilic cytoplasm arranged in a single file/complex cord-like architecture, in a prominent myxoid stromal background. No conventional high-grade spindle cell morphology was identified. Pelvic lymph nodes were positive for metastatic disease. Tumor cells were positive for GATA3, Pan-cytokeratin, 34BetaE12, and p63, while negative for AMCAR, supporting the urothelial origin of this tumor and confirming the diagnosis.

Invasive urothelial carcinoma with chordoid features is a rare entity, generally present at high stage disease, that can be mistaken for other prominent myxoid stromal neoplasms and requires careful assessment. Although, it can demonstrate similar demographic, clinical and immunohistochemical staining pattern as of conventional urothelial carcinoma, special attention should be given to exclude sarcomatoid features which is an aggressive variant of urothelial carcinoma.
Granular Cell Tumor Confined To The Muscularis Propria Of The Appendix: A Case Report
Authors: Allison D , Rao D
Published: October 2020

Introduction/Objective

Granular cell tumors (GCTs) are exceedingly rare soft tissue tumors that are usually benign and are thought to arise from Schwann cell origin. GCTs most commonly occur in the skin, subcutaneous tissue, and oral cavity. However, they can involve any organ, including the gastrointestinal (GI) tract, of which esophagus is most common, followed by large intestine. We report a case of a 58 year old female who presented with acute

appendicitis, followed by an appendectomy to reveal an incidental GCT.

Methods

This report is a retrospective study of an appendiceal GCT in which we reviewed the case and the histology. In addition, a brief literature review of gastrointestinal GCTs was performed to further elucidate the incidence, location, histopathology, and differential diagnoses for this lesion.

Results

Histological analysis of the tumor nodule reveals nests of epithelioid cells with abundant granular eosinophilic cytoplasm. The nuclei are bland, small, and round to oval, with rare spindled morphology.

Immunohistochemistry for S-100 protein shows diffuse strong cytoplasmic and nuclear positivity, which is suggestive of Schwann cell origin. In the GI tract, GCTs are routinely confined to the mucosa, submucosa, or both; however the tumor nodule in our case is contained within the muscularis propria.

Conclusion

It is estimated that 5–11% of GCTs occur in the gastrointestinal tract, while only 13 GCT cases of the appendix have been reported. In addition to the previously stated rarity, is the limited involvement of the muscularis propria, with which GCTs typically are not associated. To our knowledge, this is the first confirmed GCT of the appendix that solely involves the muscularis propria, in English medical literature.
PD-L1 Expression in Anal Intraepithelial Neoplasia Versus. Invasive Squamous Cell Carcinoma
Authors: Monsrud A , Avadhani V , Mosunjac M , Krishnamurti U
Published: October 2020

Introduction/Objective

Upregulation of programmed death-ligand 1 (PD-L1), an immunoregulatory protein is associated with adverse outcome in several malignancies. Very few studies have evaluated PD-L1 expression in anal lesions. In this study we compare PD-L1 expression in anal squamous intraepithelial lesions (SIL/AIN) with that in invasive squamous cell carcinoma (ISCC)

Methods

After IRB approval, formalin-fixed paraffin embedded sections from 84 patients (51 with ISCC and 32 without ISCC), from 2010–2018, were immunostained for PD-L1 (Dako 22C3 monoclonal antibody). These included 15 cases with normal mucosa, 60 cases with low grade squamous intraepithelial lesion (LSIL/AIN 1), 52 cases with high grade intraepithelial lesion (HSIL/AIN2-3), and 51 cases of ISCC. Overall tumor proportion score of > 1% tumor cells with partial or complete membrane staining was interpreted as PD-L1 positive (PD-L1 +).

Results

PD-L1 was positive in 18/51 (35%) and negative in 33/51 (65%) cases of ISCC. Staining was heterogenous in all PD-L1 positive cases, with invasive foci that were negative to 100% positive. Tumor proportion score ranged from 1% to 50%. No PD-L1 membrane positivity was seen in any of the normal mucosa, LSIL/AIN 1, and HSIL/AIN 2-3. Even in cases of microinvasive or invasive carcinoma, PD-L1 positivity was seen only in the invading malignant cells and not in the overlying or adjacent HSIL. One case showed aberrant nuclear staining in 10% of cells in LSIL and HSIL. About 25% of cases showed non-specific basal granular cytoplasmic staining in normal mucosa, LSIL, and HSIL, that correlated with the presence of melanin. Cases with normal mucosa, LSIL/AIN 1, and HSIL/AIN 2-3, were equally distributed between cases with no invasive carcinoma, PD-L1 positive ISCC, and PD-L1 negative ISCC.

Conclusion

No PD-L1 positivity (membrane staining) was present in normal mucosa or anal squamous intraepithelial lesion/anal intraepithelial neoplasia in our study. Any nuclear staining or granular cytoplasmic staining should not be interpreted as PD-L1 positivity. PD-L1 was only positive in a subset (35%) of invasive squamous cell carcinoma. The expression of PD-L1 is likely to be associated with an invasive malignant process and is a potential target for therapy with PD-L1 inhibitors.
A Case Report Of A Spindle Cell Sarcoma With Ntrk-3 Rearrangement And A Novel Gene Fusion Partner (Ntrk3-Eif2s2)
Authors: Shalaby A , Alhussain A , Al Hmada Y , Bernieh A
Published: October 2020

Casestudy

A group of spindle cell tumors with characteristic morphologic features, co-expression of CD34 and S100 and recurrent gene rearrangements in RAF-1, BRAF, and NTRK has recently been described. These tumors were found to be previously labeled as malignant peripheral nerve sheath tumor, infantile fibrosarcoma or unclassified spindle cell sarcoma. We describe a case of a 25-year-old female who presented with a right thigh mass. She underwent an ultrasound-guided biopsy showing a spindle cell tumor with co-expression of CD34 and S100 and subsequently underwent resection of the mass. Gross examination showed a 7.5 cm multi-lobulated, tan-pink, hemorrhagic and fleshy mass. Histologically, the tumor was relatively well-demarcated and consisted of spindle cells with moderate to high cellularity in a patternless architecture. The spindle cells showed moderate to marked pleomorphism, pale amphophilic cytoplasm, ovoid-to-elongated nuclei with vesicular chromatin, and occasional prominent nucleoli. Areas of prominent perivascular and stromal hyalinization were seen. Mitotic activity was brisk with up to 33 mitoses per 10 high power fields. Necrosis representing approximately 5% of the mass was identified. On immunohistochemistry, the tumor cells showed strong and diffuse positivity for CD34 and S100 and were negative for SOX10, broad-spectrum cytokeratin, EMA, SMA, Desmin, STAT6, MUC4, TLE1, and H3K27me3 (retained nuclear expression). EIF2S2-NTRK3 fusion gene was detected using next generation sequencing analysis.

Conclusion

A few cases of NTRK3 spindle cell sarcomas, other than classic infantile fibrosarcoma, have been previously reported in the literature with fusion genes involving ETV6, EML4, and STRN, among others. A gene fusion involving NTRK3 and EIF2S2 has not been previously reported. NTRK3-fused sarcomas typically show high-grade morphology and aggressive clinical behavior. Identification of NTRK-fused sarcomas is clinically important, as these advanced tumors are potentially amenable to NTRK inhibition. In our case, patient received adjuvant post-operative radiation therapy and returned with lung metastasis 5 months after surgery.
A Rare Presentation of Pseudomembranous Colitis in a COVID-19 patient
Authors: Jabbar A , Rana T , Ilyas G , Baqir A , Emechebe D , Agaronov M
Published: October 2020

Introduction/Objective

Recent reports suggest that though COVID-19 is predominantly a respiratory pathogen, one of its presenting features can be gastrointestinal symptoms. We hereby present a case of a female with COVID-19 infection whose hospital course was complicated by colonic pseudo-obstruction caused by pseudomembranous colitis resulting in an emergent hemicolectomy.

Methods

A 59-Year-old female with history of hypertension, diabetes, and breast cancer post mastectomy presented with pneumonia and was confirmed to be COVID-19 positive. She was admitted to the hospital and was treated with Azithromycin for 6 days. Patient developed constipation on day six of hospitalization and started having abdominal pain on day eight with elevated WBC count. Imaging showed distension of cecum and proximal colon. She underwent exploratory laparotomy which revealed a necrotic appearing cecum that was massively dilated and had a serosal tear. These findings prompted emergent hemicolectomy with loop ileostomy. Grossly cecum was black/green, dilated, thin walled with a 5 x 5 cm yellow green raised plaques. Microscopy of the plaques revealed focal erosion of colonic mucosa with overlying acute inflammatory cells, fibrin deposits, mucus, and necrotic epithelial cells consistent with pseudomembranous colitis.

Conclusion

Review of literature shows no reported cases of intestinal pseudo-obstruction due to pseudomembranous colitis in a COVID-19 patient. Not only this, but there are also only a limited number of case studies of pseudomembranous colitis presenting as intestinal pseudo-obstruction without diarrhea. Though this patient’s presentation could be from Clostridium difficile infection secondary to Azithromycin, it is not a common antibiotic to cause this. Also, one of the known causes of pseudomembranous colitis is ischemia. Given that COVID-19 infection is a pro-thrombotic condition, possible ischemia secondary to COVID-19 infection related coagulopathy should also be a consideration.
Hirschsprung’s Disease: Two Cases of Total Intestinal Aganglionosis
Authors: Ramachandran V , Nguyen J , Caruso C , Rao D
Published: October 2020

Introduction/Objective

Hirschsprung’s disease is a disorder associated with an absence of ganglion cells in a segment of the bowel. Total colonic and small bowel aganglionosis occurs in less than 1% of all Hirschsprung’s disease patients. Even rarer is the finding of Haddad syndrome, the coexistence of congenital central hypoventilation syndrome and Hirschsprung’s disease. Congenital central hypoventilation syndrome has approximately 1,000 reported cases, with colonic aganglionosis being associated with 15-20% of those cases. The prevalence of Hirschsprung’s disease with congenital renal anomalies may be another underreported finding.

Methods

Here, we report two rare cases of Hirschsprung’s disease with significant extension in the small bowel. One case involves a 38-week gestational age male infant admitted for apnea and another case involves 39-week gestational age female infant admitted for vomiting.

Results

Both infants had rectal suction biopsies confirming the absence of ganglion cells. The male infant had mapping biopsies which histologically showed hypertrophic nerve fibers and an absence of ganglion cells in the colon extending up to 70 cm proximal to the ileocecal valve. Calretinin immunostaining confirmed aganglionsis. Genetic testing showed a PHOX2B gene mutation carrying 32 polyalanine repeat mutations, confirming a diagnosis of congenital central hypoventilation syndrome coexisting with Hirschsprung’s disease. The female infant had intraoperative frozen sections that identified ganglion cells throughout the colon. On permanent sections, there was an absence of ganglion cells in the upper rectum extending up to 65 cm proximal to the ileocecal valve. She also was noted to have agenesis of the left kidney and a urachal remnant. Genetic testing was negative for RET mutations.

Conclusion

Overall, these cases provide further information on a rare variant of Hirschsprung’s disease that includes significant portions of the small bowel. Additionally, this study adds to the documented reports of Haddad syndrome and the connections between renal anomalies with Hirschsprung’s disease. Last, this series alludes to the difficulties of frozen section diagnosis of this disease.
Russell Body Duodenitis In A Patient With Duodenal Adenoma And High-Grade Dysplasia
Authors: Sun L , Allison D , Yin F
Published: October 2020

Introduction/Objective

Russell bodies are nondegradable, condensed immunoglobulins accumulated in the overstimulated plasma cells, and the plasma cells filled with Russell bodies are called Mott cells. Russell body gastroenteritis is a rare entity that is mainly occurs in stomach and is associated with Helicobacter pylori infection.

However, Russell body duodenitis is very rarely seen, so far only about four cases have been reported. Here we report a case of Russell body duodenitis within concurrent large duodenal adenoma with high-grade dysplasia in a 66- year old female.

Methods

Formalin fixed, paraffin embedded tissue was examined stained with H&E and PAS-Alcian blue stain. Immunohistochemical stains (IHC) with appropriate controls were performed with the following antibodies: H. pylori, CD138, kappa and lambda light chains.

Results

A 66-year old female had symptoms of difficult swallowing and decreased food intake. Upper GI endoscopy was performed to reveal a 7 cm multilobulated mass at the junction of the duodenal bulb and second portion of the duodenum, which involved the ampullary orifice. A biopsy for the mass showed a duodenal adenoma with high grade dysplasia. Numerous Mott cells were diffusely distributed within the lamina propria that was characterized by bright eosinophilic cytoplasmic globules with eccentric nuclei. The Mott cells were confirmed by IHC stains with positive CD138, PAS-Alcian blue, and polytypic expression of kappa and lambda light chains. The Helicobacter pylori immunostain was negative.

Conclusion

Although the etiology is unknown, most of the Russell body gastroenteritis are seen in benign conditions. It is mainly found in stomach associated with Helicobacter pylori infection. To our knowledge, this is the first reported case of Russell body duodenitis with concurrent duodenal adenoma with high-grade dysplasia. Further studies should be conducted on Russell bodies associated with high-grade dysplasia or carcinoma in gastrointestinal tract.
Next Generation Sequencing of Renal Medullary Carcinoma Diagnosed Concurrently with Sickle Cell Trait: A Case Report and Literature Review
Authors: McCool I , Dasgupta A , Jordan M
Published: October 2020

Casestudy

We present a 33-year-old African American male with 4 months of intermittent right flank pain and gross hematuria with hypermetabolic retroperitoneal lymphadenopathy, persistent right-sided hydronephrosis, perinephric fat stranding and a 5.5-cm hypermetabolic right lower pole mass demonstrated on imaging.

Results

Core needle biopsies of the mass contained atypical glands composed of epithelioid cells with pleomorphic nuclei, prominent nucleoli, eosinophilic cytoplasm and abundant mitoses infiltrating through desmoplastic stroma.

Immunohistochemical staining demonstrated CK7 and PAX8 reactivity of the tumor cells, and negative staining for CK20, WT1, PSA, PLAP and CD10. The patient underwent a radical right nephrectomy; microscopic examination illustrated invasion of the renal sinus, perirenal fat, and lymphovascular space by the neoplastic glands and sickling erythrocytes in the vasculature. Further IHC staining revealed intact mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) and a loss in expression of INI1 (SMARCB1), leading to the concurrent diagnoses of renal medullary carcinoma and sickle cell trait (confirmed with hemoglobin fractionation). Next generation sequencing of 144 clinically significant genes detected no mutations.

Conclusion

Renal medullary carcinoma is a rare, aggressive neoplasm that accounts for less than 0.5% of all renal cell carcinomas and presents at an advanced stage. Patients are usually young males who are of African or Mediterranean descent with comorbid sickling disease. Although loss of SMARCB1/INI-1 gene expression is associated with this neoplasm, no effective therapeutic targets have yet been established. Renal medullary carcinomas are usually resistant to chemotherapy and radiotherapy, making the identification of an immunotherapy target paramount. With a median survival of four months from diagnosis, additional genetic studies of these malignancies may identify an effective treatment option for renal medullary carcinoma.
Multifocal Pancreatic Neuroendocrine Neoplasms In Tuberous Sclerosis: A Rare Case
Authors: Jadhav N C , Gang D L
Published: October 2020

Casestudy: Pancreatic neuroendocrine neoplasms (PanNEN) are rare accounting for 2-5% of pancreatic tumors. Although mostly sporadic, 10-20% are associated with inherited syndromes, notably MEN-1, Von Hippel- Lindau disease, neurofibromatosis type 1, and tuberous sclerosis (TS). When compared to sporadic cases, PanNEN in hereditary syndromes occur at a younger age, are often multifocal, cystic, and may show characteristic microscopic patterns. TS is an autosomal dominant multi-system disorder with mutations involving TSC1 or TSC2 genes which function as tumor suppressors by inhibiting mTORC1 kinase. PanNEN is observed in 1.5-1.8% of patients with TS and no surveillance guidelines for the assessment of pancreatic lesions are established. Compared to other syndromes, PanNEN associated with TS are solitary. To our knowledge, only two cases of multifocal PanNEN in TS patients have been reported. We present a case of a 67-year-old gentleman with a history of TS also affecting two daughters. He presented to the emergency department with severe abdominal pain. Abdominal ultrasound suggested acute appendicitis and an incidental 2.0 cm solid lesion was noted in the head of the pancreas. Follow-up MRI revealed two additional non-cystic masses in the pancreatic tail. Endoscopic ultrasound-guided biopsy of a tail lesion revealed monomorphic tumor cells with stippled chromatin without cytologic atypia. Immunohistochemical staining was positive for synaptophysin and chromogranin. Ki-67 labelling index was under 1%. Diagnosis of a well-differentiated neuroendocrine tumor (G1) was made. The patient denied symptoms of the carcinoid syndrome and no biologically active hormones were detected. Gallium PET scan revealed multiple foci of radiotracer uptake throughout the pancreas in addition to those described on MRI. Although PanNEN are rare in TS, malignant behavior has been reported. This case reinforces the importance of early detection through active surveillance, especially as surgical options may be limited in multifocal disease.
Multiplex Assays of Luminex for Identification of COVID-19 Antibodies in Patient Serum: Performance Evaluation and Comparison to ELISA
Authors: Shapiro M S , Wang X , Mendu D R , Firpo A
Published: October 2020

Introduction/Objective

Mount Sinai Hospital has received emergency use authorization (EUA) from the FDA for Coronavirus Disease 2019 (COVID-19) antibody testing using ELISA. This serological assay detects and titrates the presence of circulating antibodies to COVID-19. Other platforms have aimed to achieve the credentials of the ELISA instrument, including the multiplex assays of Luminex. The platform is known to have a greater throughput (384 wells vs. 96 wells per microplate) and faster processing speed (8 hours vs. 17 hours).

Methods

Luminex utilizes beads that couple to the same COVID-19 antigens (mRBD and mSpike) which were utilized for the ELISA assay. The beads are read determining the mean fluorescence intensity (MFI). In order to compare the two methods, our study included 61 patients with COVID-19 at Mount Sinai Hospital, to screen and titrate their sera using Luminex, and to correspond the MFI values with the ELISA titers.

Results

The Luminex assay has achieved the same level of confidence as ELISA. The 61 patients, representing 30 negatives and 31 positives, are consistently identified as such on both platforms. Our data highlights 32% of patients with a low titer (<1:160), 42% of patients with a high titer (1:160 ~ 1:320), and 26% of patients with a very high titer level (>1:320). These titers correlated well with the MFI values. Based on a cutoff of 80,000 MFI, the sensitivity and specificity of the assay is 98% and 85%, respectively, with no overlapping of MFI between positive and negative results.

Conclusion

Overall, the study has demonstrated that the Luminex is a strong alternative for the ELISA platform. The Luminex highlights the broad dynamic range with no overlapping between positives and negatives. Migration from ELISA to Luminex, a platform with faster and greater throughput, is therefore, highly desirable.
A Challenging Case of A Myeloid Sarcoma Misdiagnosed as High Grade B-Cell Lymphoma
Authors: Herrmann A , Mai B , Elzamly S , Wahed A , Nguyen A , Chen L
Published: October 2020

Introduction/Objective

A 46-year-old female presented with severe back pain associated with progressive bilateral lower extremity weakness and paresthesia, urinary retention, and constipation. Computed tomography revealed a retroperitoneal mass encasing the right psoas muscle, obstructing the right kidney, and extending to the thoracolumbar region resulting in severe spinal compression. An epidural tumor resection was subsequently performed at an outside hospital.

Methods

Histological sections showed sheets of blastoid neoplastic cells with intermediate to large nuclei, irregular membranes, fine chromatin, and prominent nucleoli. Immunohistochemical stains showed that these cells were positive for CD43, CD79a (weak, focal), BCL2, C-MYC, and PAX5 (weak, focal) and negative for CD10, CD20, CD30, ALK1, BCL6, MUM1, and Tdt. The Ki-67 proliferation index was 75-80%. With this immunophenotype, this patient was diagnosed with a high grade B-cell lymphoma and transferred to our institution for further work-up. On review of the slides, further immunohistochemical testing was requested which revealed positivity for CD117 and myeloperoxidase (MPO).

Results

The overall morphological and immunophenotypical features are most compatible with myeloid sarcoma (MS) with aberrant expression of B-cell markers and this patient’s diagnosis was amended. Interestingly, the patient’s bone marrow examination only showed 2% myeloblasts with left shifted granulocytosis and concurrent fluorescence in situ hybridization (FISH) studies were negative.

Conclusion

A literature review showed that 40-50% of MS are misdiagnosed as lymphoma. MS can frequently stain with B-cell or T-cell markers, as seen in this case, which makes it challenging for an accurate diagnosis and sub- classification. In addition, our case is interesting in that there was only extramedullary presentation without bone marrow involvement. Typically, MS develops after the diagnosis of acute myeloid leukemia (AML) with an incidence of 3–5% after AML. It can also manifest de novo in healthy patients, who then go on to develop AML months to years later. Therefore, this patient will require close follow-up.
A Case of Enteropathy Associated T-Cell Lymphoma (EATL) with Aberrant Phenotype, CD8+, CD56+: From Diagnosis to Death
Authors: Clarke-Brodber A , Eldibany M , Victor T
Published: October 2020

Introduction/Objective

Enteropathy Associated T-Cell Lymphoma (EATL) is a rare and aggressive subtype of primary intestinal T cell lymphoma which occurs in patients with Celiac Disease (CD), most prevalent in the western world with an incidence rate of 0.22-1.9 cases per 100,000. The classic immophenotype of these neoplastic intestinal T cells show loss of CD8 and CD56. The adherence to gluten-free diet, markedly decreases the incidence of this complication.

Methods

The patient’s previous and current biopsies, autopsy and EMR were reviewed. The patient is 66-year female that was diagnosed with Celiac Disease in 2003 after duodenal biopsy showed features suggestive of CD with positive anti-endomysial IgA antibody serology. She presents currently with burning abdominal pain, with subsequent CT scan showing a mass in the small bowel with mid gut rotation and lesions in the lungs, liver and bladder.

Endoscopy showed multiple lesions extending from the hypopharynx to the large bowel, which on biopsy showed CD3+ lymphocytes expanding the lamina propria and infiltrating the crypt epithelium. Given the patient’s clinical history a diagnosis of EATL was made. The patient passed 5 days after diagnosis due to small bowel perforation.

Results

The initial duodenal biopsy showed villous blunting and increased intraepithelial lymphocytes. The biopsies of the gastrointestinal lesions show abnormal infiltrate of pleomorphic, intermediate in size lymphocytes with round to irregular and occasionally cleaved nuclei with pale to clear cytoplasm. These cells infiltrate the crypt epithelium. The immophenotype of these neoplastic cells are positive for CD3, CD7, CD8, CD56, TIA-1 and BF1, while negative for CD4, CD5 and CD30. T cell clonality was also positive. In addition to the above lesions, autopsy revealed involvement of an area of small bowel perforation with full-thickness mucosal wall involvement by the neoplastic cells. In addition, there is widely dissemenated disease involving the lung, liver, bone marrow, spleen, mesenteric lymph nodes, omentum, bladder, ovaries and myometrium (first report of uterine involvement).

Conclusion

CD8 positive EATL may occur in 19-30% of cases, and increases up to 50% in refractory CD. The differential diagnosis of MEITL, which is typically CD8 positive, is important and most be distinguished on the basis of clinical setting in the presence of Celiac Disease.
A Rare Case of Chronic Lymphoproliferative Disorder of NK Cells with an Unusual Expression of CD57
Authors: Laharwani H , Perrizo K , Jain S , Lam J
Published: October 2020

Introduction/Objective

Natural Killer cells (NK-cells) malignancies are extremely rare and the two NK-cell disorders involving the peripheral blood and bone marrow include chronic lymphoproliferative disorder of NK-cells (CLPDNK) and aggressive NK-cell leukemia (ANKL). ANKL is EBV associated with a prevalence in Asian adults and a fulminant clinical course leading to death within 2 months.

Methods

A 76-year-old female with a history of iron deficiency anemia presented for evaluation of lymphocytosis (78 TH/mm) and negative EBV with extreme fatigue, weight loss, and worsening weakness from the past 8 months.

Results

The peripheral and bone marrow aspirate showed an increase in granular lymphocytes with bland nuclei and abundant pale-staining cytoplasm containing fine to coarse azurophilic granules with no evidence of nuclear atypia. Flow cytometry demonstrated an atypical lymphocytic cell population comprising >50% of total marrow and peripheral blood lymphocytes demonstrating loss of CD56 and diminished CD7 expression. The analysis showed atypical lymphocytes with the following immunophenotype: CD2, CD8 (the majority, at least 75%),CD7 (dim), CD38, CD11c (subset) with no expression of CD3, CD5, CD4, CD56, or CD11c. Flow cytometry is important as it helps in the phenotypic detection of aberrancy. A broad panel of immunohistochemical stains revealed scattered positivity for CD3, CD4, CD7, CD8, TIA-1, granzyme, perforin, and tryptase and negative for CD56 and CD57. Our top differential with a similar clinical course included T-cell large granular lymphocytic leukemia which is characterized by a clonal proliferation of mature cytotoxic T cells and also has an indolent course. They show CD3 positivity by flow cytometry along with co-expression of NK cell-associated markers (CD16 and CD57), and variable expression of other pan T cell markers such as CD2, CD5, CD7. It is found incidentally in patients having cytopenias with a persistent increase in circulating mature NK-cells. Of note, the PET scan revealed splenomegaly with no other significant findings.The patient was started on steroids and is currently doing well.

Conclusion

Thus, overall morphologic, immunophenotypic, and molecular results with negative expression of surface or cytoplasmic CD3 as well as the absence of TCR expression were most consistent with CLPD-NK with an unusual expression of CD57 expression detected in flow cytometry.
Coagulation Testing in Acute Ischemic Stroke Patients Taking Non-Vitamin K Antagonist Oral Anticoagulants
Authors: Kamel Y S
Published: October 2020

Introduction/Objective

In patients who present with acute ischemic stroke while on treatment with non-vitamin K antagonist oral anticoagulants (NOACs), coagulation testing is necessary to confirm the eligibility for thrombolytic therapy. We evaluated the current use of coagulation testing in routine clinical practice in patients who were on NOAC treatment at the time of acute ischemic stroke.

Methods

Prospective multicenter observational RASUNOA registry (Registry of Acute Stroke Under New Oral Anticoagulants). Results of locally performed nonspecific (international normalized ratio, activated partial thromboplastin time, and thrombin time) and specific (antifactor Xa tests, hemoclot assay) coagulation tests were documented. The implications of test results for thrombolysis decision-making were explored.

Results

In the 290 patients enrolled, nonspecific coagulation tests were performed in ≥95% and specific coagulation tests in 26.9% of patients. Normal values of activated partial thromboplastin time and international normalized ratio did not reliably rule out peak drug levels at the time of the diagnostic tests (false-negative rates 11%-44% [95% confidence interval 1%-69%]). Twelve percent of patients apparently failed to take the prescribed NOAC prior to the acute event. Only 5.7% (9/159) of patients in the 4.5-hour time window received thrombolysis, and NOAC treatment was documented as main reason for not administering thrombolysis in 52.7% (79/150) of patients.

Conclusion

NOAC treatment currently poses a significant barrier to thrombolysis in ischemic stroke. Because nonspecific coagulation test results within normal range have a high false-negative rate for detection of relevant drug concentrations, rapid drug-specific tests for thrombolysis decision-making should be established.
Incidental Anaplastic Lymphoma in a Case of Herpetic Hepatitis
Authors: Perrizo K , laharwani H , Jain S , Lam J
Published: October 2020

Introduction/Objective

The role of Herpes Simplex Virus (HSV) virus in the development of lymphomas is unclear and poses a diagnostic challenge along with limited literature explaining the relationship between HSV and Anaplastic large-cell lymphoma (ALCL).

Methods

A 26-year-old female admitted for intractable fever (103.7 F), chills, and dysuria; her urine analysis was suggestive of a mild urinary tract infection. During the admission, she developed abdominal pain with subsequent CT- scan showing thickening of the gallbladder and possible cholecystic fluid. Her liver function tests were: albumin 2.8 g/dL, AST 394 U/L, ALT 303 U/L, ALP 156 U/L, total bilirubin 0.3 INR 1. A subsequent Magnetic Resonance Cholangiopancreatography (MRCP) showed heterogeneous enhancement pattern of the liver without any masses following which she underwent cholecystectomy, during which her liver was abnormal along with an enlarged peri- cholic lymph node. Intraoperative biopsy of the liver showed patchy hepatocyte necrosis and occasional hepatocytes with ground-glass nuclei. The morphologic features were suggestive for Herpes Simplex Virus (HSV) hepatitis, and an HSV immunohistochemical stain confirmed this diagnosis. Removal of the lymph node showed a sinusoidal infiltrate of atypical lymphohistiocytic cells with abundant pale cytoplasm and large moderately irregular nuclei and occasional prominent amphophilic nucleoli. A few “hallmark”-like cells with curved nuclei were noted with rare mitosis. A panel of adequately controlled immunohistochemical stains showed positivity for CD4, CD30 (variable), and CD45. CD2, CD3, CD5, CD7, CD8, CD10, CD15, CD20, CD68 (positive in adjacent macrophages), BCL2, ALK1 were negative.

Results

Flow cytometry was negative for a neoplastic leukocyte population with a polytypic B-cell population. Taken together, a diagnosis of ALK1 negative, ALCL was made. A subsequent CT scan revealed borderline enlarged para- aortic lymph nodes along with an increased number of non-enlarged lymph nodes in the bilateral axillary, mediastinal, lower neck, and subpectoral regions. A bone marrow biopsy performed was negative for lymphoma.

Conclusion

Off note, her hepatitis serology panel, CMV, and HIV screens were negative. Thus, with her unusual presenting symptoms and no signs of malignancy led to numerous workups, which further led to an infectious cause, however, the patient was ultimately discovered to have an occult ALCL.
Intracranial Hemorrhage In Patients Receiving Direct Oral Anticoagulant Therapy: Clinical Assessment, Management And Related Laboratory Studies
Authors: Xie M , Wyrzykowski M
Published: October 2020

Introduction/Objective

Direct oral anticoagulants (DOACs) have gained wide use in prevention and treatment of thromboembolic diseases. Although relatively rare with DOAC therapy, intracranial hemorrhage may become a medical emergency and needs to be managed with caution to avoid adverse consequences.

Methods

During the review of 94 patients with DOAC therapy related bleeding complications at William Beaumont hospital – Troy, Michigan, 3 patients were identified with intracranial hemorrhage. Information on DOAC therapy, the cause related to intracranial hemorrhage, and clinical assessment and management of these patients were collected from electronic medical charts with concurrent laboratory studies.

Results

There were 1 male and 2 female patients, ages 63, 67 and 86. Two patients were taking rivaroxaban 20 mg daily and 1 patient apixaban 5 mg bid for atrial fibrillation and DVT. Patients were clinically stable with no prior significant bleeding events, except for minor skin rashes. All patients experienced a minor trauma to the head and showed signs of brain injury. They were brought to the emergency department immediately. DOAC therapy was discontinued during the emergency evaluation. CT studies revealed 1 patient with subdural hematoma and 2 patients with focal intraparenchymal hemorrhage without mass effects. Both clinical and laboratory assessment revealed stable medical conditions. Patients received conservative care without surgical intervention and repeat CT studies demonstrated resolution of hemorrhage. One patient discontinued DOAC therapy permanently and the others resumed DOAC therapy with antidotes available. Clinical follow up showed no additional bleeding events.

Conclusion

Intracranial hemorrhage can occur in patients received DOAC therapy, even in clinically stable patients, and most likely happens after head injury. In this small group of patients, both clinical and laboratory evaluations showed stable medical conditions, with no need for surgery intervention. However, the decision of continuing DOAC therapy should be made with caution and it is reasonable to have antidote available for these patients.
Accuracy of the Criteria for Hemophagocytic Lymphohistiocytosis
Authors: Aksionau A , Wei E
Published: October 2020

Introduction/Objective

Regular assessment and analysis of diagnostic criteria for any type of human pathology is a prerequisite for ensuring the highest level of patient care. Hemophagocytic lymphohistiocytosis, also known as hemophagocytic syndrome, is a life-threatening condition. The syndrome can develop in critically ill patients with malignancies, severe infections, during chemotherapy, and may be associated with currently known genetic abnormalities, but this list is incomplete.

We draw attention to the accuracy of diagnostic criteria, association with a variety of clinical conditions, pathophysiological mechanisms, and outcomes of the disease.

Methods

From the medical records in our hospital, we were able to extract several cases over a 10-year period. Based on hemophagocytosis features, our list included 13 patients representing 11 bone marrow aspirates, 4 lymph node biopsies, 1 liver biopsy, and 1 spleen sample; repeated examination of the slides confirmed the accuracy.

Analyzing medical documentation, we evaluated the sequence and competence of the criteria used, the time required for diagnosis, management, and outcomes.

Results

We found that not all criteria were used for diagnosis, and the most sensitive and specific tests were bypassed. The preliminary diagnosis was made by a consultant (a rheumatologist or an oncologist-hematologist) on the 5th day of the hospital stay that delayed treatment. Of all the available treatment options, only a few were used.

Conclusion

The hemophagocytic syndrome is a very rare and fatal entity, it requires highly sensitive and specific diagnostic criteria for prompt diagnosis, targeted management, and thorough follow up. Every patient admitted to the hospital with a life-threatening condition should be suspected and tested for hemophagocytic syndrome on the first day. The criteria for hemophagocytic lymphohistiocytosis should be revised, with the most sensitive and specific ones are done in 100% of cases. Subsequently, each patient should be tested for the presence of genetic abnormalities that correlate with the syndrome.
Hemoglobin C/Korle-Bu Identified In A Patient With A Previous Diagnosis Of Hemoglobin S/C Disease
Authors: Dolezal D , Tormey C , Rinder H , Siddon A J
Published: October 2020

Casestudy

Hemoglobin Korle-Bu (Hb-KB) is an uncommon Hb variant that can be mistaken for Hb-S on electrophoretic screening. While Hb-KB alone has no clinical manifestations, there are only limited case studies describing KB in combination with other Hb variants. Here we report a rare case of Hb-C/KB misdiagnosed and managed as Hb-S/C disease for over 20 years.

Results

A 21-year-old African American woman with presumed Hb-S/C disease presented with generalized abdominal pain, nausea, and vomiting. In 1999, Hb electrophoresis showed 59% of abnormal hemoglobin presumed to be HbS and 41% HbC+A2; agar/acetate gel analysis was not employed and the hemoglobinopathy remained incompletely characterized. She had a history of back, chest, abdomen, and extremity pains requiring multiple hospital admissions, with treatments including dilaudid, oxycontin, oxycodone, and hydroxyurea. Her vital signs were normal and her examination was only significant for abdominal tenderness. Imaging studies did not show any evidence vascular occlusion, avascular necrosis, or end-organ dysfunction. RBC indices were remarkable for mild borderline anemia, microcytosis, decreased MCH/elevated MCHC, and borderline elevated RDW. Peripheral smear showed microcytic red cells with anisocytosis, scattered target cells, and a notable absence of sickled cells and Hb-C-crystals. The diagnosis of Hb-S/C disease was then revisited. HPLC showed abnormal hemoglobins in the Hb-D window at 55.1% and in the Hb-C window at 40.6%, with 3.5% Hb-A2 and no normal Hb-A. Gel electrophoresis with cellulose acetate followed by citrate agar suggested Hb-C in combination with either D, G, or Korle-Bu. Definitive diagnosis was obtained by beta globin gene sequencing that demonstrated one copy Hb-C (19G>A, Glu7Lys) and one copy Hb- Korle-Bu (220G>A, Asp74Asn). Given the absence of Hb-S/C disease, her gastrointestinal distress and pain episodes were re-evaluated.

Conclusion

Hb-S and Hb-Korle-Bu migrate similarly in cellulose acetate electrophoresis but can be distinguished on citrate agar. Challenging beta chain variants can now be readily differentiated by complete gene sequencing. This case study emphasizes the importance of distinguishing Hb-KB from clinically-significant Hb-S.
Phosphaturic Mesenchymal Tumor; A Diagnostically Elusive Cause Of Oncogenic Osteomalacia; Case Study
Authors: Chand M , Edens J , Danforth R
Published: October 2020

Casestudy: Phosphaturic mesenchymal tumor (PMT) is a rare, benign neoplasm. It is associated with oncogenic osteomalacia, a paraneoplastic condition caused by secretion of a peptide hormone-like substance, fibroblast growth factor 23, which increases renal clearance of phosphate and increased mobilization of calcium and phosphate from bone. PMT is difficult to diagnose as a primary etiology because patients usually experience non- specific symptoms associated with hypophosphatemia like bone pain, muscular weakness, and pathologic fractures. Because PMT is a benign neoplasm, surgical excision is curative and rapid resolution of symptoms typically ensues. Discussed here is a case of PMT arising in the soft tissue of the medial thigh of a 65 year old man with a five year history of osteomalacia with pathologic fractures and complicated healing. Lab studies revealed hypophosphatemia, hyperphosphaturia, hypercalcemia, and elevated serum fibroblast growth factor 23 during workup for fracture. A small superficial soft tissue mass was discovered in the proximal thigh via octreotide scan which was subsequently excised. On histologic examination it was composed of an encapsulated proliferation of spindle cells in a chondromyxoid background with distinctive areas of flocculent calcification and osteoclast-like giant cells. A diagnosis of PMT was rendered. The patient’s symptoms resolved rapidly after surgery. Despite the benign characteristics and behavior of this rare neoplasm; delayed or mis-diagnosis can have severe implications for patient’s health. Interdisciplinary communication, shrewd clinical index of suspicion, and awareness of the causes of, and the tests available to diagnose oncogenic osteomalacia can speed accurate diagnosis leading to better outcomes for patients.
New Markers For Human Ovarian Cancer That Link Platinum Resistance To The Cancer Stem Cell Phenotype And Define New Therapeutic Combinations And Diagnostic Tools
Authors: Kamel Y S
Published: October 2020

Introduction/Objective

Ovarian cancer is the leading cause of gynecologic cancer-related death, due in part to a late diagnosis and a high rate of recurrence. Primary and acquired platinum resistance is related to a low response probability to subsequent lines of treatment and to a poor survival. Therefore, a comprehensive understanding of the mechanisms that drive platinum resistance is urgently needed.

Methods

We used bioinformatics analysis of public databases and RT-qPCR to quantitate the relative gene expression profiles of ovarian tumors. Many of the dysregulated genes were cancer stem cell (CSC) factors, and we analyzed its relation to therapeutic resistance in human primary tumors. We also performed clustering and in vitro analyses of therapy cytotoxicity in tumorspheres.

Results

Using bioinformatics analysis, we identified transcriptional targets that are common endpoints of genetic alterations linked to platinum resistance in ovarian tumors. Most of these genes are grouped into 4 main clusters related to the CSC phenotype, including the DNA damage, Notch and C-KIT/MAPK/MEK pathways. The relative expression of these genes, either alone or in combination, is related to prognosis and provide a connection between platinum resistance and the CSC phenotype. However, the expression of the CSC-related markers was heterogeneous in the resistant tumors, most likely because there were different CSC pools. Furthermore, our in vitro results showed that the inhibition of the CSC-related targets lying at the intersection of the DNA damage, Notch and C-KIT/MAPK/MEK pathways sensitize CSC-enriched tumorspheres to platinum therapies, suggesting a new option for the treatment of patients with platinum-resistant ovarian cancer.

Conclusion

The current study presents a new approach to target the physiology of resistant ovarian tumor cells through the identification of core biomarkers. We hypothesize that the identified mutations confer platinum resistance by converging to activate a few pathways and to induce the expression of a few common, measurable and targetable essential genes. These pathways include the DNA damage, Notch and C-KIT/MAPK/MEK pathways. Finally, the combined inhibition of one of these pathways with platinum treatment increases the sensitivity of CSC-enriched tumorspheres to low doses of platinum, suggesting a new treatment for ovarian cancer.
Developing The Next Generation Of Clinical Laboratory Scientist Supervisors: A Study Of Supervisory Competencies In Clinical Laboratory
Authors: Kummerfeldt V D
Published: October 2020

Introduction/Objective

Developing the next generation of clinical laboratory scientist (CLS) supervisors who are competent and comprehensively prepared to meet the industry’s healthcare demands can be challenging. When a CLS is promoted to a supervisory position and then found to be incompetent due to the lack of experience, skills, knowledge and/or abilities. To identify the root cause of this phenomena a comprehensive review of the literature explored management competency theories and concepts (Katz’s three-skills approach, the Peter principle, Sandwith’s competency domain model, and National Center for Healthcare Leadership’s health leadership competency model). The management competency theories provided the foundational theoretical framework for this study.

Methods

Quantitative and qualitative data was used to address the research questions. A modified Tipton’s instrument/survey was used. The survey used demographic, open-ended, and Likert-type questions.

Results

This study had a total of 247 participants, who self-identified as CLS supervisor or manager, and completed an online survey. The results showed an increased competency level due to experience, continuous learning, mentors, formal education, leadership programs and delegation of tasks. The majority of the participants did not feel that the College of American Pathologists regulatory standard of a general CLS supervisor was sufficient to produce a competent CLS supervisor. Training and education was recommended to help transition CLS practitioner into the role of CLS supervisor. Other recommendations include mentors, succession planning, career ladder/leadership programs, experience, and support.

Conclusion

In order to develop the next generation of CLS supervisors, who are comprehensively prepared to meet the industry’s healthcare demands, healthcare organizations are going to need to employ evidence-based human resource management strategies. Human resource management strategies, such as training and development programs, leadership programs, mentor programs, and succession planning, should include administrative and interpersonal domain knowledge, skills, abilities and experience