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Introduction: Breast sarcomas (BS) are uncommon and often present both diagnostic and therapeutic challenges. Historically, radical surgery has been the mainstay of treatment for localized breast sarcomas. On the other hand, in advanced disease, since they are a heterogeneous group of neoplasms consisting of several different subtypes including angiosarcoma, phyllodes tumor, and pleomorphic undifferentiated sarcoma, there is a lack of proven specific therapy. As a result, their treatment is based on the soft tissue sarcoma (STS) paradigm, whereas histotype-tailored approaches apply to specific subtypes like dermatofibrosarcoma protuberans. To date, advanced stages constitute an incurable form of disease and chemotherapy remains the cornerstone of treatment with the aim of palliation of symptoms and increase in survival.Areas covered: In this manuscript, we review the clinicopathologic characteristics of the most common subtypes of BS, as well as the current treatment landscape of BS, with a particular focus on opportunities and challenges provided by new targeted molecules and immunotherapy.Expert opinion: The treatment approach of advanced BS is based on the pathologic subtype. A true breakthrough has still to be obtained, as the development of new agents in BS suffers from the same weaknesses as in other STS.

Uveal melanoma (UM) is the most common intraocular cancer and represents a discrete subtype of melanoma. Metastatic disease, which occurs in half of patients, has a dismal prognosis. Immunotherapy with immune checkpoint inhibitors has produced promising results in cutaneous melanoma but has failed to show analogous efficacy in metastatic UM. This is attributable to UM's distinct genetics and its complex interaction with the immune system. Hence, more efficacious immunotherapeutic approaches are under investigation.We discuss those novel immunotherapeutic strategies in clinical and preclinical studies for advanced disease and which are thought to overcome the hurdles set by UM in terms of immune recognition. We also highlight the need to determine predictive markers in relation to these strategies to improve clinical outcomes. We used a simple narrative analysis to summarize the data. The search methodology is located in the Introduction.Novel immunotherapeutic strategies focus on transforming immune excluded tumor microenvironment in metastatic UM to T cell inflamed. Preliminary results of approaches such as vaccines, adoptive cell transfer and other novel molecules are encouraging. Factors such as HLA compatibility and expression level of targeted antigens should be considered to optimize personalized management.

Although brain metastases from bone and soft tissue sarcoma are uncommon, advances in sarcoma treatment have led to an increasing incidence of them. We present a 23-year-old male with a history of metastatic femoral osteosarcoma, who presented with headache and unsteady gait and was diagnosed with a cerebellar metastasis. CT scan revealed a mass in the left cerebellar parenchyma with large intralesional central calcification and perilesional edema. Corticosteroid treatment led to neurological symptoms resolution, with a rapid tapering. The patient had also lung metastases and we opted to administer systemic treatment with the tyrosine kinase inhibitor cabozantinib. Given the relative radioresistance of osteosarcomas, the patient did not receive radiation therapy.

Introduction Everolimus is a mammalian target of rapamycin inhibitor and is approved as second-line treatment or beyond for renal cell carcinoma. We report a case of a 75-year-old male treated with everolimus for metastatic renal cell carcinoma, after sunitinib treatment, who was diagnosed with human herpesvirus 6 encephalitis. Case report After 39 months of everolimus, 10 mg per day, our patient was admitted with fever, consciousness disorders and a partial epileptic crisis. Laboratory tests revealed lymphopenia (170 lymphocytes/mm3), and polymerase chain reaction in cerebrospinal fluid was positive for human herpesvirus 6. Brain magnetic resonance imaging study demonstrated hippocampal abnormality and a pontine lesion. Management and outcome The patient stopped everolimus treatment indefinitely. He received ganciclovir initially intravenously, with a rapid clinical improvement, as well as polyvalent immunoglobulins were given to correct hypogammaglobulinemia. Two months later, antiviral therapy was switched to oral ganciclovir, which was never stopped. A new lumbar puncture was performed one month after the initiation of antiviral treatment, which did not reveal human herpesvirus 6 DNA anymore. Discussion Human herpesvirus 6 encephalitis is more common in hematopoietic stem cell transplant recipients and HIV patients. This is the first case probably associated to everolimus treatment. In contrast to most patients diagnosed with this infection, who either die or develop neurologic sequelae, our patient almost fully recovered two months later.

BACKGROUND/AIM Primary sarcomas of the lung (PSL) represent a rare, largely unknown entity. We herein present a retrospective study of 26 patients diagnosed with PSL. PATIENTS AND METHODS For a period of 10 years, the records of patients from 5 centers were gathered and analyzed. RESULTS Median age at diagnosis was 61.96 years (range=31-75 years). Eight patients (33.33%) had mediastinal node invasion (MNI). From 17 patients (70.83%) with localized disease, 11 patients (64.70%) underwent surgery. Recurrence rate was 72.72%. Median disease-free interval was 15 months. The median overall survival (OS) of patients with metastatic disease was 4 months and 10 months for the whole population. Only surgery had an impact on survival. CONCLUSION Prognosis of PSL is somber. The high proportion of patients with MNI at diagnosis may serve as an indication for surgical evaluation of mediastinum and raises the question whether patients with locoregional PSL should be treated with a more aggressive approach.

Brain metastases are rare events in patients with sarcoma and the available information is relatively limited. We retrospectively reviewed medical records of patients with sarcoma who developed brain metastases between April 2010 and April 2020 in six centers. Thirty-four adult patients were included with a median age at brain metastases diagnosis of 55.5 years (range, 18–75). The primary sarcomas originated either from soft tissue (n = 27) or bone (n = 7) and the most common subtypes were leiomyosarcoma (n = 8), Ewing sarcoma/peripheral neuroectodermal tumor (PNET) (n = 7) and osteosarcoma (n = 3). Most primary tumors were of high grade and located mainly in the extremities (n = 18). The vast majority of patients at the time of brain metastasis diagnosis already had extracranial metastatic disease (n = 26). The median time from sarcoma diagnosis to cerebral metastasis diagnosis was 16 months (range, 1–136). Treatment modalities for brain metastatic disease included whole-brain radiation therapy (WBRT) (n = 22), chemotherapy (n = 17), exclusive palliative care (n = 5), surgery (n = 9), targeted therapy (n = 6) or stereotactic radiosurgery (n = 2). Most patients experienced a progression of brain metastases (n = 11). The median overall survival from brain metastasis diagnosis was 3 months (range, 0–80). OS was significantly influenced by time-to-brain metastases (p = 0.041), WBRT (p = 0.018), surgery (p = 0.002) and chemotherapy (p = 0.006). In a multivariate analysis, only the localization of the primary (p = 0.047) and WBRT (p = 0.038) were associated with survival with statistical significance. Patients with sarcoma brain metastases have a particularly poor prognosis and an appropriate therapeutic approach is yet to be defined.

Simple Summary Adrenocortical carcinoma is a rare but aggressive malignancy with poor outcomes even for patients with early-stage disease. Several immunotherapy clinical trials, many of which are still in progress, have yielded modest results so far. In-depth understanding of the tumor microenvironment in other cancer types has helped the scientific community to identify novel therapeutic targets and gain a better insight of cancer biology. The present review aims to provide an update of the current knowledge regarding adrenocortical carcinoma tumor microenvironment and describe how the latter potentially affects patient response to immunotherapy. Following the paradigm of other cancer types, exploiting tumor microenvironment could open new therapeutic avenues. Abstract Adrenocortical carcinoma is a rare malignancy with aggressive behavior, with up to 40% of patients presenting with metastases at the time of diagnosis. Both conventional chemotherapeutic regimens and novel immunotherapeutic agents, many of which are currently being tested in ongoing clinical trials, have yielded modest results so far, bringing the need for a deeper understanding of adrenal cancer behavior to the forefront. In the recent years, the tumor microenvironment has emerged as a major determinant of cancer response to immunotherapy and an increasing number of studies on other solid tumors have focused on manipulating the microenvironment in the favor of the host and discovering new potential target molecules. In the present review we aim to explore the characteristics of adrenocortical cancer’s microenvironment, highlighting the mechanisms of immune evasion responsible for the modest immunotherapeutic results, and identify novel potential strategies.

Salivary gland cancers (SGCs) consist of a rare family of neoplasms with varying histology and biological behavior. Therapeutic regimens have been relatively unchanged for decades. The recent successes of immunotherapy have raised hopes for the development of more effective strategies in SGC, thus emphasizing the role of tumor microenvironment (TME) in the design for more effective therapies.This review presents an overview of the current knowledge on the pathobiology of SGC TME and discusses the potential of immunotherapeutic targeting.Most data on the role of TME in SGC carcinogenesis are derived from preclinical studies. Signaling cascades of immunotherapeutic interest, PD-1/PD-L1 and PD-1/PD-L2, are active in many SGCs and might be associated with biological behavior and prognosis. Immunotherapeutic attempts are very limited, but recent findings in other tumors on the role of exosomes and PD-L2 signaling suggest that TME of SGCs warrants further research, emphasizing larger cohorts, histology-based stratification, and standardized evaluation of immunomodulatory molecules, to explore the potential of targeting tumor stroma and its signaling cascades. Furthermore, combination of immunotherapies or immunotherapies with the antineoplastic agents targeting AR, HER2, and tyrosine kinases, recently introduced in SGC treatment, constitutes a promising approach for the future.

The therapeutic armamentarium for advanced soft tissue sarcoma (STS) has increased over the last few years. Doxorubicin monotherapy or in combination is now the established first line treatment. Beyond first line treatment, no standard therapy has been established. Novel drugs have reached the late-clinical stage development demonstrating to be effective in controlled studies. While these novel treatments can be beneficial to a subset of patients, even producing long lasting remissions, a significant fraction of the STS population derives limited benefit. This is due to the fact that STS is a very heterogeneous disease with different histopathologic features, biological characteristics and clinical behaviour. Areas covered: The primary aim of this review is to summarize data from recent phase III clinical trials in unselected STS population, and to discuss their impact on the current clinical practice. Phase I-II trials of special interest are discussed as well. Expert commentary: Although our efforts in this research task are ongoing, the integration of biological therapies, the anti-angiogenesis targeted treatments as well as immunotherapy that may further improve the long term control of advanced STS are of special clinical interest. Clinical management of advanced STS should be tailored to each patient in order to optimize therapy.

Invasive lobular carcinoma of the breast is the second most common subtype of breast carcinoma. It accounts for 5-15% of the breast carcinoma cases reported. It shows a different metastatic pattern compared to invasive carcinoma of no special type. There are several variants of this cancer including the classic, solid, signet ring cell, tubulolobular, alveolar, trabecular, pleomorphic, and mixed subtypes each one with a distinctive morphology. Invasive lobular carcinoma has been associated with intracellular mucin production, in the form of intracytoplasmic lumina and signet ring cells whereas extracellular mucin production has been related to carcinomas of ductal origin. A new variant that displays extracellular mucin production was described recently. Only nineteen cases of this rare entity have been reported to date. In this manuscript, we report an additional case of invasive lobular carcinoma with extracellular mucin production, describing its clinico-pathological characteristics, and review the literature on the same.

Matrix-producing carcinoma (MPC) is a rare subtype of metaplastic breast carcinoma (MBC) that was first described in 1989 by Wargotz and Norris. It accounts for less than 1% of breast carcinomas and has distinctive clinical, morphological, and immunohistochemical features. Histologically it consists of invasive carcinoma of no special type with transition to cartilaginous or osseous matrix without a spindle cell component. Data on this entity are limited with the literature consisting mostly of case reports and a small number of case series. We report a case of matrix-producing breast carcinoma, with excellent clinical outcome. We also discuss the histogenesis, imaging, histological, and immunohistochemical characteristics, treatment, and focus on the differential diagnosis of this rare tumor.

Immunotherapy (IO) with anti-PD1 inhibitors is available for the treatment of recurrent/metastatic squamous cell carcinomas of the head and neck (SCCHD) since 2016. Both nivolumab and pembrolizumab were tested in phase 3 randomized trials in adults progressing on or after platinum-based therapy and were found to confer an overall survival benefit compared to investigator’s choice. However, very limited data exist concerning IO use in rare subtypes of head and neck carcinoma, like salivary gland carcinoma. We retrospectively collected clinical data of all patients diagnosed with rare subtypes of head and neck carcinoma, who were treated with immune checkpoint inhibitors in our department during the last 5 years. We analyzed safety and efficacy of these therapies. We identified six patients who received nivolumab for recurrent or metastatic head and neck carcinomas, between 31 and 57 years old. All patients had received at least one line of platinum-chemotherapy, as well as radiation therapy. Treatment was administered every 2 weeks, at a dose of 3 mg per kilogram of body weight. Number of nivolumab cycles varied between 2 and 18. Progression-free survival varied from 1 to 12 months and overall survival from 4 to 24 months. Tolerance was very good, except for one case of diabetes and hypothyroidism requiring medication. There is currently insufficient evidence regarding the optimal treatment of the rare non-squamous cell carcinoma of the head and neck. Our case series supports a role for immunotherapy in these patients. However, larger collaborative studies are needed to evaluate this treatment.

Ovarian metastasis is common with secondary tumors representing up to 15% of ovarian neoplasms. The malignancies most commonly involving the ovaries are carcinomas of the stomach, colon, breast, endocervix, endometrium, and lymphoma. Secondary ovarian involvement by kidney carcinoma occurs very rarely and is usually associated with widespread dissemination. We conducted a review of kidney carcinoma with ovarian metastasis in the literature using the keywords clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma collecting duct carcinoma, and ovarian metastasis on Google Scholar and PubMed indices in April 2018, including a case diagnosed in our department. To date, 30 articles presenting 41 cases of kidney carcinoma with ovarian metastasis are reported in the literature. All reviewed cases were analyzed for diagnosis, surgical and systemic therapy, and outcome. Diagnosis may sometimes be challenging, requiring appropriate immunohistochemical markers in difficult cases. A combination of surgery and adjuvant therapy offers significant benefit in disease control or palliation of symptoms. Due to inconsistency in the reported data, further studies are needed to make safe conclusions regarding survival.

Background/aim Subcutaneous (s.c.) trastuzumab was introduced in the (neo)adjuvant setting, based on the non-inferiority results and patient preference. In the advanced setting, preliminary safety data have only been reported. We conducted an observational study of s.c. trastuzumab in combination with i.v. pertuzumab and docetaxel in the first-line setting of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. Patients and methods In this single-institution study, patients received 600 mg s.c. trastuzumab in combination with 840 mg pertuzumab for the first cycle and 420 mg for the following cycles, and 75-100 mg/m2 docetaxel, followed by maintenance with s.c. trastuzumab and pertuzumab until disease progression or unacceptable toxicity. Endpoints were efficacy and safety. Results Forty patients were enrolled. The median number of cycles with docetaxel was six, while the median number of maintenance cycles was 21. With a median follow-up of 37 months, median progression-free survival and overall survival were 24 and 35 months. Conclusion Subcutaneous trastuzumab in combination with pertuzumab and docetaxel is well tolerated and effective in HER2-positive advanced breast cancer.

Background/aim During recent years, a survival advantage was reported for first-line treatment of advanced pancreatic cancer with two new regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel, over gemcitabine monotherapy. Gemcitabine/nab-paclitaxel administration on days 1, 8 and 15 of a 4-week cycle is associated with some practical disadvantages. We adopted a biweekly regimen with the same dose density. Patients and methods Patients with Eastern Cooperative Oncology Group performance status 0-2 diagnosed with advanced histologically or cytologically confirmed pancreatic cancer and no prior treatment were included in the study. Study combination included 1.5 g/m2 gemcitabine and 175 mg/m2 nab-paclitaxel given every 2 weeks. Survival analysis was performed using the Kaplan-Meier method. Results Forty-six patients were treated with this regimen. Adverse events were similar to those of the original regimen. Median progression-free and overall survival were 5 and 10 months, respectively. Conclusion Biweekly gemcitabine/nab-paclitaxel seems to have a similar safety and efficacy profile as the original regimen.

A 61-year-old female patient with no previous medical history presented to our hospital with a palpable right breast mass as well as palpable axillary lymph nodes. Microscopic examination revealed a bifocal primary carcinoma of the breast displaying characteristics similar to that of follicular variant of papillary thyroid carcinoma. Three axillary lymph nodes contained metastases. Immunohistochemical study for TTF-1, Thyroglobulin, GATA-3, ER and PR was consistent with a primary breast carcinoma, excluding the possibility of a metastatic tumor.The above unusual morphological features were caused by improper fixed tissue. Suboptimal fixation may cause tissue artifacts such as shrinkage, streaming, diffusion, vacuolation and nuclear or cytoplasmic changes as well as decreasing tissue antigenicity. Occasionally, altered morphology may mislead to major diagnostic pitfall.