Glomus tumors belong to the category of soft tissue sarcomas. These tumors arise from the neuromyoarterial glomus body, developing within the reticular dermis of modified smooth muscle cells. Neuromyoarterial glomus body controls skin thermoregulation and blood pressure through peripheral blood flow; this explains that symptom onset can be frequently characterized by cold hypersensitivity and localized pain [1],[2],[3].

The exceptional rarity of these tumors is well known, approximately 2% of all mesenchymal soft tissue sarcomas [1].

Although most lesions reported are benign, occasionally they can be characterized by histopathological changes such as large dimension, infiltration, high nuclear grade, increased mitotic activity, and atypical mitosis; reported malignant glomus cases account for less than 1% of all glomus tumors [3].

In patients with progressive disease, BRAF [c.1799T>A, p.V600E] mutation, associated with malignant histologic characteristics, could be a promising molecular target [4],[5],[6].

Glomus tumors frequently arise from peripheral soft tissues, involving especially dermal and subdermal subungual areas of the digits and the extremities of the limbs; furthermore, they barely occur in visceral organs such as airway and gastrointestinal tracts, where the presence of the glomus body is rare to find; the few cases of glomus tumors of the gastrointestinal region mainly involve the antrum of the stomach and the duodenum [1],[2],[3].

To the best of our knowledge, no data regarding the effectiveness of oncological systemic treatment in these rare histopathological entities is documented in literature.

We report the first case of malignant glomus tumor arising from a pelvic organ responding to chemotherapy treatment and pazopanib.

In December 2015, a 65-year-old female, in a good performance status, presented at Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy, with a 5.4 cm mass arising from the right adnexa of the uterus.

A bilateral hysteroannessiectomy was performed and the histopathological review showed a malignant glomus tumor. Histological examination showed small round tumor cells with moderate nuclear pleomorphism, prominent nucleoli, eosinophilic cytoplasm, and perivascular proliferation. Immunohistochemistry revealed diffuse and strong immunostaining for smooth muscle actin (SMA) and negative results for S100 stains, C-Kit, desmin, and CD34. Markers including epithelial, neuroendocrine, melanoma-associated, STAT6, S-100 protein, and ß-catenin were negative.

The mutational analysis of the genomic region of BRAF exon 15 bearing the mutations of codon 600 was performed by direct sequencing on DNA extracted by FFPE tissue (containing more than 50% tumor cells). The sensitivity limit of the method was 5%. The result was a wild type (non-mutated) configuration of the BRAF exon 15.

Pathological diagnosis was centrally reviewed by expert pathologists referral for soft tissue sarcomas, following the most updated histopathological criteria.

In March 2016 a full body computed tomography scan (CT scan) documented three peritoneal nodules. In April 2016 surgical resection of the three nodules was performed and the histopathological findings were consistent with metastatic glomus tumor disease. After surgery the patient underwent clinic and radiological follow-up with whole body CT scans periodically every 3–4 months.

In August 2016, when a new CT scan showed further peritoneal progression with multiple nodules, we proposed first line sarcoma-oriented chemotherapy with Epirubicin 105 mg/m² and Ifosfamide 9000 mg/m² in three days every three weeks for six cycles. Adverse events reported after the first cycle were G4 neutropenia and G4 anemia. The doses were reduced by 20%. The New Response Evaluation Criteria in Solid Tumours (Revised RECIST criteria version 1.1) [7] were used to evaluate the response to oncological treatments, performing whole body CT scans periodically every 3–4 months. According to Revised RECIST criteria, the best response was partial response on the peritoneal metastases after three and six cycles (Figure 1A and Figure 1B), defined as at least a 30% decrease in the sum of the longest diameter of target lesions. The response was maintained for seven months after treatment.

In August 2017, a follow-up CT scan showed progressive peritoneal disease. The patient started second line pazopanib 800 mg/day. After one month, oncology treatment-related adverse event was G2 diarrhea treated and controlled by loperamide with benefit; after three months she developed palmar-plantar erythrodysesthesia grade 1–2 which required adequate local treatments. No kidney failure or febrile neutropenia were observed, as well as any other unexpected major toxicities. In August 2018, worsening skin toxicity required a 25% dose reduction of pazopanib.

According to RECIST criteria, the best response was partial response on the peritoneal disease after seven months in March 2018 (Figure 2A and Figure 2B).

Until May 2019 follow-up CT scans showed stable disease. This patient’s case was discussed at the multidisciplinary team meeting: Pazopanib was stopped and the patient underwent surgery to remove the residual abdominal nodules in June 2019. Histopathological diagnosis deposed for necrotic nodules with dystrophic calcifications.

From June 2019 to date regular follow-up with positron emission tomography (PET) CT scan showed no evidence of oncological disease (last CT scan was performed on March 29, 2022).

At this moment the patient is alive in good clinical conditions. A new radiological evaluation with a full body PET CT scan is planned in July 2022.

The Institutional Ethics Committee of our Hospital approved the drafting of this case report.

We report an anecdotal case of metastatic glomus tumor originating from a pelvic organ responsive to systemic oncological treatment.

Among mesenchymal cancers, glomus tumor represents a very rare subtype. In addition, glomus tumors originating from the pelvic viscera are even rarer and our knowledge about their clinical course and prognosis is scarce to date [1],[3].

Definitely, it is evident that all the few data collected in literature about this rare neoplasm mainly concern the natural history of the disease or the molecular and histological characteristics; the behavior that distinguishes this rare entity of malignant tumors is of intermediate grade [1],[3].

It is now established that BRAF p.V600E mutation may be related with a malignant phenotype. Dahlin et al. [5] described a glomus tumor characterized by an uncertain malignant potential in the median nerve with BRAF p.V600E mutation.

A molecular study of 28 sporadic glomus tumors by Chakrapani et al. [6] found that approximately 11% of glomus tumors harbored BRAF p.V600E mutation.

Karamzadeh Dashti et al. detected BRAF p.V600E mutation in six cases affected by glomus tumors, all of which were malignant or characterized by an uncertain malignant potential[4].

DNA sequencing shown in our case a wild type configuration at the codon 600 of the BRAF. However we cannot exclude the involvement of other mutations activated genes that can be responsible of malignant behavior and that they could eventually become target of successful biologic inhibition. Due to the particularity of the glomus tumors, we could lead an extended analysis in Next Generation Sequencing (NGS) in order to identify other possible pathogenetic patterns other than BRAF.

The role of BRAF mutation in these tumors is still unclear, but it may be meaningful in tumor progression given the association with malignant histologic characteristics.

It is certainly indispensable to collect more evidence regarding malignant glomus tumors to better define the role of molecular analysis and in particular the role of BRAF as it could be a promising molecular target in this rare tumor.

Our case describes an advanced glomus tumor arising from a pelvic viscera responding to systemic oncological treatment.

To the best of our knowledge, in literature no data regarding the activity of a standard oncological therapy in metastatic glomus tumors have been described for the time being.

This case report describes a metastatic malignant glomus tumor’s response to soft tissue sarcoma-oriented oncological treatments.

There are few reports of patients affected by malignant glomus tumor treated with chemotherapy: Milia et al. [8] report a case on adjuvant chemotherapy in a patient affected by a malignant paraganglioma of the glomus vagale of the upper right cervical region who underwent surgery. Subsequently, he was treated with conformal radiotherapy and concomitant cisplatin and at five years follow-up there was no tumor recurrence.

In adult metastatic mesenchymal tumors first-line chemotherapy based on anthracycline and ifosfamide is clinically active [9]. The efficacy of the oncological treatment given to our patient mirrors the activity of the standard oncological therapy used in sarcomas in general.

Still today there is an open debate about the sequence of therapeutic lines in advanced mesenchymal tumors, while the gold standard at the forefront is a chemotherapy treatment based on anthracyclines [9],[10].

Certainly the histological types can provide help to address the different therapeutic lines of treatments following a histology-driven choice [10].

Indeed, in terms of histology-driven choice, Pazopanib, an oral multiple tyrosine kinase inhibitor demonstrated activity in metastatic non-lipomatous sarcoma [11].

In such a rare histopathological type and especially in orphan diseases it is really arduous to conceive prospective studies as well as to collect retrospective studies focusing on the activity of an oncological treatment.

Rare tumors have always been associated with a series of difficulties and problems related primarily to their characteristic of rare diseases. These difficulties involve both the diagnostic-therapeutic process, the obstacle in finding the clinical skills necessary for diagnosis and the limited availability of effective therapies, which connects to the difficulty of developing clinical trials due to the small number of patients and the potential lack of interest in the development of new therapies.

Therefore the data reported so far do not provide evidence regarding the activity of a systemic oncological treatment in glomus tumors.

Even though this is a single case, it supplies data regarding the activity of chemotherapy treatment oriented to soft tissue sarcomas.

In this regard, our case report adds to the data present in the literature more information supporting clinicians toward a choice of the most appropriate therapeutic regimens.

In the field of rare cancers, it is imperative to promote and encourage data collection, patient registries, and databases. They represent key tools for assessing the feasibility of adequate clinical research and the right way to pool data in order to obtain a sufficient sample size for the planning of proper clinical trials in rare cancers. It is needful to collect a pool of anecdotal data to provide a better knowledge about the natural history of rare cancers, to support the medical decision on the appropriate treatment options for these patients with the aim of perfecting the diagnostic and therapeutic pathways and improving health planning and patient care.