Clinical outcomes and safety of immune checkpoint inhibitors in patients with solid tumors and paraneoplastic syndromes.

BACKGROUND: Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce. METHODS: In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT). RESULTS: Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58-74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7-3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4-3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS. CONCLUSIONS: Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.

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.

[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.

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.

Granulocyte-colony stimulating factor producing cervical cancer with elevated levels of parathyroid hormone-related protein: a case report and literature review.

Systemic effects associated with hormones and cytokines secreted by tumor cells can cause paraneoplastic syndrome. Leukemoid reactions and hypercalcemia are relatively common manifestations of paraneoplastic syndrome. Here, we describe the case of a 90-year-old woman who presented with leukocytosis and hypercalcemia and was diagnosed with granulocyte-colony stimulating factor (G-CSF)-producing cervical cancer with elevated levels of parathyroid hormone-related protein (PTHrP). The patient visited our hospital complaining of general fatigue and anorexia. On admission, she presented with marked leukocytosis, hypercalcemia, and an increase in C-reactive protein level. On the basis of abdominal magnetic resonance imaging and histopathological examination, the patient was diagnosed with cervical cancer. Additional tests confirmed elevated plasma levels of G-CSF, PTHrP, and serum interleukin-6. Immunostaining of pathological specimens of the uterine cervix showed expression of G-CSF in tumor cells. The patient was diagnosed with G-CSF-producing cervical cancer accompanied by elevation of PTHrP levels. As a treatment for hypercalcemia, discontinuation of oral vitamin D derivative and administration of saline and elcatonin were ineffective, and therapeutic intervention with zoledronic acid hydrate was required. Considering the patient's advanced age, surgical resection of cervical cancer was not performed. She died from congestive heart failure approximately 3 months after hospitalization. This case was indicated to be a paraneoplastic syndrome in which G-CSF and PTHrP-induced leukocytosis and hypercalcemia. To the best of our knowledge, there have been no reports of G-CSF-producing cervical cancer with elevated PTHrP levels, and our case is the first report.

Tumor-induced osteomalacia: An overview.

Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin tumors with distinct pathological features, called 'phosphaturic mesenchymal tumors'. FGF23 is the most well-characterized of the phosphaturic factors. Tumors are often small and located anywhere in the body from head to toe, which makes the localisation challenging. Functional imaging by somatostatin receptor-based PET imaging is the first line investigation, which should be followed with CT or MRI based anatomical imaging. Once localised, complete surgical excision is the treatment of choice, which brings dramatic resolution of symptoms. Medical management in the form of phosphate and active vitamin D supplements is given as a bridge to surgical management or in inoperable/non-localised patients. This review provides an overview of the epidemiology, pathophysiology, pathology, clinical features, diagnosis, and treatment of TIO, including the recent advances and directions for future research in this field.

Clinical Characteristics of Malignant Phosphaturic Mesenchymal Tumor Causing Tumor-Induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by oversecretion of fibroblast growth factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). PMTs are usually benign neoplasms but some of them show malignant characteristics. OBJECTIVE: The aim of this study was to compare the clinical characteristics of benign and malignant PMTs inducing TIO. METHODS: On March 31, 2023, we performed a systematic review of individual patient data analysis in Medline, Google Scholar, Google book, and Cochrane Library using the terms "tumor induced osteomalacia," "oncogenic osteomalacia," "hypophosphatemia," with no language restrictions and according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria. RESULTS: Overall, we collected data from 837 patients with TIO in which the diagnosis of benign and malignant PMT was specified. Of them, 89 were affected by malignant PMT and 748 by benign PMT. Patients with malignant PMTs were younger and presented bone pain, functional impairment, and bone deformities more frequently. Malignant PMTs showed higher values of intact FGF23 and a higher mortality rate. CONCLUSION: The study results identify the clinical characteristics of patients with malignant TIO, permitting the early identification of patients with PMT at increased risk of malignancy. This may significantly improve the diagnostic approach to disease. Further experimental studies are mandatory to clarify the role of FGF23 in the pathogenesis of malignancy in PMTs.

Paraneoplastic Dermatoses and Cutaneous Metastases.

Paraneoplastic syndromes include a variety of cutaneous presentations that have an associated internal malignancy. Some syndromes have a strong correlation to specific internal malignancies, whereas others are associated with a multitude of tumors. There are many cutaneous manifestations that suggest hematologic disorders, which will be reviewed in detail. Cutaneous metastases are commonly from breast and lung cancers and can present as nodules, vascular lesions, eczematous dermatitis, or inflammatory lesions. The most common histologic presentation of cutaneous metastasis is that of a dermal-based or subcutaneous-based nodule with sparing of the epidermis. Determination of origin of tumor requires immunohistochemistry and clinical correlation.

[FGF23 tumor induced osteomalacia with localization of neoplasm in the tympanic cavity]. / FRF23-indutsirovannaya osteomalyatsiya opukholevogo geneza s lokalizatsiei novoobrazovaniya v barabannoi polosti.

Tumor induced osteomalacia is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients complain of progressive bone pain, muscle weakness and brittle fractures. Delayed diagnosis of osteomalacia caused by a tumor is often found in clinical practice. When verifying the exact localization of the neoplasm, radical removal within healthy tissues is recommended. The article considers a clinical example of FGF23 tumor induced osteomalacia with localization of neoplasm in the tympanic cavity.

Tumor-induced Osteomalacia: A Case Report and Etiological Analysis with Literature Review.

BACKGROUND: Tumor-induced osteomalacia (TIO) belongs to a rare disease of the paraneoplastic syndrome. Phosphate uric mesenchymal tumor (PMT) is the most common cause of TIO, while the possibility of other tumors cannot be excluded. CASE PRESENTATION: We present a case of a 36-year-old female patient with systemic skeletal abnormalities. The woman complained of low back pain with mild motor dysfunction for 2 years. Laboratory examination showed abnormalities in markers of bone metabolism, parathyroid hormone (PTH), vitamin D and serum phosphorus. Pooled imaging examination indicated extension abnormalities in the skeletal system and a single lesion in the right femoral head. The lesion of the right femoral was imaging with somatostatin receptor-positive, which was highly suggestive of a single neuroendocrine tumor. CT guided right femoral tumorectomy and bone grafting were performed when medical treatment failed. Postoperative pathological diagnosis was phosphate urinary mesenchymal tumor secreting fibroblast growth factor 23 (FGF23), which accorded with pre-operative expectations. The postoperative symptoms were effectively relieved, and indicators returned to normal. CONCLUSION: The tumors causing TIO exhibited significant heterogeneity in terms of tissue origin, pathological characteristics and biological behavior, but the unique common characteristic is the secretion of FGF23. With significant progress in diagnosis and treatment, the clinical follow-up of most TIO patients shows a good prognosis, but the prognosis of those with malignant tumors is relatively poor.

The Leser-Trélat Sign in a Patient with Gastric Adenocarcinoma.

Dear Editor, The Leser-Trélat sign is a rare paraneoplastic cutaneous marker of internal malignancy characterized by sudden eruption of multiple seborrheic keratoses (SK). It is mostly associated with gastrointestinal adenocarcinomas (gastric, colon, rectal), and less frequently with breast cancer and lymphoproliferative disorders/lymphoma (1). It can be also associated with lung, kidney, liver, and pancreas malignancy (1). Pruritus occurs in half of the patients. Lesions rarely require any treatment, as they mostly tend to resolve once management of the underlying malignancy has started (2). A 32-year-old female patient with family history of colorectal cancer presented with an acute eruption of SK. She reported that the first symptoms were the loss of appetite and intense pruritus. The brown papules appeared over a period of 2-3 months, first on her back, then on the abdomen, thorax, neck, and lasty on the extremities (Figures 1a and b.). Physical examination showed numerous brown hyperkeratotic papules and plaques on the trunk, neck, and extremities. The patient complained of night sweating, epigastric pain, and heartburn. Over the last three months, she had lost over 15 kg. The patient had experienced an episode of acute gastritis 10 years ago and had been treated for Helicobacter pylori infection 4 years ago. Laboratory results showed elevated sedimentation rate and decreased levels of hemoglobin, erythrocytes, and hematocrit. CA-19-9 and CEA levels were elevated. Gastroscopy with multiple biopsies confirmed gastric adenocarcinoma. An abdominal CT scan revealed enlarged retroperitoneal lymph nodes. SK withdrew after total gastrectomy and commencement of chemotherapy. The Leser-Thrélat sign was named after two surgeons, Edmund Leser and Ulysse Trélat, who described the eruption of cutaneous lesions in patients with cancer (3). However, the correlation between multiple SK and internal malignancy was described by Hollander in 1900 (4). Acute eruption of SK has also been reported in some other cases, such as benign tumors, pregnancy, human immunodeficiency virus infections, use of adalimumab, and others, which indicates that the Leser-Trélat sign is not highly specific (5). It is also somewhat controversial whether a sudden appearance of SK can be considered a marker for internal malignancy, since both SK and malignancies occur more frequently in the elderly population, thus allowing for a higher likelihood of coincidence (6). However, the patient in this case was young and therefore less likely to suddenly develop such a large number of SK, which are more commonly seen after the age of 50 (7). Although the pathogenesis of Leser-Thrélat sign is not fully understood, there are data suggesting an association with tumor-secreting growth factors including epidermal growth factor and transforming growth factor-alpha, both of which can stimulate the epidermal growth factor receptor (8). Sudden appearance of eruptive SK is uncommon in young patients. This specific sign highlights the importance of considering internal malignancy in the differential diagnosis of patients presenting with eruptive SK.

Advances of autoimmune rheumatic diseases related to malignant tumors.

BACKGROUND: Malignant neoplasms are a well-recognized global public health concern, with significant impacts on human health and quality of life. The interplay between tumors and autoimmune rheumatic diseases is complex, and the resulting tumor-associated rheumatic diseases represent a rare and intricate group of conditions that occur in the context of malignant tumors. In addition, various rheumatic diseases can arise as a consequence of oncology treatment. These diseases present with intricate clinical manifestations and pathological features, often rendering them challenging to diagnose and impacting patients' quality of life. Despite this, they have yet to be fully recognized. METHODS: This article presents a literature review of published original articles and review articles concerning paraneoplastic rheumatic syndromes and rheumatic diseases associated with cancer treatment. We conducted a comprehensive literature search in PubMed, Web of Science and Google Scholar databases, excluding duplicated and irrelevant studies. In cases of duplicated research, we selected articles with higher impact factors for the review. RESULTS: This review focuses on the clinical features, diagnosis, and treatment of paraneoplastic rheumatic diseases, as well as the pathogenesis of these diseases. Additionally, we summarize the autoimmune rheumatic diseases associated with cancer treatment. Ultimately, the goal of this review is to enhance recognition and improve the management of autoimmune rheumatic diseases related to tumors.

Seronegative paraneoplastic encephalomyelitis in occult colonic carcinoma.

Paraneoplastic neurological syndromes are immune-mediated neurological attacks triggered by malignancies. They are commonly associated with lung, breast, thymus, gynaecological and haematological malignancies. We report a case of a male patient in his late 40s with paraneoplastic encephalomyelitis due to a colonic adenocarcinoma emphasising a low threshold for extensive cancer evaluation in all subacutely presenting neurological syndromes. We also emphasise that the absence of a positive onconeural antibody does not preclude the diagnosis of a paraneoplastic syndrome.

Imitated Guillian-Barré syndrome in paraneoplastic syndrome.

Guillian-Barré syndrome (GBS) is an immune mediated disease which is most commonly caused by infections. Symptoms are rapidly progressive and may include servere weakness of the extremities, bulbar weakness, autonomic dysfunction and respiratory insufficiens. In rare cases paraneoplastic syndrome may mimic GBS, which is important to know as treatment will fail unless the underlying malignancy is treated. This is a case report of paraneoplastic non-small cell lungcancer mimicking GBS with effect of the checkpoint inhibitor pembrolizumab.

A Case Series of Nephrotic Syndrome: A Harbinger of Catastrophic Oncologic Diseases.

INTRODUCTION: A cancer patient can have numerous complications involving the kidneys, ranging from acute kidney injury, chronic kidney disease, glomerulopathies, electrolyte, and acid-base disorders. It can be due to the malignancy itself or due to chemotherapeutic agents. Paraneoplastic glomerulopathy is a rare presentation of neoplastic disease. CASE DISCUSSION: We present a case series of two patients presenting with nephrotic syndrome as a paraneoplastic syndrome associated with a gynecologic tumor. Both patients responded only partially to steroids and immunosuppressive therapy. Complete remission was only achieved after treatment of primary malignancy. CONCLUSION: It is critical to recognize this entity as immunosuppression may induce a flare in the tumor course and worsen outcomes. So, age-appropriate screening of malignancy should ideally be performed in any adult patient with nephrotic syndrome.

Annular and acral/facial dyskeratotic paraneoplastic disorders.

Annular and acral/facial dyskeratotic paraneoplastic disorders are inflammatory dermatoses that occur in association with distant cancers but are not precursors, extensions, or metastases of them. There are four classical entities under this rubric: two gyrate entities, erythema annulare centrifugum and erythema gyratum repens, and two acral/facial dyskeratotic entities, acrokeratosis paraneoplastic (Bazex syndrome) and tripe palms. Each of these entities may also occur in association with another etiopathogenesis and may present either as a classical entity or as a barely recognizable disease. We discuss these entities, their associated causes, and their differential diagnoses in turn.