Clinical Features of Cutaneous Paraneoplastic Syndromes in Hodgkin Lymphoma.

Cutaneous paraneoplastic syndromes due to Hodgkin lymphoma present with a wide spectrum of clinical manifestations from generalized pruritus to exfoliative erythroderma. We summarize the clinical findings and outcomes of 14 patients with Hodgkin lymphoma and associated cutaneous paraneoplastic syndromes treated at Mayo Clinic over the past 3 decades. Cutaneous paraneoplastic syndromes may be present at the time of lymphoma diagnosis, whereas in other patients, it may appear at the time of relapse, including patients with initial absence of cutaneous manifestations during the initial lymphoma presentation. Our results indicate that complete resolution of the paraneoplastic syndrome is associated with significantly improved overall survival. Recognition of cutaneous paraneoplastic syndromes is a crucial surrogate of relapsed malignancy and treatment requires targeting the underlying malignancy.

Digital Gangrene as a Paraneoplastic Manifestation of Peripheral T-cell Lymphoma Not Otherwise Specified Type.

BACKGROUND: Peripheral T cell lymphoma (PTCL), not otherwise specified (NOS) is a heterogenous group of predominantly nodal T cell lymphomas that generally presents with lymphadenopathy with or without extra nodal involvement. Acral vascular syndrome clinically presents as digital ischemia with Raynaud's phenomenon and acral cyanosis. Although, this condition is commonly associated with connective tissue disorder, smoking and vasculitis, its association with lymphoid malignancy is very rare. Here, we present a case report of a patient with digital gangrene of all toes and fingers as a presenting symptom of PTCL-NOS. CASE DESCRIPTION: A 62 year old male presented with digital ischemia associated with pain, low grade fever, loss of appetite and significant weight loss of 6 kilograms over a period of 3 months. On examination, he was found to have bilateral inguinal and axillary lymph nodes with gangrenous changes over toes and fingers but peripheral pulses were palpable. On evaluation he had anemia, elevated ESR and CRP. CT angiogram revealed thinned out digital arteries with multifocal areas of narrowing. Patient was screened for other causes of digital gangrene and was tested negative for ANCA, ANA, cryoglobulins and viral markers. Lymph node biopsy with IHC was suggestive of peripheral T-cell lymphoma-NOS and was started on CHOP regimen. Lymph nodes size decreased and gangrenous changes resolved. CONCLUSION: Though digital ischemia is a rare paraneoplastic presentation of lymphoma, it should be considered if there is a rapid progression of gangrene. Early initiation of chemotherapy may result in the reduction of further progression of digital gangrene and thus prevent permanent disability. In our patient, progression of gangrene was prevented even though it was an aggressive variant of T cell lymphoma.

Thymic carcinoma presenting with overlap polyarthritis and myositis: A rare paraneoplastic syndrome in childhood.

Thymic tumors are very rare neoplasms in children and account for less than 1% of mediastinal tumors in pediatric patients. One-third of the pediatric patients present with symptoms related to the compression of the tumor mass on the surrounding anatomic structures, and paraneoplastic syndromes such as myasthenia gravis, pure red cell aplasia, acquired hypogammaglobulinemia, and connective tissue disorders, which rarely occur in children with thymic tumors. Herein, we report a case of thymic carcinoma mimicking the symptoms of a connective tissue disease with symmetrical polyarthritis accompanying myositis, fever, weight loss, and malaise in a 15-year-old male patient. To our knowledge, this is the first case pediatric thymic carcinoma accompany with severe polyarthritis and myopathy, thus we have reviewed the current literature regarding the cases of thymic malignancies coexisting with paraneoplastic syndromes in children.

Tumour-induced osteomalacia: the long road to diagnosis and recovery.

Tumour-induced osteomalacia is caused by tumorous production of fibroblast growth factor 23 (FGF23) leading to urinary phosphate wasting, hypophosphataemia and decreased vitamin D activation. The resulting osteomalacia presents with muscle weakness and bone pain but progresses to multiple pathological fractures. Patients often remain undiagnosed for years with severe physical, psychological and economic ramifications. A young woman presented with multiple spontaneous fractures including bilateral femoral fractures. Laboratory tests revealed severe hypophosphataemia, elevated bone turnover markers and low to normal calcium and 25-hydroxy-vitamin D levels. Treatment with phosphate, alfalcalcidol, calcium and magnesium was initiated. 68Gallium-DOTATOC positron emission tomography imaging revealed a mass in the right foot and venous sampling of FGF23 from all extremities confirmed this tumour as the culprit. Biopsy and histology were consistent with a phosphaturic mesenchymal tumour, which was surgically resected. Phosphate levels quickly normalised postoperatively but a long convalescence with hungry bone syndrome, fracture healing and physical therapy followed.

Membranous Nephropathy as a Paraneoplastic Syndrome in Cancer of Unknown Primary.

BACKGROUND/AIM: Membranous nephropathy (MN) is a nephrotic syndrome with both idiopathic and secondary etiologies. The mechanism of cancer-associated MN is presumed to involve the immunological production of antibodies against a tumor antigen, although little is known about the detailed mechanism. Lung cancer is a major neoplasm associated with cancer-associated MN. However, the simultaneous occurrence of secondary MN in patients with cancer of unknown primary (CUP) remains unclear. CASE REPORT: Here, we present a case of secondary MN in a 72-year-old female as a paraneoplastic syndrome in CUP. Thoracic radiotherapy up to a total of 60 Gy was initially performed on the right subclavian and mediastinal lymph nodes. Computed tomography revealed marked shrinking of these lymph nodes, and the secondary MN also improved without any symptoms. CONCLUSION: The presence of proteinuria in patients with CUP suggests the possibility of secondary MN as a rare differential diagnosis.

A 50-Year-Old Man Presenting with Multiple Bone Lesions and a Diagnosis of Phosphaturic Mesenchymal Tumor of the Femur.

BACKGROUND Phosphaturic mesenchymal tumor (PMT) is an extremely rare mesenchymal neoplasm that is commonly seen in bone and soft tissue. It is associated with a paraneoplastic syndrome, oncogenic osteomalacia, due to tumor-induced urinary phosphate wasting. It is demonstrated to be predominantly mediated by fibroblast growth factor 23 (FGF23)/fibroblast growth factor receptor 1 (FGFR1) axis. Clinically, PMT usually presents as a solitary lesion in the bone. The diagnosis of PMT is challenging due to its non-specific clinical manifestation, radiologic findings, and morphological features. CASE REPORT We report the case of a 50-year-old man presenting with multiple lytic bone lesions and associated pathologic fracture of the right femur, clinically suspicious for multiple myeloma or other metastatic malignant process. Resection from the right femur showed a hypercellular lesion composed of oval-to-spindled cells infiltrating the native trabecular bone with admixed multinucleated giant cells. Immunohistochemical (IHC) staining and in situ hybridization (ISH) demonstrated the tumor cells were positive for SATB2, ERG, FGFR1, and FGF23 ISH. DNA and RNA next-generation sequencing showed marked increases in mRNA levels of FGF23 and FGFR1. The constellation of clinicoradiologic, histomorphologic, IHC, and molecular findings supported a diagnosis of primary benign PMT. CONCLUSIONS This case report discusses a patient with PMT presenting with multifocal lesions due to tumor-induced osteomalacia at initial presentation. We hope that this report will increase the awareness of clinician and pathologists of PMT as a differential diagnosis in patients presenting with multifocal lytic bone lesions. In turn, this will prevent misdiagnosis and overtreatment of a typically benign process.

Management of Paraneoplastic Syndromes in the Era of Immune Checkpoint Inhibitors.

OPINION STATEMENT: Our understanding of paraneoplastic neurologic syndromes (PNS) has blossomed over the past few decades. Clinicians have access to more robust diagnostic criteria and have a heightened index of suspicion for these disorders. Nonetheless, treatment, which typically includes immunosuppression, and response to treatment, varies. Due to persistent difficulty in making a definitive diagnosis, we favor empiric treatment when a possible diagnosis of PNS is suspected, and other alternative causes have substantially been excluded (e.g., infections, toxic-metabolic derangements, metastasis, or leptomeningeal disease). Treatment of the underlying cancer, if identified, is the first therapeutic step and can prevent disease worsening and in rare cases, can reverse neurologic symptoms. In addition to anti-cancer treatment, first line immunotherapies, which include corticosteroids, intravenous immunoglobulins (IVIG), or plasma exchange (PLEX) are typically used. If partial or no benefit is seen, second line immunotherapeutic agents such as rituximab are considered. Additionally, the severity of the initial presentation and possible risk for relapse influences the use of the latter agents. Symptomatic management is also an important component in our practice and will depend on the syndrome being treated. One of the more novel entities we are facing currently is the management of immune checkpoint (ICI)-induced PNS. In those cases, current American Society of Clinical Oncology (ASCO) guidelines are followed.

Tubular phosphate transport: a comparison between different methods of urine sample collection in FGF23-dependent hypophosphatemic syndromes.

OBJECTIVES: Tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is used to evaluate renal phosphate reabsorption and it is a useful tool for the differential diagnosis of hypophosphatemic syndromes. TmP/GFR is typically calculated from fasting plasma and second morning void urine samples, obtained 2 h after the first void (TmP/GFR 2 h). The purpose of this study was to evaluate if TmP/GFR calculated from 24 h urine collection (TmP/GFR 24 h) can be used as an alternative for TmP/GFR 2 h in patients with urine phosphate wasting. METHODS: We enrolled adult patients with X-linked hypophosphatemia (XLH) or tumor-induced osteomalacia (TIO). All patients underwent blood and urine sample collections, to calculate TmP/GFR 24 h and TmP/GFR 2 h. RESULTS: Twenty patients (17 XLH and 3 TIO), aged 24-78 years, were included. All patients had low TmP/GFR 2 h (0.35 mmol/L, IQR 0.24-0.47 mmol/L) and TmP/GFR 24 h (0.31 mmol/L, IQR 0.22-0.43 mmol/L). The concordance correlation coefficient between TmP/GFR 2 h and TmP/GFR 24 h was 0.86 (95 % CI: 0.69-0.93), with a systematic bias of 0.05 mmol/L (95 % limits of agreement: -0.10 to 0.20). Furthermore, in 70 % (i.e., 14 patients out of 20) and 80 % (i.e., 16 patients out of 20) of cases the difference between TmP/GFR 2 h and TmP/GFR 24 h was within ±30 % and ±35 %, respectively. CONCLUSIONS: Despite TmP/GFR 2 and 24 h show a relatively suboptimal agreement, the difference between the two parameters appears to be small and not clinically significant in the setting of adult patients with FGF23-dependent urine phosphate wasting and secondary hypophosphatemia.

Updates in the Management of Paraneoplastic Syndrome.

Paraneoplastic neurological syndromes (PNS) are defined as remote neurologic immune-mediated effects triggered by underlying systemic tumors. While recognizing specific syndromes can aid early cancer detection, overutilization of paraneoplastic assays in the absence of a classic syndrome can precipitate overdiagnosis and overtreatment. PNS involve autoantibodies targeting intracellular or extracellular antigens, with variable immunotherapy responses based on antigen type. Diagnosing PNS is challenging, requiring exclusion of other differential diagnoses. New diagnostic criteria classify PNS into high-risk and intermediate-risk phenotypes based on clinical phenotype, neuronal antibodies, and cancer presence. Patients with cell surface antibodies respond better to immunotherapies compared to those with intracellular antigen targets. Understanding PNS syndromes, serological markers, and oncological features guides management, which facilitates initiation of immunosuppression for PNS alongside treatment of the underlying neoplasm, thereby improving neurologic and oncologic outcomes. Initial treatments often include intravenous methylprednisolone, plasma exchange, or intravenous immunoglobulins. Second-line immunosuppressants like rituximab or cyclophosphamide may be necessary if initial treatments fail. Specific therapies vary based on antibody target. Here, we summarize the current approach to the investigation, diagnosis, and treatment of patients with suspected PNS.

Risk factors and prognosis of malignant peritoneal mesothelioma with paraneoplastic syndrome.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare and highly aggressive tumor. Its clinical manifestations are diverse, and the symptoms are not specific. Some patients will develop paraneoplastic syndrome (PS) during the disease course. This study aims to analyze the risk factors of PS in patients with MPM and their impacts on prognosis. METHODS: The clinical data of MPM patients who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) at our center from June 2015 to May 2023 were retrospectively analyzed. MPM patients were divided into PS group and non-PS group according to the diagnostic criteria. Univariate and multivariate analyses were performed to explore the risk factors of PS in MPM patients, and to analyze the impact of PS on prognosis. RESULTS: There were 146 MPM patients in this study, including 60 patients (41.1%) with PS and 86 patients (58.9%) without PS. The highest incidence of PS was thrombocytosis (33.6%), followed by neoplastic fever (9.6%). Univariate analysis revealed 8 factors (P < 0.05) with statistically significant differences between the two groups: prior surgical scores, targeted therapy history, Karnofsky performance status score, preoperative carbohydrate antigen (CA) 125 level, vascular tumor embolus, peritoneal cancer index, completeness of cytoreduction (CC) score and intraoperative ascites. Multivariate analysis identified 3 independent factors associated with PS: preoperative CA 125 level, vascular tumor embolus, and CC score. Survival analysis demonstrated that MPM patients with PS had worse prognosis, although PS was not an independent prognostic factor. CONCLUSIONS: PS is not rare in patients with MPM, and is independently associated with preoperative CA 125 level, vascular tumor embolus and CC score. PS often indicates advanced disease and poor prognosis.

[Bazex syndrome: a rare paraneoplastic disease]. / Síndrome de Bazex: una enfermedad paraneoplásica infrecuente.

Bazex syndrome is a paraneoplastic disorder most commonly linked to squamous cell carcinomas of the upper aerodigestive tract, followed by lung cancer and other malignancies. It manifests through three stages of skin involvement that mirror the tumor's progression. Remarkably, skin lesions precede tumor symptoms or diagnosis in two-thirds of cases, underscoring the crucial role of suspecting this condition as it can promptly reveal an underlying neoplasm. Treatment primarily focuses on addressing the root neoplasm, with recurrent skin lesions potentially indicating tumor relapse. In this context, we present a clinical case involving a male patient whose manifestation of this syndrome facilitated the timely diagnosis of lung adenocarcinoma. This case underscores the significance of understanding this uncommon syndrome and its link to cancer, enabling early and accurate oncological diagnosis.

El síndrome de Bazex es una enfermedad paraneoplásica que se asocia con mayor frecuencia a carcinomas de células escamosas del tracto aerodigestivo superior, seguido en frecuencia por el cáncer de pulmón y otras neoplasias. Afecta a la piel en tres etapas que tienen un comportamiento paralelo al crecimiento del tumor. En dos tercios de los casos, las lesiones cutáneas preceden a los síntomas o al diagnóstico del tumor. De ahí la importancia de la sospecha de esta entidad, que puede desenmascarar a la neoplasia asociada en una etapa temprana. Su tratamiento consiste en tratar la neoplasia subyacente. La recurrencia de las lesiones cutáneas puede revelar la recaída del tumor. Comunicamos el caso clínico de un paciente de sexo masculino en el cual el hallazgo de este síndrome permitió realizar el diagnóstico de un adenocarcinoma de pulmón, lo cual destaca la importancia de conocer a esta rara enfermedad y su asociación con cáncer, para poder realizar el diagnóstico oncológico de forma temprana y oportuna.

Lung Cancer Wherein Durvalumab Induced Both Anti-CRMP-5 Antibody-related Paraneoplastic Neurological Syndromes and Neurological Adverse Events.

A 68-year-old man with small-cell lung cancer developed anti-collapsin response-mediator protein (CRMP)-5 antibody-related paraneoplastic neurological syndrome (PNS) presenting with ataxia and chorea during treatment with durvalumab. As a result of steroid therapy, anti-CRMP-5 antibodies became negative, hyperintense lesions on brain magnetic resonance imaging disappeared, and neurological symptoms improved. After resuming durvalumab, he became unable to walk due to neurological adverse events (nAEs). There have been no reported cases manifesting PNSs and nAEs as a result of the same immune checkpoint inhibitors (ICIs) administered at different times. Resuming ICIs in patients diagnosed with PNSs should be performed with prudence.

Whole-Exome Sequencing Reveals the Genomic Profile and IL6ST Variants as a Prognostic Biomarker of Paraneoplastic Pemphigus-Associated Unicentric Castleman Disease.

Unicentric Castleman disease (UCD) is a rare lymphoproliferative disorder. Paraneoplastic pemphigus (PNP) is a major complication associated with poor UCD prognosis. However, the genomic profiles and prognostic biomarkers of PNP-associated UCD remain unclear. In this study, we performed whole-exome sequencing analysis for 28 matched tumor-normal pairs and 9 tumor-only samples to define the genomic landscape of Chinese patients with PNP-associated UCD. An integrative analysis was performed to identify somatic variants, the mutational signatures, and key pathways in tumors. Besides, we analyzed the relationship among mutated genes, clinical characteristics, and prognosis. Sixty-one somatic mutant genes were identified in >1 patient with PNP-associated UCD. Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%). Signaling molecules and interactions, cellular processes, and signal transduction pathways were enriched. Furthermore, we found that poor overall survival was related to IL6ST variants (P = .02). Finally, we classified PNP-associated UCD into 4 genomic subgroups: IL6ST, PDGFRB, IL6ST-PDGFRB, and an unknown subgroup. In summary, we defined the molecular profile of PNP-associated UCD and identified a potential molecular biomarker for predicting prognosis, which may provide therapeutic targets for treating this severe disorder.

Atezolizumab-induced cerebellar ataxia in a patient with metastatic small cell lung cancer: A case report and literature review.

INTRODUCTION: The use of immune checkpoint inhibitors, which have an important role in the treatment of malignant tumors, is increasing. Although rarely observed, neurological immune-related adverse events associated with immune checkpoint inhibitors result in high morbidity and mortality. Small cell lung cancer is a common cause of neurological paraneoplastic syndromes. The differentiation between paraneoplastic syndromes and neurological immune-related adverse events is important in patients using immune checkpoint inhibitors. Cerebellar ataxia caused by atezolizumab is a rare immune-related adverse event. CASE REPORT: In this context, we present a 66-year-old man with small cell lung cancer who developed immune-mediated cerebellar ataxia after three cycles of atezolizumab, a programmed cell death ligand-1 inhibitor. The admission of brain and spinal gadolinium-based contrast-enhanced magnetic resonance imaging supported the preliminary diagnosis and indicated leptomeningeal involvement. However, the blood tests and a lumbar puncture did not reveal any structural, biochemical, paraneoplastic, or infectious cause. MANAGEMENT AND OUTCOME: High-dose steroid treatment resulted in an improvement in the radiological involvement, as evidenced both clinically and on follow-up whole spine magnetic resonance imaging. Therefore, the immunotherapy was discontinued. The patient was discharged on day 20 without neurological sequelae. DISCUSSION: In light of this, we present this case to emphasize the differential diagnosis of neurological immune-related adverse events originating from immune checkpoint inhibitors, which require rapid diagnosis and treatment, and clinically similar paraneoplastic syndromes and radiologically similar leptomeningeal involvement, in a case of small cell lung cancer.

Phosphaturic mesenchymal tumor: two cases highlighting differences in clinical and radiologic presentation.

Phosphaturic mesenchymal tumors are rare, usually benign neoplasms that occur in the soft tissue or bone and are the cause of nearly all cases of tumor-induced osteomalacia. Tumor-induced osteomalacia due to phosphaturic mesenchymal tumor is a challenging diagnosis to make-patients present with variable clinical and radiologic findings and the culprit neoplasm is often small and can occur anywhere head to toe. We present two cases of phosphaturic mesenchymal tumor in the scapular body and plantar foot. In both cases, the patient endured years of debilitating symptoms before a tissue diagnosis was eventually reached. Descriptions of clinical presentation, laboratory workup, surgical resection, and imaging characteristics, with a focus on CT, MRI, and functional imaging, are provided to assist with the diagnosis and management of this rare entity. A brief review of current literature and discussion of the differential diagnoses of phosphaturic mesenchymal tumor is also provided.

Cytological findings of phosphaturic mesenchymal tumor: Report of a case with summary of prior published cases.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm causing tumor-induced osteomalacia (TIO) and is characterized by secretion of FGF23, renal phosphate wasting and hypophosphataemia. It can be completely cured by resection and therefore its diagnosis is of utmost importance. Although the histology is well described, there is sparse literature on cytology of PMT and only three cases have been described so far. A 45-year-old lady presented with a non-tender mass in hard palate for 2 years from which fine-needle aspiration was done. The smears were paucicellular and showed bland spindle cells embedded in osteoid-like stromal matrix in a hemorrhagic background. Here we take the opportunity to describe the cytological findings of PMT along with its cytological differentials and a summary of prior published cases.