Triple negative breast cancer (TNBC) is a subtype of breast cancer traditionally defined by its lack of hormone receptor (estrogen and progesterone) expression and human epidermal growth factor receptor2 (HER2) expression/amplification. HER2 negativity includes tumors that are not HER2-amplified, those that stain 0 or 1+ by immunohistochemistry (IHC), or are HER2 equivocal by IHC 2+ and not HER2 amplified. Because these receptors represent some of the most viable targets for treatment, patients with TNBC until the recent past have encountered a relative dearth of therapy options outside of traditional cytotoxic chemotherapy, compared to hormone receptor positive and HER2 positive populations. Due to the lack of hormone receptor and HER2 targets, (neo)adjuvant chemotherapy is offered in patients with early-stage disease, who are chemotherapy-eligible. However, checkpoint inhibitors in combination with chemotherapy and molecularly targeted agents are emerging as newer therapeutic options in the (neo)adjuvant and metastatic setting.

Myelodysplastic syndrome (MDS) refers to a spectrum of myeloid neoplasms describing clonal proliferation of hematopoietic stem cells, ineffective hematopoiesis, cytopenias, and a tendency to progress to acute myeloid leukemia. The incidence of MDS in the general population is 4.5 per 100,000 individuals per year. MDS is through to arise from the expansion of a somatically mutated clone of hematopoietic stem cells. First, an initial driver mutation conferring a survival advantage occurs within a normal hematopoietic stem cell capable of self-renewal, forming a clonal population of aberrant hematopoietic progenitor and precursor cells. The next step involves migration and propagation of these abnormal stem cells through the peripheral blood and other bone marrow compartments, forming local clones in distinct bone marrow reservoirs throughout the body. Management of MDS requires proper classification and risk stratification, along with careful assessment of comorbidities and attention to goals of care.

Neuroendocrine neoplasms (NEN) are a diverse set of malignancies that can arise from endocrine cells throughout the body. They most commonly present as tumors of the gastrointestinal (GI) tract, lungs, bronchi, thymus, and pancreas. Most NENs are thought to be sporadic, and risk factors for the majority of NENs outside genetic syndromes are poorly understood. These tumors share common characteristics however, unique features related to the primary site of the tumor and the produced hormones from these neoplasms distinguish the different subtypes. NENs can be found incidentally due to non-specific symptoms related to mass effect or constitutional symptoms such as weight loss but may also have symptoms attributable to functional hypersecretion of hormones, which necessitate biochemical testing. For accurate diagnosis of pathology, both specimen differentiation and grade reporting are necessary on pathology.

Lung cancer is the leading cause of cancer deaths for men and women worldwide. In the United States small cell lung cancer (SCLC) accounts for approximately 13% or 30,000 new cases of lung cancer each year. It is strongly associated with tobacco smoke with 98% of patients having a smoking history. Small cell lung cancer (SCLC) is also called a high-grade neuroendocrine carcinoma and is associated with multiple paraneoplastic syndromes. Its characteristic rapid doubling time makes it sensitive to chemotherapy. Recently, the addition of programmed death-ligand 1 inhibitor atezolizumab or durvalumab to chemotherapy followed by maintenance immunotherapy improved survival for patients with the extensive-stage disease and is considered the treatment of choice. Patients with the limited-stage disease receive thoracic radiotherapy concurrently with chemotherapy and have a small chance to be cured. Patients are encouraged to participate in clinical trials to improve their quality of life and survival.

Globally, the cumulative risk of being diagnosed with multiple myeloma (MM) from birth to 74 years of age is 0.24% for men and 0.17% for women, making the diagnosis of MM 1.5 times more likely for men compared to women. Encouragingly, 5-year survival has increased from 23.7% in 1976 to 53.9% in 2016, owing to rapid advances in MM therapy. Risk factors for MM include male sex, older age, African American race, and increased body mass index. Increased body mass index has also been noted as a risk factor in developing MM. Workup of MM generally consists of a complete metabolic panel, complete blood count, serum ß2 microglobulin, lactate dehydrogenase (LDH), and protein electrophoresis of the serum and urine (UPEP) followed by serum and urine immunofixation. The bone marrow biopsy is critical to the diagnosis of MM, which is used to determine the percentage of clonal plasma cells.

For adults (over age 40) with a suspicious radiographically identified bone lesion, it should be assumed this lesion is metastatic and these patients should undergo evaluation to identify the primary tumor. Specifically, these patients should be evaluated for prostate or breast cancer as well as multiple myeloma with a PSA, mammogram, and SPEP/UPEP, respectively. In addition to these studies, imaging of the chest, abdomen, pelvis, and other extremities is recommended. If this workup does not yield additional sites of disease and there is concern for a primary bone lesion, given the rarity of these tumors, the heterogeneous presentation, and potential for associated morbidity, these patients should be evaluated at a specialty care center by a multidisciplinary team. This chapter presents cases that illustrate the workup, treatment, and staging for the most common bone sarcomas affecting adults.

Esophageal cancer is the eighth most common cancer diagnosed worldwide and the sixth most common cause of cancer-related death. Despite advances in staging modalities and treatment, esophageal cancer continues to be associated with a high mortality rate. The esophagus is divided into thirds: upper, middle, and lower. There are two main histologic subtypes of esophageal cancer: squamous cell carcinoma and adenocarcinoma. Esophageal adenocarcinoma is the most common subtype in the United States and the western world, and incidence has increased dramatically due to risk factors such as higher body mass index and incidence of gastroesophageal reflux disease. Squamous cell carcinoma remains the most common histologic subtype worldwide but has decreased in incidence due to a reduction in alcohol and tobacco consumption. The risk factors for adenocarcinoma of the esophagus include gastroesophageal reflux disease and Barrett’s esophagus, with an annual 1% risk of progression from Barrett’s esophagus to adenocarcinoma.

The majority of head and neck cancers originate from the squamous cells that line the mucosal surface of the head and neck (oral cavity, pharynx, larynx). The strongest risk factors for head and neck cancer are alcohol and tobacco use, although the incidence of human papilloma virus-associated oropharyngeal cancer is notably increasing. Infection with Epstein-Barr virus is also a risk factor for the development of nasopharyngeal and salivary gland cancers. Due to the diverse anatomic structures that comprise the head and neck, the presenting symptoms, staging, prognosis and treatment vary greatly depending on the site of origin of the malignancy. Management, accordingly, requires a multidisciplinary approach that may include surgery, radiation, and/or systemic therapy with cytotoxic chemotherapy, targeted therapy, or immunotherapy. This chapter discusses the presenting symptoms, staging, prognosis and treatment of oropharynx cancer, nasopharyngeal cancer, metastatic adenoid cystic carcinoma, and metastatic squamous cell carcinoma.

Cancers of unknown primary (CUP) are metastatic tumors with unidentified primary site that are heterogenous in histologic subtype with variable clinical presentation and overall poor prognosis. For about 80% of patients diagnosed with CUP, prognosis is poor with a median overall survival of 3-10 months. There is a subset of CUP with favorable prognosis (about 20%) with median overall survival of 12-36 months that include those with a resectable tumor, isolated inguinal adenopathy involving squamous cell carcinoma, women with adenocarcinoma only involving axillary lymph nodes, women with papillary adenocarcinoma of the peritoneum, and poorly differentiated neuroendocrine tumor. There exists a subset of patients, about 20% of those diagnosed with CUP, that present with a defined, favorable risk disease and should be treated accordingly. Additionally, molecular gene expression profiling to predict tissue of origin is important as it can identify origin and allow for site-specific therapy.

Soft tissue sarcomas are a rare and heterogeneous group of tumors. There are more than 50 subtypes that vary in histology, patient demographics, and clinical behavior. These tumors can be further categorized into low grade and high grade based on pathologic findings. Amongst high grade sarcomas, these can be further divided into translocation and non-translocation driven subtypes. In adults, the most common translocation driven sarcoma is synovial sarcoma, characterized by an SSX-SYT gene fusion. The non-translocation subtypes are characterized by multiple chromosomal gains and losses (aneuploidy). Common examples of non-translocation associated sarcomas are undifferentiated pleomorphic sarcoma, leiomyosarcoma, and dedifferentiated liposarcoma. Given the rare nature of soft tissue sarcomas, patients should be referred to a specialty cancer center for treatment by a multidisciplinary team consisting of medical oncology, radiation oncology, orthopedic or surgical oncology, and a pathologist with expertise in sarcoma.