A neurological paraneoplastic syndrome in a patient affected by severe obesity: a case report

Introduction: Obese women experience a greater occurrence of tumors that impact the reproductive system, frequently leading to delayed diagnosis because of postponed access to medical care and unconventional manifestations. Case presentation: A 52-year-old woman was hospitalized due to an unexplained fever. After ruling out the typical reasons for fever, our patient experienced an episode of metrorrhagia she attributed to her regular menstrual cycle. Further assessments, including measurements of FSH and LH levels, as well as subsequent diagnostic imaging, revealed the existence of an abnormal growth mass affecting the uterus. Conclusion: The objective of our paper is to emphasize the signi�cance of exploring paraneoplastic signs and symptoms in this kind of subjects, enabling prompt diagnosis and the subsequent establishment of an appropriate therapeutic approach.


INTRODUCTION
Women who are obese are more likely to develop tumors affecting their reproductive system, often resulting in delayed detection due to postponed medical care access and unusual symptoms.
Our case report serves as a symbol to emphasize the importance of early diagnosis, especially among individuals who often delay seeking medical attention due to obesity-related issues such as feelings of shame and transportation di culties.
In our case report, the development of endometrial tissue appears to be linked to a paraneoplastic syndrome, which presents with neurological symptoms.

CASE REPORT
A 52-year-old woman was admitted to the Emergency Room of the Fondazione Policlinico A. Gemelli IRCCS Hospital's on summer 2023, due to onset of high body temperature (T: 40°C or 104°F) and confusional state over about a week.She suffered from severe obesity (height 160 cm, weight 130 kg, BMI 50.7 kg/m 2 ) associated to binge eating and anxiety disorder, bed rest syndrome and hypothyroidism.Furthermore, she complained low back pain and arthralgia at the lower limbs -she started therapy with pregabalin -and episodes of falling to the ground like drop attack.
The patient was unable to precisely report the onset of symptoms due to retrograde amnesia.
Once stabilized from the hemodynamic point of view, she underwent a brain CT scan and chest x-ray, both negatives.Thus, a total body CT was performed, that highlighted thickening of the gallbladder walls and hyperplastic appearance of the left adrenal gland, but with no lymphadenopathies.
The urine toxicology test was negative, as well as blood and urine cultures.
According to our neurologist and infectious disease Consultants, an electroencephalogram and a cerebrospinal uid analysis were performed, both providing negative results.However, empiric endovenous antibiotic therapy was instituted with ceftriaxone (2 grams twice a day) and vancomycin (1 gram/day).
Due to the persistence of hyperpyrexia and confusional state, the patient was transferred to the intensive care unit to start invasive ventilation support.Thus, all microbiological tests (broncho wash cultures, central and peripheral blood cultures, urine cultures, urinary antigen for Legionella, and beta-glucan) resulted negative.
Empiric endovenous Thiamine therapy was administered at a dose of 300 mg per day.
After the improvement of the clinical conditions, the patient was transferred to our medicine ward.About medical history, she dates back the onset of fever to approximately 10 days earlier.
She reported occasional xerophthalmia and xerostomia with oral aphthous stomatitis, and without any skin manifestations.Furthermore, she referred to have metrorrhagia that she associated to menstrual ow: no gynecological examination was ever carried out.
A pituitary magnetic resonance (MRI) showed no signi cant results.Thus, a transvaginal ultrasound showed a bicornuate uterus and hyperechoic endometrium (13 mm), with a no-homogeneous and no-vascularized echo structure (Fig. 1).
An MRI of the pelvis documented at the level of the body-cervix passage the presence of an elongated formation with a posterior peduncle and endocervical and endo-vaginal development, with evidence of multiple lymph nodes increased in size in the right external iliac, right obturator, bilateral common iliac and bilateral external iliac sites (Fig. 2).
Therefore, she was entrusted to our Gynecologists to perform diagnostic hysteroscopy, that she was unable to perform due to poor compliance.
A diagnosis of heteroformation of the uterine cavity was then made, to be characterized histologically by hysteroscopy.

DISCUSSION
Our case report can be used as a symbol to highlight the signi cance of early diagnosis, particularly in individuals who frequently seek medical attention late due to issues related to obesity, including feelings of shame and transportation challenges.
There is strong epidemiologic evidence on the association between obesity and endometrial cancer risk and mortality [1].Obesity de ned as a BMI value from a 30 to 35 kg/m 2 was associated with a 2.6-fold increase in endometrial cancer risk, while severe obesity (BMI > 35 kg/m 2 ) was associated with a 4.7-fold increase compared to normal-weight women [2].The pivotal role in the association of obesity to cancer is played by increate visceral adipose tissue, that was shown to increase endometrial cancer risk by 1.5-to twofold [1,2].
The adipocyte tissue and its surrounding microenvironment might contribute to carcinogenesis, the formation of metastases, and the advancement of the disease [3].
The excessive accumulation of fat leads to dysfunction in adipose tissue, resulting in an elevated production of proin ammatory cytokines, sex hormones, and lipid metabolites.Additionally, there is a disturbance in adipocyte-derived cytokines or adipokines pro les, coupled with insulin resistance.The modi ed adipose tissue becomes a source of extracellular matrix (ECM) remodeling, brosis, cancerassociated adipocytes, impaired microbial metabolism, adipocyte progenitors, in ammation, and an altered microenvironment.These factors collectively contribute to the initiation, growth, and recurrence of tumors [4].
Among post-menopausal women, the risk of breast, endometrial, and ovarian cancers exhibit a notable rise with the escalation of BMI classi cation from normal to class II obesity [5].
According to the Italian association of medical oncology (AIOM), endometrial cancer (EC) represents the sixth most common cancer in women worldwide [6]. 5 years.Nevertheless, oral contraceptives and parity are considered protective factors [7].
EC is typically divided into type 1 and type 2. Type 1 endometrial endometrioid carcinoma (EECs) is the most common low-grade tumor, usually expressing hormone receptors, and with a good prognosis [8].Type 2 non-endometrioid carcinomas (NEECs) that doesn't express hormone receptors [8].
The typical clinical presentation of EC is abnormal vaginal bleeding.Abdominal, pelvic, lumbosacral and buttock pain, sub occlusive syndromes, bone pain and leucoxanthorrhea are typical signs and symptoms of advanced disease [6].
Trans-Vaginal Sonography is the rst test to be performed that allows to evaluate the endometrial thickness (suspicious if > 5mm postmenopausal).The diagnosis of EC is based on targeted biopsy samples.Staging is performed using MRI medium with paramagnetic contrast medium [6].
A meta-analysis including a total of 1980 patients and 2345 controls from 25 studies, analyzed the diagnostic value of single CA125 and HE4 or association between CA125 + HE4 [11].
Results underlined a greater diagnostic e cacy of HE4, whether dosed individually or coupled with CA125.
In our case report, endometrial formation seems to be associated to paraneoplastic syndrome, with neurological signs.
Paraneoplastic syndromes of nervous system associated with EC are rare.Clinical manifestations include encephalitis or encephalomyelitis usually linked to autoantibodies such as anti-Hu, Ma2associated, anti-CRMP5, anti-Ri, anti-KLHL1 that are generally secreted by neuroendocrine tumors [12].Thus, it can also reveal as a subacute sensory neuronopathy associated with anti-Hu or anti-collapsinresponsive mediator protein 5 (CRMP5) antibodies, or as sensory-motor neuropathy.
A different way of presentation of EC is also dermatomyositis or polymyositis.Dermatomyositis is an in ammatory myopathy that presents with proximal muscle weakness and skin rashes [13].Polymyositis is characterized by myalgia with progressive and symmetric involvement.Furthermore, systemic symptoms such as loss of appetite, weakness and mild fever may be present [14].Laboratory tests usually underline rhabdomyolysis and chronic in ammation, as happens in our patients [15].
CSW presents with hypovolemia and hyponatremia responsive to supplement treatment, as well as our patient.

CONCLUSIONS
This case report describes a rare case of paraneoplastic syndrome involving nervous system associated with a probable endometrial cancer, not yet well documented in medicine literature.
The relevant implications of this case report are on one side the association with severe obesity, that acts as a risk factor of gynecological tumors especially in the post-menopausal state, and on the other, the importance of considering paraneoplastic syndromes when present as key diagnostic tools with respect to gynecological symptoms alone.