United States

Introduction:

Light chain (AL) amyloidosis is a rare plasma cell dyscrasia characterized by extracellular deposition of light chains in various organs, showing distinctive Congo Red (CR) staining on involved organ biopsy. Most patients with plasma cell dyscrasias will have evidence of a monoclonal protein in the serum or urine but it can be absent in approximately 3% of patients. For such patients, serum free light chain (FLC) assay is a critical component of diagnostic evaluation. Amyloidosis can have broad clinical findings with non-specific manifestations including cutaneous, musculoskeletal, and cardiac, that overlap with certain rheumatological disorders like scleroderma. This makes amyloidosis a challenging diagnosis, which is often diagnosed after significant delay or misdiagnosed as another entity. We present a case of amyloidosis initially misdiagnosed as scleroderma. 

Case presentation: 

A 54-year-old woman with a past medical history of ulcerative colitis and rectal adenocarcinoma treated with surgical resection presented with severe skin thickening, pruritus, macroglossia, Raynaud’s phenomenon, and inflammatory arthritis. An extensive serologic workup for rheumatologic conditions was negative for a definitive diagnosis. As part of the workup, serum protein electrophoresis (SPEP) was obtained which showed hypogammaglobulinemia, however, no immunofixation (IFE) or FLC assay was ordered. Despite the negative serologic workup, due to high clinical suspicion, she was treated for a presumed diagnosis of scleroderma with sequential trials of prednisone, methotrexate, and mycophenolate mofetil, without improvement in her symptoms. About 2 years later with macroglossia still present, repeat SPEP, IFE, and FLC were obtained and revealed no M spike but did show lambda light chains elevated to 36.58 mg/dL, kappa light chains 0.5 mg/dL, with a FLC ratio of 73 (normal 0.26 to 1.65). Subsequently, a bone marrow (BM) biopsy was performed, which showed mildly hypocellular BM for her age (30% cellularity) and an abnormal plasma cell population constituting approximately 30% of the marrow, identified by immunohistochemistry against CD138, and they were found to be lambda light chain restricted by in-situ hybridization. CR stain was negative on the BM biopsy. Due to suspicion of underlying amyloidosis given history of macroglossia, an echocardiogram was ordered, which revealed moderate concentric hypertrophy of the left ventricle, consistent with infiltrative cardiomyopathy, which was then confirmed on cardiac MRI. An endomyocardial biopsy was subsequently performed, which stained positive for CR, and liquid chromatography/mass spectrometry confirmed AL amyloidosis. The patient was treated with amyloidosis directed therapies followed by an autologous peripheral blood stem cell transplant. Her prior symptoms resolved after treatment and macroglossia improved by over 50%.


Discussion: 

Amyloidosis may initially present with non-specific manifestations like skin thickening and infiltrative cardiomyopathy that can have clinical overlap with various rheumatologic disorders such as scleroderma. Our patient was initially misdiagnosed with scleroderma. Increased awareness and checking FLC may have led to earlier diagnosis and improvement in morbidity. This case highlights the need to consider an alternative diagnosis when symptoms fail to respond to appropriate therapy and the need for provider awareness regarding complete workup for paraproteinemia including FLC with SPEP and IFE when looking for amyloidosis as 50% of amyloidosis cases have light chain only involvement. 


AMA Research Challenge 2024 

Amyloidosis Masquerading as Scleroderma: A Case Report

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An unusual Hemophilia: Acquired Coagulation Factor Inhibitor
Le Yen Ly Nguyen, Pragti Garg, Arshdeep Singh, Amanpreet Kaur, Akhilesh Sharma, Matthew B Maturasingh, Dileep Duggineni, Dolshi Bhatia, Kanish Chandrashekhar, Daniela Benitez, Fabian Andres Lituma Orellana, Ratesh Khillan MD

Background
Acquired Factor V deficiency (AFVD) is an exceedingly rare coagulation disorder, usually caused by development of an inhibitor, that may directly affect Factor V/V activity (FVa) or storage and processing of the protein. Only approximately 200 case reports or case series describing this disorder have been reported in the literature. Presenting symptoms include bleeding from gastric, urinary, and respiratory mucosa, post-surgical bleeding, hematoma, intracranial and retroperitoneal bleeding with hematuria being the most common. Several diagnoses may be postulated for patients affected by bleeding i.e., platelet deficiency or deficiency of coagulation factors. AFVD should also be considered in patients who present with bleeding after ruling out more common bleeding conditions. With the fact that AFVD is an extremely rare disorder, the optimal treatment of patients with factor V inhibitors is uncertain with no Factor V concentrates available.
In this study, we present a unique case of an 81-year-old African American male with AFVD without any history of autoimmune diseases, surgery, malignancy, exposure to bovine thrombin or recent antibiotics use.

Case presentation
An 81-year-old African American male presented to our clinic in 2013 after being admitted to hospital with chest pain, where he subsequently developed a hematoma on his lower abdomen and bilateral thighs, painless macrohematuria, anemia, and swelling of left extremities. The bloodwork showed hemoglobin 6.0, INR 6.7, aPTT >100.0, and normal coagulation factor activity except for FVa <1.5%. Mixing studies showed presence of Factor V inhibitor. Following discharge, he experienced recurrent painless macrohematuria. The patient was started on oral prednisone, and the dose was adjusted according to FVa. 4 cycles of Rituximab were also given.
In subsequent years, he developed recurring painless superficial bruises on elbows, abdomen, back and thighs, microhematuria and epistaxis. The patient was given 4 cycles of Cytoxan along with Prednisone, a few months later followed by Dexamethasone pulse therapy to maintain FVa levels.
Presently, the patient’s FVa is at 80%, and he has been taking oral Prednisone daily for the past 11 years.

Discussion
Acquired hemophilia is a rare hematological disorder mostly affecting Factors VIII or IX due to a clotting factor inhibitor. Although inhibitors may affect any clotting factors, Factor V inhibitor is exceedingly rare, making treatment challenging with no standards. Our patient responded to cyclophosphamide and prednisone. His treatment course included a drop in factor V levels without bleeding, managed by increasing steroid doses.

An unusual Hemophilia: Acquired Coagulation Factor Inhibitor.

Introduction
Post-obstructive pneumonia (POP) is an infection of the lung parenchyma that arises distal to a bronchial obstruction, commonly associated with malignancies such as lung cancer. In these cases, the tumor obstructs the bronchus, impairing secretion clearance and creating a favorable environment for infection. In patients with multiple myeloma, the occurrence of AL amyloidosis, where amyloid light chains deposit in various organs, further complicates the clinical picture. In non-smoker patients with a history of multiple myeloma and new-onset POP, the presence of a bronchial mass should raise suspicion for amyloidoma and plasmacytoma.

Case
A 58-year-old non-smoker female with a history of multiple myeloma, neuropathy, and chronic kidney disease presented with shortness of breath, fever, productive cough, hypotension, tachycardia, tachypnea and a dull, constant pain radiating from the right chest to the back. Initial chest X-ray revealed consolidation and a mass in the right middle lobe. After treatment for pneumonia, a follow-up chest CT identified a 4.6 cm x 5.4 cm mass with calcifications and septation, raising suspicion for malignancy due to bronchial obstruction. The mass was surgically resected, and histopathological analysis confirmed amyloidoma. Further workup was negative for systemic amyloidosis, and myeloma evaluation indicated the patient was in remission.

Discussion
Tracheobronchial amyloidosis is the most common form of localized primary pulmonary amyloidosis, characterized by the deposition of amyloid light chain (AL) proteins within the bronchial structures. This condition can present with symptoms that closely resemble bronchogenic carcinoma, including cough, dyspnea, hemoptysis, and wheezing, largely due to airway obstruction and luminal stenosis. Bronchoscopic evaluation often reveals nodules, masses, or diffuse narrowing of the bronchial lumen, making biopsy critical for accurate diagnosis. Post-obstructive pneumonia, a common complication of bronchial obstruction, can lead to serious outcomes such as empyema, lung abscess, and fistula formation if not treated promptly. To mitigate these risks and improve airway patency, treatment typically involves bronchoscopic interventions, including laser resection, stenting, and external beam radiation, which help to alleviate symptoms and prevent further complications.


Bronchial Amyloidoma: An Unusual Etiology of Post-Obstructive Pneumonia in a Patient with Multiple Myeloma


Non-small cell carcinoma (NSCC) accounts for 85-90% of lung cancer cases. Generally, treatment options depend on the staging and metastases of the tumor and can consist of surgical resection, radiation therapy, chemotherapy, or immune checkpoint therapy. We present a rare case of a 63-year-old male with a history of NSCC who presented with shortness of breath and low sodium levels and was found to have an unusually high rate of 49.5% for an EGFR (L858R domain, an exon 21 mutation), allowing for better-individualized therapy and opening new avenues for research and more effective treatments.

Cancer Genomics: A Gateway To Personalized Medicine

Background: Chronic Lymphocytic Leukemia (CLL) is a common hematologic malignancy characterized by the proliferation of mature B lymphocytes. The disease accounts for a significant proportion of adult leukemias, with an estimated annual incidence of 4.5 cases per 100,000 individuals. Despite its prevalence, CLL can present with diverse clinical manifestations, posing diagnostic and therapeutic challenges. One of them is clonal evolution, which refers to the acquisition of genetic mutations by leukemic B cells over time, resulting in the development of subclones with distinct genetic characteristics. As the disease progresses, different sub-clones may become dominant, contributing to disease relapse and resistance to treatment.
Methods: This case report presents the clinical evolution of a 65-year-old patient diagnosed with CLL, focusing on clonal evolution and treatment response. The patient was first diagnosed with CLL in 2017, with flow cytometry revealing CLL characterized by negative CD34 and positive CD49d markers. Fluorescence in situ hybridization (FISH) analysis revealed trisomy 12 in 65% of cells. The patient received 5 cycles of chemotherapy out of 6 prescribed cycles. The therapy was withheld due to thrombocytopenia. Although the patient received his last chemotherapy in March 2018, he continued to exhibit persistent pancytopenia during blood work conducted in July 2023, prompting a bone marrow biopsy and FISH analysis. Results demonstrated a decrease to 57% in trisomy 12 prevalence, accompanied by the emergence of a NOTCH1 mutation. In flow cytometry, CD49d was negative, indicating a change in the phenotype of the leukemic cells as well.
Results: The patient's CLL exhibited dynamic clonal evolution, as evidenced by changes in cytogenetic abnormalities and the acquisition of a NOTCH1 mutation over the course of the disease. Despite initial responses to treatment, including a complete remission with incomplete bone marrow recovery after chemoimmunotherapy, the disease eventually progressed, necessitating the initiation of targeted therapy.
Conclusion: This case highlights the dynamic nature of CLL and the impact of clonal evolution on disease progression and treatment response. Molecular monitoring, including FISH analysis and mutation profiling, is essential for identifying changes in disease biology and tailoring treatment strategies accordingly. Understanding the underlying mechanisms of clonal evolution in CLL is crucial for optimizing treatment outcomes and improving patient care.

Dynamic Clonal Evolution in Chronic Lymphocytic Leukemia: Case Study and Treatment Implications

Background
Kagami-Ogata syndrome (KOS, OMIM 608149) is a rare genetic imprinting disorder involving microdeletions and epimutations affecting a maternally inherited locus (14q32.2) in chromosome 14. Neonates commonly present abnormal phenotypic features such as facial dysmorphia, abdominal wall defects, and skeletal abnormalities.  Around 80 cases of KOS were reported in literature, and the incidence rate is estimated at less than 1 in 1,000,000 newborns.

Case Presentation
We describe the clinical case of a preterm newborn found with polyhydramnios who was delivered by C-section at 32 weeks by a 30-year-old African American female (G4 P3 Ab1 LC2) with a history of severe pre-eclampsia and sickle cell trait. Fetal ultrasound revealed an omphalocele, lung mass, and left-axis deviation of the heart. Chest X-ray indicated features associated with respiratory distress syndrome (RDS) and a bell-shaped chest indicating pulmonary hypoplasia. A chromosome microarray was performed to determine the underlying cause of this newborn presentation.

Discussion
Chromosome microarray analysis confirmed homozygosity of chromosome 14, indicating paternal uniparental isodisomy, which supports the diagnosis of KOS. This case demonstrates the classical symptoms including coat hanger deformity, presence of omphalocele, and bell-shaped thorax revealed by imaging. This patient exhibits facial dysmorphism characterized by hirsute forehead, depressed nasal bridge, micrognathia, webbed neck, and small ears. KOS can be mistaken for other diseases like Beckwith-Wiedemann syndrome, trisomy 18, androgenic mosaicism due to phenotypic overlap. That is why when there are symptoms suggestive of BWS like macrosomia, polyhydramnios, and omphalocele are present, with genetic testing not confirming it, KOS should be tested. The management entails supportive measures like mechanical ventilation, tube feeding, and therapy for developmental delay, necessitating a multidisciplinary approach.

Exploring Kagami-Ogata Syndrome: Insights from a Case Report​

Background: Hepatosplenic T-cell lymphoma (HSTL) is a rare and aggressive form of peripheral T-cell lymphoma that affects the liver and spleen without involving the lymph nodes. It typically occurs in young adults with cytotoxic T-cell proliferation of the TCR γδ type and is associated with immunosuppression. In this case, we present an elderly patient who developed HSTL of the TCR αβ type after being treated for indolent b-cell lymphoma.

Case Presentation: A 76-year-old man with a history of chronic lymphocytic leukemia (CLL) presented with altered mental status. He completed treatment for CLL with obinutuzumab and venetoclax 3 years prior and was in remission. On examination, patient appeared confused. Laboratory data showed hepatocellular liver injury (ALT 342 U/L, AST 800 U/L, ALP 821 U/L, T. Bilirubin 7.1 mg/dL). A CT scan of abdomen and pelvis demonstrated hepatomegaly and mild splenomegaly without lymphadenopathy. Histological analysis of liver biopsy revealed benign hepatocytes with prominent atypical lymphoid infiltrate involving hepatic sinusoids and portal tracts. The lymphoid population appeared atypical with enlarged irregular nucleus and increased apoptosis. Immunohistochemistry revealed atypical lymphoid cells which were positive for CD3, CD2, TCR-β, TIA-1and Granzyme B. The Ki-67 index was up to 40%. Flow cytometry analysis of the peripheral blood demonstrated lack of B-cells and no immunophenotypic abnormal T-cells. The abnormal T-cells were also identified in the bone marrow. The diagnosis of hepatosplenic T-cell lymphoma, TCR- αβ type was rendered. The patient received cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone with 50% dose reduction due to renal failure. Initially his condition improved; however, on day 5, he developed acute hypoxic respiratory failure secondary to Influenza A and Rhinovirus pneumonia and died from shock and multiorgan failure.

Discussion: HSTL is a rare, aggressive disease with a variable clinical presentation. About 20% of cases occurs in chronic immunosuppression. Our patient had a history of CLL in remission and at HSTL diagnosis, showed hypogammaglobulinemia and no B-cells in the peripheral blood flow cytometry. This clinical setting has not been reported before. Historically, HSTL primarily affects adolescents and young adults, with a median age at diagnosis of approximately 35 years. Most HSTL cases express TCR γδ (~75%) or TCR αβ (~20%), the latter with worse prognosis. There is currently no standard of care treatment, and outcomes are poor without a stem cell transplant.


Hepatosplenic T-cell Lymphoma, αβ type, presenting in an elderly patient status post indolent B-cell lymphoma treatment


Background
Immune thrombocytopenia (ITP) remains a diagnostic challenge, with many primary and secondary causes that are often difficult to discern. COVID-19 infection and vaccination have been implicated in causing ITP; however, no case of ITP has been documented after receiving multiple uneventful COVID vaccine doses. Here we present a case of ITP presumably secondary to his 5th mRNA COVID-19 booster. 

Case Presentation
A 76-year-old male with Type 2 Diabetes Mellitus, Hypertension, and Hyperlipidemia, presented to the emergency department for a low platelet count of 8x10^3/uL found on outpatient blood work done at his primary care physician’s office. The patient had received the 5th dose of mRNA COVID-19 vaccine booster 4 days before presentation and developed a rash on bilateral lower extremities the day after receiving the vaccine. On the day of admission, the patient had minorbleeding from the gums. Otherwise, he denied fevers, lymphadenopathy, URI symptoms, epistaxis, hemoptysis, abdominal pain, nausea, vomiting, diarrhea, hematochezia, melena, new medications, or new illness. The patient denied personal or family history of bleeding, clotting or thrombocytopenia. The patient had received 4 doses of the Moderna vaccine in the past without any adverse reaction. 

Peripheral smear revealed 1-2 schistocytes, PLASMIC score of 3. Treatment included dexamethasone 40mg daily x 4 days and intravenous immunoglobulin (IVIG) 0.5g/kg x 3 days. The fourth dose of IVIG was held in the setting of acute kidney injury with Creatinine rise 1.1 to 1.4, which improved to 1.3 after IV fluids. The patient did not require transfusion and platelet count improved to 126x10^3/uL on discharge. Of note, the patient developed marginal zone B-cell lymphoma 6 months after his initial presentation. 

Discussion
This case illuminates the potential for confounding variables and the elusive nature in diagnosing ITP. Recognizing the distinction between primary ITP and secondary ITP is crucial in guiding management and improving patient outcomes. Primary ITP is a diagnosis of exclusion, and typically responds well to steroids and IVIG. Despite this patient’s subsequent diagnosis of marginal zone B-cell lymphoma, he responded well to combination of IVIG and steroid treatment. As secondary ITP induced by lymphoma treatment is usually successful only when underlying disease is controlled, patient’s thrombocytopenia may not be related to lymphoma. Identifying the root cause of thrombocytopenia informs appropriate treatment strategies and management of the patient's overall health. IVIG is an expensive therapy, and its use should be carefully considered to reduce medical expenditure and improve patient outcomes.

Immune Thrombocytopenia After 5th Dose of mRNA COVID Vaccine

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.

New treatment options in CUP: a case report

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.

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An unusual Hemophilia: Acquired Coagulation Factor Inhibitor.

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