Delineating the Molecular Events Underlying Development of Prostate Cancer Variants with Neuroendocrine/Small Cell Carcinoma Characteristics

The treatment landscape of prostate cancer has changed dramatically following the advent of novel systemic therapies, most of which target the androgen receptor (AR). Agents such as abiraterone, enzalutamide, apalutamide, darolutamide were designed to further suppress androgen receptor signaling following gonadal suppression achieved by first-line androgen deprivation therapies. These potent AR targeting agents are increasingly used in the earlier stages of the disease spectrum with the goal of delaying disease progression and extending survival. Although these therapies are effective in controlling prostate tumors dependent on or addicted to AR signaling, prostate tumors surviving the onslaught of potent treatments may evolve and develop drug resistance. A substantial proportion of treatment failures can be explained by the development of treatment-induced aggressive prostate cancer variants such as neuroendocrine/small cell carcinoma. These emerging disease entities demand detailed characterization and precise definitions. We postulate that these treatment-induced prostate cancer entities should be defined molecularly to overcome the drawbacks associated with the current clinical and pathological definitions. A precise molecular definition conforms with current knowledge on the molecular evolution of this disease entity and will enable early detection and early intervention.

A Case of Metastatic Small Cell Neuroendocrine Carcinoma Presenting as Intractable Back Pain

A 59 year old male with a past medical history of cholecystectomy and essential hypertension, presented to the emergency department with severe back pain, abdominal discomfort, poor appetite, generalized fatigue and progressive weight loss of 10 kgs over a three-month period. He has never been a smoker and drinks alcohol occasionally. He has no known allergies and no familial history of cancer. His current home medication includes beta blocker; angiotensin receptor blocker and low dose acetylsalicylic acid. His back pain started two months prior to presentation; it is not well localized to specific vertebra, not irradiating to lower limbs and sometimes related to weight lifting and cough. It is rarely exacerbated at night. His orthopedic surgeon attributed it to osteoarthritis since the patient used to practice hard manual work and weights lifting at his shop. He has been treated since that time with NSAIDs, muscle relaxant and opioids without complete analgesic response. At presentation, he had no fever, chills or night sweats. He had no urinary or sexual complaints that would suggest prostatic disease and was otherwise asymptomatic. The physical examination showed diffuse pain on lumbar vertebral percussion and abdominal tenderness in the right upper quadrant. He has no skin lesions and no palpable peripheral lymph nodes. His neurologic examination was also normal. On admission, significant laboratory findings showed hemoglobin 11.8 g/dl, platelets of 97,000 k/ul, white blood count 4,400 k/ul, ESR=40, creatinine 0.4 mg/dl,CRP 7.5 mg/L, lactate dehydrogenase 2256 U/L, alanine aminotransferase (ALAT) 70 U/L, gamma-glutamyl transferase (GGT) 1500 U/L, total bilirubin 2.32 mg/dl, and a creatine kinase (CK) 167 U/L. Prostatic specific antigen (PSA) was normal and equal to 1.17 ng/ml. Peripheral smear displayed normal pattern and thyroid tests were all within normal ranges. He was negative for salmonellosis, brucellosis and HIV. Tuberculin PPD test was negative as well. His chest X-ray was normal and abdominopelvic ultrasound showed only multiple liver nodules and mild prostate hypertrophy without ascites or significant abdominal lymph nodes. Lumbar MRI done one week before his admission revealed multiple vertebral lytic lesions without spinal cord compression. PET/CT done on the third day at hospital revealed a significant uptake of radiotracer by multiple small nodules in the right lung, in the liver and by multiple lymph nodes within the abdominal cavity. Moreover there were many lytic lesions in the dorsal and lumbar vertebrae. Surprisingly, the scan also showed focal, intense uptake of the prostate with a SUVmax of 8, 28 with evidence of seminal vesicles invasion. Both gastroscopy and colonoscopy was normal as well as his brain MRI. Ultrasound-guided liver nodules biopsies performed on the fifth day after stopping the acetylsalicylic acid revealed neuroendocrine small cell carcinoma as it showed immunohistochemical (IHC) positivity for synaptophysin and CD56. IHC was negative for TTF1 and PSA. Ultrasound-guided biopsy of the prostate was not performed for medical reasons as on his hospital day 7, the patient started feeling numbness and muscle weakness in his lower limbs more severe on the left side associated with urinary incontinence and revealing a spinal cord compression by secondary bone lesions. Regarding this rapidly progressive disease, high dose dexamethasone subcutaneous therapy and ten sessions of focused proton beam radiotherapy has been conducted on daily basis to release the spinal cord compression without significant improvement. Meanwhile, and based on liver biopsy findings, treatment by octreotide 100mg S/C twice daily was started, followed by chemotherapy with Carboplatin, Etoposide, and Atezolizumab (TECENTRIQ) 1200mg. Few days after, the patient developed severe prolonged pancytopenia requiring blood and platelets transfusions and treatment with double dose of granulocyte stimulating growth factor. His prolonged neutropenia was complicated by CMV colitis with unretractable diarrhea, bilateral pneumonia and pseudomonas aeroginosa septicemia. After one month of large spectrum antibiotics, antiviral and antifungal treatment, and while he was still neutropenic, bone marrow biopsy revealed severe infiltration by neuroendocrine small cell carcinoma. The patient was still deteriorating clinically and showing further weight and appetite loss, total muscle weakness and asthenia. At this point, he was no longer a candidate for chemotherapy but only symptomatic treatment was maintained. He died 45 days after his admission.

Composite tumor of the larynx: A Case Report

Composite tumor of larynx, a recently included entity in the current WHO classification, is often a difficult pathological diagnosis, especially in small biopsies. We report a case of laryngeal composite tumor, initially misdiagnosed as squamous cell carcinoma, which later turned out to be composite in nature, with associated neuroendocrine (small cell carcinoma) component. This report emphasizes the need for obtaining deeper biopsies and their thorough pathological examination to improve the diagnostic accuracy.

Neuroendocrine Small-Cell Carcinoma of the Gallbladder: Case Report

Gallbladder neuroendocrine carcinoma is a very rare entity, accounting for <0.2% of all neuroendocrine tumours [1]. Of the cases described in the literature, the initial presentation is usually locally advanced or even with disseminated disease [2]. In this paper we report the case of a 43-year-old female patient with an incidental diagnosis of gallbladder neuroendocrine carcinoma. Although clinical presentation is the most common, it is a very rare condition that poses a therapeutic and prognostic challenge.