United States

Background: Cancers of Unknown Primary (CUPs) are undifferentiated neoplasms for which standardized diagnostic work-up fails to identify the primary tumor responsible for metastatic seeding. They can be categorized into favorable and unfavorable subsets. Unfavorable subsets include poorly differentiated neuroendocrine carcinomas and poorly differentiated peritoneal serous carcinomas. Favorable subsets include metastatic squamous cell carcinoma (SCC) and adenocarcinoma confined to isolated nodes or a single metastatic site. SCC originating in the retroperitoneal cavity is exceedingly rare. Some of the cases were reported as SCC of unknown primary. Little is known about its pathogenesis and clinical features; therefore, the optimal treatment is unclear. Here, we report a case diagnosed as SCC caused by human papillomavirus (HPV) infection and possibly arising in the retroperitoneal cavity. Next-generation sequencing (NGS) determined the treatment in this rare case.

Case presentation: A 61-year-old female presented to our clinic with incidental right retroperitoneal paraaortic lymphadenopathy found on a CT scan following hospitalization for urosepsis. She underwent a biopsy at the hospital, which revealed a SCC associated with HPV. SCC was positive for HPV, a known risk factor for gynecological and head and neck cancers. Extensive ENT workup with pan endoscopy and full gynecologic workup was done, followed by colonoscopy, GI endoscopy, and mammography. No primary source was detected. NGS was performed, and it revealed ER and PIK3CA mutations, which are primarily positive in primary breast cancer. It was also positive for PD-L1 mutation, commonly found in many solid tumors. The patient was started on a 12-week chemotherapy with Paclitaxel and Carboplatin. Post-chemotherapy PET scan showed a decrease in size and intensity of lymph nodes with no hypermetabolic activity, suggestive of radiological remission. Based on the sequencing results, the patient was started on Anastrozole as she was ER-positive. Serial CT scan surveillance showed lymph nodes decreasing in size, signifying the patient was still in remission.

Discussion:
The management of CUPs is highly challenging. However, with the advent of genomic sequencing, we could identify targetable mutations. In our case, three targetable mutations were detected: ER, PIK3CA, and PDL-1. These mutations give us specific targets against which very effective therapeutic options are available, highlighting the importance of genomics for the future treatment of CUP. NGS helps personalize cancer care and tailor the management of these poorly understood diseases. Further research and case studies are needed to understand better the etiology, optimal treatment strategies, and prognostic factors of this uncommon condition.

AMA Research Challenge 2024 

New treatment options in CUP: a case report

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Opsoclonus-myoclonus-ataxia syndrome (OMAS) due to Pembrolizumab: a case report
Background
Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare yet debilitating neurological condition in adults; few reports have documented this condition in relation to immune checkpoint inhibitors (ICIs). Pembrolizumab, an ICI, used in the treatment of many forms of cancers can cause a wide range of side effects referred to as immune-related adverse events (IRAEs).
Case
We report a case of a patient with breast cancer who developed OMAS while receiving neoadjuvant chemotherapy that included pembrolizumab. Extensive work-up was unrevealing. She received steroids for treatment of OMAS that were discontinued due to side effects.
Discussion
ICI toxicity needs to be considered on the differential for patients with new-onset OMAS. Paraneoplastic panels play an important role in determining the etiology of OMAS. Establishing an etiology for OMAS is important, especially in patients with underlying malignancy, due to the impact on the treatment of OMAS and the malignancy.

Opsoclonus-myoclonus-ataxia syndrome (OMAS) due to Pembrolizumab: a case report

Introduction 
Serum free light chain assay (FLC) is a valuable tool in diagnosing multiple myeloma. The prozone phenomenon, or hook effect, occurs with exceptionally high antigen levels, leading to underestimated FLC levels and false negatives. (2). FLC levels are routinely used for confirming multiple myeloma suspicions. This is a case of newly diagnosed multiple myeloma (MM) that exhibited the prozone effect on the FLC assay, delaying diagnosis.  

Case 
A 62-year-old woman presented to the emergency department after her outpatient lab work showed evidence of renal failure. Her symptoms included fatigue, shortness of breath, pallor and back pain. Labs revealed BUN 118 mg/dL, creatinine 11.9 mg/dL, hemoglobin 7 g/dl, calcium 10 mg/dL, and profound hypogammaglobulinemia. Computed tomography of the chest abdomen and pelvis showed small lytic lesions in the posterior aspect of T10-11. The patient was admitted for acute renal failure secondary to suspected multiple myeloma. Serum protein electrophoresis revealed M spike in the gamma globulin region. Initial FLC showed low levels of kappa light chain free serum <0.6 mg/L with high kappa/lambda ratio. Bone marrow biopsy demonstrated a hypercellular marrow (80% plasma cells), with FISH studies showing 4:14 translocation. Repeat FLC with dilution showed kappa light chain of 18403.8 mg/L and a kappa/lamda ratio of > 1000.00. Beta 2 microglobulin was found to be elevated at 36.89 mg/L, significant proteinuria with Bence-Jones protein was noted, and lytic foci were found in the calvarium, bilateral humeral shafts, and bilateral radial shafts on osseous survey. Initial therapeutic regimen consisted of cyclophosphamide, bortezomib, dexamethasone and daratumumab. Cyclophosphamide and dexamethasone were stopped due to intolerable side effects. Repeat kappa free light chains measured at 40 mg/L and ratio at 2.0. The patient remains dialysis dependent and ultimate plan is for autologous bone marrow transplant.  

Discussion 
The prozone effect, a rare lab phenomenon, occurs when high FLC levels interrupt complex formation, leading to underestimated antigen levels. (2). In FLC assays, multivalent proteins act as linkers, but very high FLC levels saturate binding sites, paradoxically decreasing fully formed complexes. (4). This effect can be overcome by dilution of the sample.  In the above case, the initial findings of FLC were variable, notable for an elevated kappa/lambda ratio and decreased kappa light chains. After dilution high levels of FLC resulted. This confirms that the low levels initially noted were a result of the Prozone effect. Timely recognition of the prozone effect ensures accurate diagnosis, prevents delays in therapy thus reducing disease morbidity.

Prozone Puzzles: Navigating the Quirky Realm of Diagnostic Testing

Background
Hemolytic transfusion reactions due to red blood cell (RBC) alloantibodies are one of the leading causes of transfusion-associated death. RBC alloantibodies also cause significant morbidity in the form of delayed hemolytic transfusion reactions. Herein, we present the case of one allo-immunized patient with severe anemia, who had to wait 3 months to receive a blood transfusion due to the unavailability of compatible blood in the United States.
Case Presentation
A 59-year-old female with a history of chronic anemia requiring frequent transfusions, and end-stage kidney disease (ESRD) on hemodialysis (HD) presented to the hospital with complaints of fatigue and worsening anemia (hemoglobin [Hb] < 6mg/dl). She denied chest pain, shortness of breath, syncope, and active bleeding. She had consulted 3 different hospitals in New York requesting a blood transfusion, which hadn’t been done due to the unavailability of compatible blood. Laboratory results showed severe normocytic, normochromic anemia (Hb 5.0
g/dl) and a low reticulocyte count of 2.55%. Haptoglobin, lactate dehydrogenase, and bilirubin were within normal limits, ruling out hemolysis. Endoscopy and colonoscopy were negative for gastrointestinal bleeding. Iron, B12, and folate levels were found to be normal; all of which were suggestive of chronic disease anemia. The patient’s blood group was A, RhD negative.
She was found to have antibodies against I, JKa, U, E, S and s antigens. The NY Blood Center was contacted, confirming the unavailability of RhD-negative, compatible packed red blood cell units (PRBC). The patient’s sister was tested and found to have compatible blood for donation. 1 PRBC was administered 2 weeks after hospital admission, after which the patient was stable to continue HD.
Discussion
The prevalence of alloimmunization in chronic transfusion patients is around 2-
8%. Alloimmunization risk is determined by the differences between donor and recipient RBC antigens, recipient genetic characteristics, and recipient inflammatory state at the time of initial antigen exposure. In our case, the patient had an increased risk for alloimmunization due to a history of multiple transfusions, female sex, and being RhD negative.
Conclusion
Alloimmunization can lead to significant morbidity in chronic transfusion patients due to a lack of compatible blood units. It is imperative to establish strategies to decrease primary RBC alloimmunization and mitigate the dangers of existing RBC alloantibodies in this population. Both antigen-matched transfusion and using leukocyte filters during transfusion might represent effective strategies to prevent alloimmunization due to white blood cells.

Significant Delays in Transfusion Due to Unavailability of Compatible Blood for a Highly Allo-immunized Patient: A Case Report

Background
Pembrolizumab is a humanized recombinant monoclonal antibody to the programmed cell death receptor-1 (PD-1) which has immunomodulatory activity and is approved for treatment of many cancers. Aside from side effects associated with infusion therapy patients can develop immune related adverse events (irAEs). IrAEs occur in approximately 15-25% of patients on pembrolizumab as a result of immune enhancement leading to inflammatory toxicity. In clinical trials of pembrolizumab, less than 1% of immune mediated hepatitis (IMH) was observed, making liver toxicity an extremely rare side effect of PD1 inhibition.


Case Presentation

An 68 year-old male with urothelial cell carcinoma (UCC) who underwent radical nephroureterectomy with negative margins was found to have a suspicious mass along the surgical bed during surveillance imaging. Follow-up PET/CT confirmed a 2.4 cm mass with subsequent biopsy confirming relapse. The patient was started on Enfortumab vedotin and Pembrolizumab. Two weeks after the first cycle of therapy the patient developed colitis, tumor lysis syndrome and Steven Johnson syndrome (SJS). His liver enzymes were also elevated. Liver ultrasound was obtained shortly after due to development of ascites which showed coarsened echotexture suggestive of diffuse hepatocellular process without focal hepatic lesions. Ascitic fluid studies were negative for malignancy. CT abdomen/pelvis revealed cirrhosis not seen on imaging two weeks prior.


Discussion and Conclusion

Pembrolizumab associated hepatic injury presents after 1-3 months after initiation of treatment. Studies have shown earlier onset of liver dysfunction resulted in shortened overall survival. The pattern of injury is usually hepatocellular however there have been cases of mixed or cholestatic. Even though histology usually reflects IMH with prominent lymphocytic infiltrates of activated T cells, immunoglobulin levels are usually normal and autoantibodies are not present. Historically, fatal cases associated with immune checkpoint inhibitors (ICI) have occurred in patients with cholestatic patterns of liver injury or severe irAEs such as SJS.

Due to potentially fatal outcomes associated with liver injury, monitoring with routine liver tests should be protocol for patients receiving ICI therapy. Rapid improvement of alkaline phosphatase and bilirubin has been seen with corticosteroid treatment. In instances of inadequate response to corticosteroids alone, addition of a second immunosuppressive agent may be beneficial. However, complete recovery is rare with long-term cholestasis or hepatic failure being the eventual outcome. As ICI use becomes more prevalent, prompt recognition and proper management of irAEs will aid clinical decision making and improve outcomes.


Single dose of pembrolizumab leading to rapid, irreversible hepatic injury

Background
Rhabdomyosarcoma (RMS) is the most common soft-tissue tumor in children and adolescents but is rare in adults. RMS has three main subtypes: alveolar, embryonal, and pleomorphic. The embryonal subtype includes sarcoma botryoides, anaplastic type, and spindle cell type. Spindle cell rhabdomyosarcoma(SCR), comprising 5%-10% of RMS cases, is considered a distinct entity related to embryonal RMS. These tumors resemble leiomyomas histologically. With a 5-year survival rate of only 27% in adults, further research is needed. We report a case of a 21-year-old female with spindle cell rhabdomyosarcoma in the left frontal region.

Case Presentation
A 21-year-old female presented with a left frontal extracranial mass and intermittent headaches for the past year. Initial CT imaging revealed a 3.2 x 2.3 x 2.9 cm mass extending from the subcutaneous tissue through the bone intracranially. Initially suspected as a meningioma, MRI and angiogram later confirmed its growth and hypervascularity. Surgical resection was performed, and the pathology identified spindle cell rhabdomyosarcoma with FUS:TFCP2 fusion and positive IMHC markers (MYOD1, CKAE/AE, desmin, CD9, SSX-C, myogenin). Postoperatively, she developed a pulmonary embolism and was treated with apixaban. Subsequent visits for nausea, vomiting, and headaches led to observations of intracranial bleeding. Apixaban reversal was administered, and a six-week chemotherapy regimen (vincristine, adriamycin, cyclophosphamide) was initiated. A chest X-ray suggested possible pulmonary metastasis. Remaining treatment was continued at another facility.

Discussion
Sarcomas represent 1% of adult solid malignancies, with SCR being exceptionally rare (0.041 per 100,000). Predominantly found in the paratesticular region and head/neck of children, it is rarer in adults, especially in females. Diagnosis relies on histology, with MYOD1 as a primary marker, indicating poor prognosis when mutated. PIK3CA, involved in the mTOR pathway and also associated with SCR, was negative in this case. Spindle cell rhabdomyosarcoma in adults presents unpredictably, often forming in the lower extremities, abdomen, or inguinal region. Therefore, the frontal lobe tumor in this case demonstrates a distinct, uncommon location. Treatment follows general rhabdomyosarcoma guidelines, including cyclophosphamide and vincristine, with additional monitoring needed for metastasis and recurrence.

Spindle cell rhabdomyosarcoma in adults is a rare and complex malignancy. This case highlights the importance of recognizing its distinct pathological and immunohistochemical characteristics and demonstrates the effectiveness of surgical intervention followed by targeted chemotherapy. Understanding these nuances is crucial for enhancing diagnostic accuracy, optimizing treatment plans, and improving patient outcomes.


Spindle Cell Rhabdomyosarcoma in a Young Adult: A Rare Case with Unique Clinical Features

Objectives:
1. Outline the clinical background and pathophysiological mechanisms of spur cell hemolytic anemia
2. Discuss and highlight the presentation and interventions for a case of severe cirrhosis with associated end-stage hemolytic anemia
3. Evaluate and explore factors contributing to the unexpected clinical improvement of hemolytic anemia without liver transplantation

Background:
- Spur cell hemolytic anemia was first discussed in 1964 when a peripheral blood smear from a cirrhotic patient revealed erythrocytes with irregularly shaped projections
- Commonly associated with end-stage liver disease, this condition arises from disruptions in membrane lipid metabolism which leads to formation of acanthocytes— derived from the Greek word “acantho” meaning thorn
- Spur cell hemolytic anemia is a poor prognostic indicator, often requiring a liver transplant for clinical amelioration

Case Presentation: 
A 41-year-old female patient with decompensated cirrhosis secondary to chronic alcohol use (MELD 38) presented with jaundice and laboratory evidence of new onset acute anemia

Discussion:
- Cirrhosis disrupts lipid and cholesterol metabolism in the liver, leading to the accumulation of abnormal proteins, which alters the erythrocyte membrane and increases susceptibility to hemolysis
- The exact pathophysiology remains unclear, but it is believed that these membrane alterations result in the formation of abnormal red blood cells, such as target cells and acanthocytes, which are prone to hemolysis
- Liver transplantation is the only definitive treatment for spur cell hemolytic anemia, as it directly addresses the underlying cause of the condition
- The median survival for patients diagnosed with spur cell hemolytic anemia is approximately 1.9 years, with significantly higher mortality rates in those who are unable to undergo a liver transplant
- For patients ineligible for transplant, supportive care is the mainstay of management, aimed at minimizing symptoms and improving quality of life

Conclusion: 
- Spur cell hemolytic anemia, though associated with poor prognosis, can be managed with supportive care, including blood transfusions, liver disease management (albumin, diuretics), alcohol abstinence, and nutritional support
- The effectiveness of these treatments depends on the patient’s clinical status, MELD score, and the presence of comorbidities

Supportive Treatment of Spur Cell Hemolytic Anemia in the Setting of Decompensated Liver Failure

While Gastric cancer is the second leading cause of cancer-related mortality worldwide, its metastatic spread to the breast is extremely rare. This article illustrates a patient with primary diffuse-type gastric cancer which metastasized to the breast. 


A 52-year-old post-menopausal woman presented to the hospital with severe abdominal pain and constipation. Imaging showed lymphadenopathy gastric wall thickening, and a pulmonary nodule. Biopsy revealed diffuse type, poorly differentiated adenocarcinoma. A CT-PET showed hypermetabolic nodularity suspicious for primary breast malignancy versus metastatic disease. This was subsequently proven to be metastatic via immunochemistry staining. This case represents one of very few documented cases of gastric adenocarcinoma metastasizing to the breast and emphasizes the key role of immunohistochemistry in the diagnostic process.

Uncommon Pathways: A Rare Case of Breast Metastasis from Diffuse Gastric Cancer with Sporadic CDH1 Mutation


Abstract Title
A Cavernous Sinus Mass Resection Develops Into An Eye-Opening Complication

Background
Brain tumors are a rare disease in the general population, with a reported incidence of 5 – 13 out of 100,000. Cavernous sinus tumors are a subset of brain tumors and are also rare. Cavernous sinus tumors may impact internal carotid artery, cranial nerves 3 and 4, and the ophthalmic or maxillary branches of the trigeminal nerve. When tumors are located within this structure, ophthalmoplegia, proptosis, and paresthesias may develop. Management is affected by their involvement of surrounding structures and their mass effect which may cause significant pain.

Case Presentation
This is a case of a 35-year-old male with no past medical history but three months of constant headaches associated with left facial numbness and progressive diplopia. His diplopia progressed to persistent binocular diplopia in upgaze, right gaze, and down gaze. Physical exam was remarkable for left cranial nerve 3 palsy and decreased sensation to the left face. Labs were only remarkable for a cortisol of 0.5. During workup, magnetic resonance imaging of the brain demonstrated an extra-axial mass in the left Meckel’s cave, left cavernous sinus, and left middle cranial fossa. The differential diagnosis at that time included schwannoma, spindle cell tumor, lymphoma, meningioma, pituitary adenoma, and metastases. His biopsy was inconclusive. For his palsy, the patient was given a pirate patch. 
Upon progression of symptoms, he presented to the emergency department. He underwent transsphenoidal biopsy that demonstrated a spindle cell tumor. He was then discharged, and later saw neurosurgery in clinic, who scheduled him for an elective left craniotomy with mass resection. He underwent this procedure with a postoperative course complicated by a pseudomeningocele, complete ophthalmoplegia along with proptosis, inferior displacement and lagophthalmos, with severe exposure keratopathy. Ophthalmology recommended lubricant, steroid eye drops, moxifloxacin eye drops and completed a tarsorrhaphy. The patient lost vision in his left eye due to the significant exposure keratitis due to postoperative swelling of the cavernous sinus.

Discussion
Traditionally, management of ophthalmoplegia is achieved through use of lubricant eye drops and ointments. Surgical intervention can be considered depending on the severity and duration of lagophthalmos, in which a temporary vs permeant tarsorrhaphy is considered. Mild exposure keratopathy has a very good prognosis, while more severe disease can lead to permeant corneal scarring, perforation, and vision loss. Timely consultation and treatment for cavernous sinus masses are needed to prevent progression of these symptoms.


A Cavernous Sinus Mass Resection Develops Into An Eye-Opening Complication

Acquired methemoglobinemia is rare, however it could be fatal. Symptoms such as headache, fatigue, dyspnea, and syncope occur as methemoglobin levels rise, while levels above 50% can precipitate seizures, arrhythmias, coma, and even death. We are presenting a case where a middle-aged male ingested an energy drink named as “PWED super rush "for recreational purposes. Upon checking, it was noted that this drink contains isobutyl nitrite as the main ingredient that enhances sexual experience due to its vasodilatory properties.  
A 52-year-old male with past medical history of hypertension, hyperlipidemia, asthma, and alcohol use disorder presented via EMS with acute onset of lightheadedness, a near-syncopal episode shortly after drinking an energy drink followed by nausea and vomiting.  Vital signs in the ER showed significant hypoxia and otherwise unremarkable. CXR showed no findings concerning fluid overload or community acquired pneumonia. He tested negative for covid. The patient was started on nonrebreather, however, SpO2 remained in 84-88% with supplemental oxygen. To find out the cause of unexplained refractory hypoxia, blood gas analysis was obtained that showed pH of 7.357, pCO2 44, pO2 64, with methemoglobin 25.2%. Based on ABGs results and the initiation of sequence of events following ingestion of an energy drink, toxicology was consulted, and patient was started on methylene blue. He was admitted to ICU for close monitoring and after two doses of methylene blue 1mg/kg, his clinical symptoms significantly improved, successfully transitioned to nasal cannula. Repeat ABGs afterwards showed improvement in methemoglobin levels to 1.0%. His hospital course was uncomplicated, and he was discharged home in stable condition after counseling on substance use.  
Methemoglobinemia is treated with hyperbaric oxygen, methylene blue, ascorbic acid, riboflavin in high doses and exchange transfusion in refractory cases. The first line treatment-Methylene blue acts via the NADPH reductase pathway to regenerate ferrous heme and reduce further oxidation. This case emphasizes the need for a high index of suspicion for methemoglobinemia in cases of refractory hypoxia, especially in the setting of possible toxic ingestion. Point-of-care co-oximetry can quickly diagnose elevated methemoglobin levels when unavailable on ABG analysis.  Additionally, enhanced public awareness and restricting access to agents like isobutyl nitrite are needed to prevent further recreational cases that can overburden emergency departments, intensive care units, and hospitals.  


A Dangerous Rush: When Recreational Use Turns Life-Threatening​

Background: Amiodarone is a class III antiarrhythmic agent used for the management of certain cardiac arrhythmias. Although effective and relatively safe, amiodarone is associated with a spectrum of adverse effects including neurotoxicity. There have been sparse reports of drug-induced parkinsonism (DIP) as a consequence of amiodarone use; however, the mechanism and clinical implications remain an area of limited understanding and documentation. Parksinon’s disease (PD) is associated with degeneration of dopaminergic pathways in the basal ganglia, manifesting in the classic constellation of symptoms, including “pill-rolling” tremors. These dopaminergic pathways can also be disrupted by certain medications, notably antipsychotics, antiemetics, and antiepileptics, which may mimic the symptoms of PD.

Case Presentation: 92 year-old female with a past medical history of atrial fibrillation, hypothyroidism, heart failure, COPD, and dementia presented with resting tremors of the bilateral hands for 2 months. Pt endorsed no new bradykinesia, loss of balance, or muscle stiffness. Denied any fever, chills, myalgia, cough, dysuria, nausea, vomiting, diarrhea, or weight gain or loss. Physical exam demonstrated isolated bilateral resting tremors, with an otherwise unremarkable neurologic exam. There was no muscle rigidity, cerebellar dysfunction, motor/sensory deficits, or bradykinesia compared to baseline. Vital signs were normal and labwork including TSH, RPR, and vitamins B12 and B9 were unremarkable. Following review of the patient’s medication regimen, we reduced amiodarone dosing from 200mg to 100mg due to concern for neurotoxicity rather than late-onset PD. On follow up at 2 weeks and 1 month, resting tremors resolved completely and the patient had no further concerns.

Discussion: Despite the established neurotoxicity of amiodarone, reports of amiodarone-induced Parkinsonism remain sparse. Here, we present a case of Parkinsonism occurring in a patient receiving long-term amiodarone therapy. Through this case report, we aim to broaden understanding of potential neurotoxic effects of amiodarone and emphasize the importance of recognizing drug-induced parkinsonism (DIP). DIP is a reversible form of Parkinsonism caused by the blockade of dopamine receptors or interference with dopamine transmission in the basal ganglia, mimicking the dopaminergic deficiency seen in PD. Misdiagnosing DIP as Parkinson's disease could lead to inappropriate treatment, potentially causing harm. Hence, clinical vigilance is warranted in patients receiving long-term therapy with amiodarone. 


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