Marianna Tortora

Sarcomas of the thoracic cavity are rare entities that predominantly affect children and young adults. They can be very heterogeneous encompassing several different histological entities. Ewing Sarcoma (ES) can potentially arise from every bone, soft tissue, or visceral site in the body. However, it represents an extremely rare finding when it affects the thoracic cavity. It represents the second most frequent type of thoracic sarcoma, after chondrosarcoma. ES arises more frequently in sites that differ from the thoracic cavity, but it displays the same biological features and behavior of extra-thoracic ones. Current management of ES often requires a multidisciplinary treatment approach including surgery, radiotherapy, and systemic therapy, as it can guarantee local and distant disease control, at least transiently, although the long-term outcome remains poor. Unfortunately, due to the paucity of clinical trials purposely designed for this rare malignancy, there are no optimal strategies that can be used for disease recurrence. As a result of its complex biological features, ES might be suitable for emerging biology-based therapeutic strategies. However, a deeper understanding of the molecular mechanisms driving tumor growth and treatment resistance, including those related to oncogenic pathways, epigenetic landscape, and immune microenvironment, is necessary in order to develop new valid therapeutic opportunities. Here, we provide an overview of the most recent therapeutic advances for ES in both the preclinical and clinical settings. We performed a review of the current available literature and of the ongoing clinical trials focusing on new treatment strategies, after failure of conventional multimodal treatments.

Thymic epithelial tumors are rare tumors usually presenting as a mass located in the anterior mediastinum and/or with symptoms deriving from associated paraneoplastic syndromes. Unresectable platinum-refractory tumors are often treated with alternative regimens, including chemotherapeutic agents as well as chemo-free regimens. The most popular unconventional therapy is represented by the somatostatin analog octreotide, which can be used alone or with prednisone. The in vivo expression of somatostatin receptors documented by imaging with indium-labeled octreotide or gallium-68 Dotapeptides, the successful use of octreotide and prednisone in a chemo-refractory patient, and, thereafter, the experiences from a case series have enforced the idea that this treatment merits consideration—as proved by its inclusion in the National Comprehensive Cancer Network guidelines. In the present review, we analyze the preclinical basis for the therapeutic use of somatostatin and prednisone in refractory thymic tumors and discuss the available studies looking at future perspectives.

Mucosal melanomas (MM) are rare tumors, being less than 2% of all diagnosed melanomas, comprising a variegated group of malignancies arising from melanocytes in virtually all mucosal epithelia, even if more frequently found in oral and sino-nasal cavities, ano-rectum and female genitalia (vulva and vagina). To date, there is no consensus about the optimal management strategy of MM. Furthermore, the clinical rationale of molecular tumor characterization regarding BRAF, KIT or NRAS, as well as the therapeutic value of immunotherapy, chemotherapy and targeted therapy, has not yet been deeply explored and clearly established in MM. In this overview, focused on anorectal and genital MM as models of rare melanomas deserving of a multidisciplinary approach, we highlight the need of referring these patients to centers with experts in melanoma, anorectal and uro-genital cancers treatments. Taking into account the rarity, the poor outcomes and the lack of effective treatment options for MM, tailored research needs to be promptly promoted.

Recently, syndrome coronavirus type 2 (SARS-CoV-2) infection outbreak has determined the use of thoracic CT scan for diagnostic purposes, leading to incidental detection of mediastinal masses. However, the differential diagnosis between benign and malignant mediastinal neoplasms could be challenging. Furthermore, in a recent study, thymus hyperplasia was observed significantly more frequently in COVID 19 patients compared to controls. Here, we describe a case series of patients with incidental detection of mediastinal masses after COVID 19 infection. (I) The first patient was a 43-year-old male, who performed a CT scan in December 2020 after COVID infection, showing a hypodense lesion of 48×31 mm in the superior anterior mediastinum. Subsequently, the patient developed dysphagia, difficulty in swallowing and right eye ptosis, thus he underwent FDG-PET scan that revealed an uptake of the tracer with a standardized uptake value (SUVmax) of 6. Therefore, thymectomy by robotic assisted surgery was performed. The histological diagnosis was: “thymoma AB, Stage: pT1 a”. (II) The second patient was a 33-year-old female, who performed in January 2021 high resolution chest CT scan, after COVID infection, due to persistence of breath shortness and fatigue. Imaging detected a mass of about 30 mm in the anterior mediastinal space, although a subsequent FDG-PET scan showed no significant tracer uptake. The patient, who is still symptomatic, is currently in follow up. (III) The third patient, a 36-year-old female, performed in April 2021 a chest CT scan due to persistent respiratory distress syndrome, related to SARS-Cov-2 infection that was contracted during pregnancy. The imaging was performed after delivering and showed a solid wedge-shaped lesion of 26 mm in the thymic loggia. The FDG PET scan carried out in June 2021 showed tracer uptake (SUVmax 2.7) in anterior mediastinal space. The patient was initially candidate to thymectomy, but due to the size reduction of the thymic mass observed on a follow-up CT scan, she was deemed eligible for follow up. In conclusion, our experience suggests that differential diagnosis in young symptomatic patients experiencing mediastinal masses after COVID infection is challenging and requires multidisciplinary expertise.

Mediastinum is a complex anatomic space in which different malignancies can occur, originating from different cell types, such as epithelial thymic, lymphoid, germinal cell and mesenchimal cell. Their diagnosis requires dedicated knowledge and expertise, due to heterogeneous features. Indeed, there is also a frequent overlap between different histologies leading to uncertainty in the diagnostic process. Here, we present an uncommon mediastinal mass challenging in its characterization. A thirty-year-old woman performed thoracic CT scan for dyspnea and persistent cough. Imaging showed a solid mass of 14×11 cm involving the left thorax with mediastinal deviation to the right side. Patient underwent resection en bloc of left endothoracic mass and segmental resection of the left upper lung lobe, and of the 3rd, 4th and 5th ribs. Initial histological examination was suggestive for B3 thymoma/thymic carcinoma due to the positivity for p63, CD99, CD117 and vimentin. Pathological stage pT1b. Patient was then referred to our rare tumor Reference Center. Histological review showed small-medium sized tumor cells. The immunohistochemical panel showed negativity for cytokeratins (CKMNF116, CKAE1/AE3, CK19), as well as PAX8, CD56 NSE and CD117; while CD99 was positive, excluding the diagnosis of thymic/thymoma neoplasms; c-kit and other thymoma related genes resulted negative for mutations at a next generation sequencing (NGS) analysis. On the other hand, the negativity of different types of cytokeratins and the elevated mitotic index associated with the sporadic positivity for p63 was not specific for an epithelial neoplasm. Morphological pattern and positivity for CD99 led to a diagnosis of undifferentiated sarcoma. A third revision, was performed at the National Sarcoma Center and included the assessment of markers for sarcoma cluster differentiation. Tumor cells were characterized by the positivity for CD99 and NKX2.2 consistent with a diagnosis of Ewing’s sarcoma, despite the negativity for ETV4. The evaluation of expert centers was critical to establish a correct diagnosis in this complex case. Taking into account the time lasting from the diagnosis and the aggressiveness of this kind of neoplasm, the patient was candidate for chemo-radiotherapy after a multidisciplinary discussion.

The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience of Center of reference for both GCTs and cancer predisposing syndromes.

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.

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The association between high risk human papillomaviruses (HPV) and cervical cancer has been firmly established. HPV genome is present in nearly all cases of cervical cancer and detection of viral DNA could therefore be used as a surrogate marker of micrometastasis in peri-tumor tissues and lymph nodes. We analyzed primary cervical carcinomas, peri-tumor biopsies and pelvic lymph nodes in 20 women with invasive cancer (FIGO stage I-II) who underwent radical pelvic surgery and lymphadenectomy. HPV DNA was searched by broad spectrum PCR in 142 DNA samples extracted from paraffin embedded tissues. Viral genotypes were identified by direct sequencing analysis. HPV DNA sequences were identified in all available primary cervical tumors (n = 15). The most common genotype was HPV16 (60 %), followed by HPV18 (20 %), HPV35 (7 %), HPV45 (7 %) and HPV66 (7 %). Seven out of 20 (35 %) women had metastatic spread in peri-tumor tissues and/or lymph nodes, as determined by histology. HPV DNA was detected in all histological positive samples as well as in 16 and 25 % of histological negative peri-tumor tissues and lymph nodes, respectively. Three out of 20 (15 %) women without histological evidence of metastatic spread had HPV-positive lymph nodes. HPV genotype was found always concordant between primary tumor and metastatic lesions. The remaining 10 women (50 %) were histology and HPV-negative in all peri-tumor biopsies and lymph nodes analyzed. Evaluation of HPV DNA in peri-tumor tissues as well as pelvic lymph nodes could be a sensitive marker to identify micrometastasis or isolated tumor cells and to monitor the risk of disease recurrence in women with cervical cancer.