Learning Objectives

1. Distinguish between several amyloidogenic proteins through the use of micro­dissection and gene sequencing techniques and rule out potential differentials before making a denitive conclusion.

2. Understand the necessity of withholding empiric chemotherapeutic agents as it may react adversely to the conrmatory subtype of amyloidosis.

Amyloidosis is a term used for multiple diseases caused by the extracellular deposi­tion of insoluble proteins resulting in organ failure. This proteinaceous element forms misfolded aggregates resulting in a characteristic β-pleated sheet. Congo red dye binds to the extracellular aggregates producing apple-green birefringence under

polarized light [1]. Amyloidosis is an autosomal dominant disease [2] that happens due to mutation in the proteins with amyloidogenic potential [1–3]. Systemic amy­loidosis is a relatively uncommon disease and not many populations-based studies have been conducted. Some of the studies showed amyloidosis to be apparent in 6 (0.2%) of 3141 autopsies between 1937 and 1946 at the Royal Victoria Hospital in Belfast, Ireland. When the study was repeated at the same institution, 43 (0.4%) of 11,586 autopsies revealed systemic amyloidosis [3]. Another study in the United Kingdom mentions systemic amyloidosis as the cause of death in more than 1in 1500 people [4]. Though reports have shown high penetrance of hereditary amyloi­dosis, amyloidogenic mutations have been occasionally witnessed in asymptomatic elderly individuals [4].

This case describes a rare occurrence where the patient having apolipoprotein C-II was misdiagnosed as light chain amyloidosis. The report lays emphasis on the understanding of sensitivity and specicity of various diagnostic modalities. Though serum protein electrophoresis (SPEP) and ow cytometry are highly sensitive modalities, it should not be used for making a denitive diagnosis. Mistreatment could be detrimental to the patient’s health due to their adverse effects such as in this case [7]. Chemotherapy has no role in treating hereditary amyloidosis and may expose the patient to unnecessary harm [4–6].

Through this case report, we hope to raise awareness regarding apolipoprotein C-II amyloidosis. We would also like the physicians to avoid pitfalls from valuable learnings of this case report and encourage a more strategic approach to diagnose the type of amyloidosis and amyloidogenic proteins involved. Recent advancements in diagnostic modality to identify the polypeptides must be included as routine workup in patients presenting with systemic amyloidosis.

has been managed with multiple antihypertensive medications for the past year. She was prescribed furosemide 20mg once daily and hydralazine 25mg thrice a day. Previously, she was on lisinopril, losartan-hydrochlorothiazide, and amlodipine which were then discontinued due to their side effects. The patient’s past medical history consisted of hypertension for the last 3 years, hypothyroidism, depression, colonic polyps, mitral valve prolapse, anxiety, and hyperlipidemia. Her family his­tory included coronary artery disease, hypertension in her father, and uterine and breast cancer in her sister. The patient also admits to 18-pack-year smoking history but quitted 29years ago. She claims to be a social drinker and has no history of drug abuse. Her other medications consisted of levothyroxine, alprazolam, escitalopram, and atorvastatin. All systems were unremarkable. The only concerning nding was the presence of bilateral pitting edema along with elevated blood pressure of 190/100. Laboratory tests revealed creatinine of 2.3mg/dl, which was elevated from her baseline creatinine of 1.3mg/dl. Complete blood count, electrolytes, and liver function tests were within normal limits. Urine dipstick came back positive for >3+ proteinuria, which was consistent with her last 3 years of proteinuria levels. Eleven to 24 red blood cells were visible in a high-power eld (HPF). The urine protein to creatinine ratio was increased to 6.3 mg/g. Hypoalbuminemia was witnessed on complete blood count. Several tests and imaging were ordered to identify the under­lying cause of patient symptoms. Chest X-ray indicated bilateral pleural effusions. Stress myocardial perfusion imaging showed normal ventricular thickness and nor­mal ejection fraction. Serum electrophoresis with immunoxation revealed immu­noglobulin A (IgA) kappa monoclonal protein which was identied as two bands in the beta globulin region. Free kappa light chain level was noted to be 2.45 (0.35–2.49mg/dl), and free lambda level was 0.93 (0.5–2.71mg/dl), with their ratio elevated at 3.91 (0.27–1.8). To keep the blood pressure under control, the patient was started on losartan, spironolactone and the dosage of hydralazine and furose­mide were subsequently increased [15–19]. After controlling her blood pressure, the patient was scheduled for a renal biopsy after 1 month. The histopathological examination of the biopsy exposed amorphous, pale, eosinophilic, acellular mate­rial in the mesangium, tubular wall, and walls of the arterioles. The eosinophilic material displayed a positive reaction to Congo red staining on polarized micros­copy, giving an apple-green birefringence. These ndings led to the diagnosis of amyloidosis. Electron microscopy exhibited randomly arranged brils within the mesangium. The presenting features were characteristic of amyloid brils. Immunouorescence reactions within the glomeruli to the antibodies targeted against IgG, IgM, IgM, and kappa and lambda light chains returned negative. Antibodies against C3 deposits reacted positively. Bone marrow biopsy exhibited 6% plasmacytosis and minimal amyloidosis. The ow cytometry showed kappa plasma cells within the bone marrow. The patient was devoid of any lytic lesions, and a positron emission tomography (PET) scan did not show any elevated uptake or other signs of malignancy. Bone marrow biopsy ndings and renal biopsy results allowed for a presumptive diagnosis of kappa light chain amyloidosis (AL amyloi­dosis). The patient was started on combination chemotherapy with bortezomib, dexamethasone, and cyclophosphamide for presumed AL amyloidosis. At the same time, the peptides in kidney tissue were evaluated through laser microdissection

Amyloids are proteins misfolded and aggregated through various mechanisms, los­ing their normal functionality [1, 5–10]. Identifying the type of protein involved in the formation of amyloid is important while differentiating amyloid diseases and helps determine their diagnosis and management [1–9]. There are more than 20 polypeptides that are known to cause amyloidosis invivo [11]. In the absence of family history, hereditary amyloidosis is usually neglected when considering dif­ferentials of systemic amyloidosis [4, 5]. Sometimes hereditary amyloidosis can present sporadically despite having a negative family history like this case. The kidneys are one of the most affected organs in apolipoprotein-associated amyloido­sis [5]. Renal amyloidosis often manifests as nephrotic-range proteinuria [12]. Signs of proteinuria include edema, anasarca, hypoalbuminemia, and hypercholes­terolemia [5]. The clinical presentation of hereditary amyloidoses like apolipopro­tein C-II-associated amyloidosis and light chain amyloidosis (AL amyloidosis) is very similar. This leads to patients being misdiagnosed initially as having acquired amyloidosis and managed incorrectly with chemotherapy [4–6]. Amyloidosis is diagnosed by the presence of amyloid in the abdominal fat pad or the biopsy of the affected tissue. Apple-green birefringence under the polarized light and brillar aggregates on electronic microscopy are classical signs of amyloidosis. However, the management of amyloidosis vastly depends on the type of protein involved in the formation of amyloid [9]. Detection of the structure of the polypeptide is

Apolipoprotein C-II-associated renal amyloidosis is a rare type of systemic amy­loidosis. Due to a signicant increase in the number of proteins associated with amyloid formation, the chance of misdiagnosis is always a possibility. Identifying the etiology and the amyloidogenic protein involved in the early stages helps avoid mistreatment and protect the patient from unnecessary harm. More studies on the epidemiological aspect of the rare causes of systemic hereditary amyloido­sis should be done. Emerging techniques like LMD/MS have established their usefulness in determining the polypeptide’s structural conguration leading to a more accurate diagnosis. This highly specic diagnostic tool should be more fre­quently used in patients presenting with systemic amyloidosis. More clinical trials must be conducted in the future to develop an effective treatment modality for the currently incurable.

Learning Objectives

By the end of this presentation, the clinician will be able to:

1. Discuss rare differential diagnoses like the phyllodes tumor, especially in young patients presenting with dysuria and urgency.

2. Appreciate the imaging ndings specically in this case where the pelvic mag­netic resonance imaging revealed a hyperplastic nodule with clear boundaries. This nodule could have given an inclination toward an obstructing tumor.

3. Raise awareness due to the rarity of the phyllodes tumor of the verumontanum wherein it has potential to cause obstructive symptoms like dysuria.

To our knowledge, there have been no reports of phyllodes tumors of the verumon­tanum. The case report discussed below might be the rst case of verumontanum phyllodes tumor [1]. Phyllodes tumor is termed as a neoplasm with a foliated struc­ture composed of cellular stroma and benign epithelial elements. There are pub­lished articles for phyllodes tumors of the prostate and seminal vesicles. However, the presence of this tumor in the verumontanum has not been reported anywhere.

The clinical outcomes and management protocols of phyllodes tumors of the pros­tate are not very well established. Poorly dened clinical courses are largely a prod­uct of little to no follow-up [2]. This neoplasm, though rare, is generally observed in female breasts and shares morphological resemblance to prostatic phyllodes tumor [3].

A 42-year-old gentleman presented to the urology department with a 6-month his­tory of pain during micturition and urinary urgency. He denied any frequency or hematuria. A general physical examination revealed nothing signicant and was within normal limits. A hard nodule was palpable on the right side of the prostate on a digital rectal examination. A cystic structure and hyperplasia of the prostate were feared possibilities on transrectal ultrasound. The patient was subjected to urody­namic ow studies, revealing bladder outlet obstruction. The maximum urine ow rate identied was 6ml/sec. His serum prostate-specic antigen (PSA) level came to 21ng/ml, and the histopathology reports of transrectal ultrasound-guided pros­tate biopsy conrmed benign prostatic hyperplasia. Magnetic resonance imaging of the transverse section displayed long T2 signals of multiple lobulations on the right side of the prostate. The sagittal section showed a bump of the posterior urethra

The primary reason for the tumor being misdiagnosed as benign prostatic hyperpla­sia lies in the rarity of the phyllodes tumor of the verumontanum. Though phyllodes tumors are common in breasts, this was the rst case reported of the tumor being present on the verumontanum in 2015.

In January 2020, Ali et al, published a case report of a phyllodes tumor of the pros­tate in a 35-year-old man. Phyllodes tumor of the prostate is poorly understood in management, clinical importance, and outcome. The criteria for benign and malig­nant differentiation are also obscure [2]. Phyllodes tumor of the prostate was rst reported by Cox and Dawson, which is a rare occurrence [3]. Phyllodes tumor is commonly seen in breast tissue. Histopathological examination shows multiple lobes with epithelial hyperplasia and variable cellularity of secretory and basal layers [4].