Hospital Residency; Residenza di Ospedale

Esophageal cancer

(EC) is the eighth most common type of cancer worldwide and affects predominantly male individuals (3:1). The two main forms are esophageal adenocarcinoma and squamous cell carcinoma. Adenocarcinomas are considered the fastest-growing neoplasms in Western countries, while squamous cell carcinoma is still most common in the resource-limited countries. Development of EC is associated with a number of risk factors. Adenocarcinoma, which usually affects the lower third of the esophagus, may be preceded by gastroesophageal reflux disease and associated Barrett esophagus. Other risk factors are smoking and obesity. Major known risk factors for squamous cell carcinoma include carcinogen exposure (e.g., in form of alcohol and tobacco) and a diet high in nitrosamines, but low in fruits and vegetables. Initially, EC is usually asymptomatic, so locally advanced disease is common at time of diagnosis. Weight loss and dyspepsia can precede the primary symptom progressive dysphagia. Late stages may be characterized by cervical adenopathy, hoarseness or persistent cough, and signs of upper gastrointestinal bleeding, such as hematemesis or melena. Esophagogastroduodenoscopy is used for direct visualization and allows biopsy of the lesion for histopathological confirmation. Staging of the tumor includes transesophageal endoscopic ultrasound, CT scans of chest and abdomen, and bronchoscopy. Curative surgical resection may be considered for locally invasive cancers, but in about 60% of patients EC is already unresectable at time of diagnosis. In those cases, treatment options includes chemotherapy, radiation, and palliative stenting. Prognosis is generally poor due to the aggressive nature of EC and oftentimes late diagnosis. Sex: ♂ > ♀ (3:1) [1] Incidence: an estimated 18,440 new cases of esophageal cancer will be diagnosed in 2020 in the United States [1] Median age of onset: between 60 and 70 years of age Adenocarcinoma: most common type of esophageal cancer in the US [2] Squamous cell carcinoma (SCC): most common type of esophageal cancer worldwide Etiology Adenocarcinoma [4] Exogenous risk factors Smoking (twofold risk) Obesity Endogenous risk factors Male sex Older age (50-60 years) Gastroesophageal reflux Barrett esophagus Localization: mostly in the lower third of the esophagus The most important risk factors for esophageal adenocarcinoma are gastroesophageal reflux and associated Barrett esophagus. Squamous cell carcinoma (SCC) [4][5] Exogenous risk factors Alcohol consumption Smoking (ninefold risk) Diet low in fruits and vegetables Hot beverages Nitrosamines exposure (e.g., cured meat, fish, bacon) [6] Caustic strictures HPV [7] Radiotherapy Betel or areca nut chewing Esophageal candidiasis [8][9] Endogenous risk factors Male sex Older age (60-70 years) African American descent Plummer-Vinson syndrome Achalasia Diverticula (e.g., Zenker's diverticulum) Tylosis Localization: mostly in the upper two-thirds of the esophagus The primary risk factors for squamous cell esophageal cancer are alcohol consumption, smoking, and dietary factors (e.g., diet low in fruits and vegetables). Clinical features Early stages [10] Often asymptomatic May manifest with swallowing difficulties or retrosternal discomfort Advanced stages [10] General signs Weight loss Dyspepsia Signs of anemia Signs of advanced disease Progressive dysphagia (from solids to liquids) with possible odynophagia Retrosternal chest or back pain Cervical adenopathy Hoarseness and/or persistent cough Horner syndrome Signs of upper gastrointestinal bleeding Hematemesis Melena Initially, esophageal cancer is often asymptomatic. It typically becomes symptomatic at advanced stages. Diagnostics Esophagogastroduodenoscopy Best initial and confirmatory test [11] Direct visualization of the tumor Allows biopsy of any suspicious lesions Barium swallow Overview Sensitive, but does not allow confirmation or staging of a malignancy Inferior to endoscopy Indications Severe stricture that inhibits endoscopic evaluation Suspected tracheoesophageal fistula Findings: asymmetrical and irregular borders of the esophagus with characteristic stenosis and proximal dilatation (apple core lesion) Staging [11] Chest and abdominal CT To identify the location and content of the lesion and to exclude distant metastases In case CT scan does not show metastatic disease, a PET scan can be added to increase diagnostic accuracy Transesophageal endoscopic ultrasound Used to determine the infiltration depth and register regional lymph node disease Should be combined with FNA to increase sensitivity and specifity for the identification of lymph node disease Bronchoscopy: for staging of lesions at or above the carina to rule out airway involvement Laparoscopy: in some cases, to increase accuracy of detecting small liver metastases Siewert classification of adenocarcinoma of the esophagogastric junction This classification was proposed by Siewert and is applied in clinical practice. Recent guidelines suggest that tumors located ≤ 2 cm below the z-line (i.e., Siewert types I and II) should be treated as esophageal cancer.

Bone tumour

Benign bone lesions are a heterogeneous group of slow-growing neoplasms that arise from cartilage or bone. They appear on x-ray as localized lesions with sharp margins and without soft tissue involvement. Surgical removal or curettage may be required to manage pain and/or prevent pathological fractures. Overview of benign bone tumors Benign bone tumors are usually asymptomatic and do not require treatment until they become symptomatic (pain, swelling, etc). Surgery is indicated for symptomatic lesions and may involve curettage, bone grafting, or resection.

Growing pains

Etiology: unknown Epidemiology Affects up to 35% of all children Most commonly seen at 3-12 years of age Clinical features Episodic, bilateral pain that affects predominantly the lower extremities (shins, calves, thighs, popliteal fossa) Pain typically occurs late in the day or during the night → children awakening from sleep Pain is not present during the day or activities. May be mild to severe and lasts for a few minutes to several hours; usually resolves by morning Diagnostics The diagnosis is clinical. Imaging shows no abnormalities and is not indicated. Treatment Reassurance Acetaminophen/NSAIDs and massages during acute pain episodes may alleviate symptoms. Prognosis Usually good Most cases resolve spontaneously by late childhood.

Ewing sarcoma

Highly malignant bone tumor arising from neuroectodermal cells Some sources suggest that Ewing sarcoma originates from mesenchymal stem cells. [1][2] Etiology: associated with various chromosomal translocations of the EWSR1 gene (chromosome 22) Epidemiology Incidence: peak at 10-20 years Sex: ♂ > ♀ Ethnicity: primarily affects white individuals Localization Primary tumor: often diaphyses of long bones (particularly femur, tibia, fibula, and humerus) and bones of the pelvis Metastasis: lungs, skeletal system, bone marrow Clinical features Frequently first manifests with localized pain (progressive, worsens at night), hyperthermia, and swelling after trauma to the bone (tissue mass that is tender to palpation and accompanied by erythema) B symptoms are common. Diagnostics Conventional X-ray Lytic bone lesions Onion skin appearance of the periosteum Biopsy Anaplastic small-blue-round-cell malignancy Tumor cells resemble lymphocytes. Differential diagnoses include lymphoma and chronic osteomyelitis. Chromosomal translocation t(11;22)(q24;q12) which leads to expression of fusion protein EWS-FLI1 Cells contain glycogen accumulations and are usually CD99-positive. [3] Laboratory findings: ↑ ESR, ↑ LDH, leukocytosis Treatment [4] Surgery (definitive resection) plus neoadjuvant and adjuvant polychemotherapy Additionally: radiation therapy Prognosis Extremely aggressive, early metastases Usually responsive to chemotherapy Five-year survival rate of ∼ 80% for localized disease • Children/adolescents • Diaphysis of long bones • Onion skin appearance • Surgery • Polychemotherapy • Radiation • ∼ 70%

Malignant bone tumours

Malignant bone tumors can be classified as primary (arising from abnormal bone or cartilage cells) or secondary (bone metastases of other tumors). The most common primary bone tumors are osteosarcomas, Ewing sarcomas, and chondrosarcomas. These tumors differ with regard to primary localization, radiographic characteristics, and the patient age at which they usually develop. Progressive, localized pain that worsens at night or with physical activity is common and usually accompanied by swelling. In Ewing sarcoma and osteosarcoma, symptoms often first manifest after an injury. Diagnosis is confirmed by imaging and biopsy. Depending on the type and stage of the tumor, chemotherapy, radiation therapy, and/or definitive surgical resection may be required. Bone tumors may also occur secondary to metastases of other primary cancers. The metastases are commonly detected in the spine and pelvis and usually arise from the lung, breast, and prostate cancer. Treatment focuses on the underlying malignancy and additional management of pain and prevention of fractures related to the metastases.

Prostate cancer

Prostate cancer is one of the most common cancers that affect men, especially those > 50 years of age. Typically, prostate cancer has an indolent course and is usually discovered while still localized in the prostate. This allows many patients to undergo monitoring for progression rather than active treatment, preventing unnecessary treatment-related adverse effects. Prostate cancer is typically diagnosed and monitored using prostate-specific antigen (PSA) testing, multiparametric MRI (mpMRI), and guided biopsy. Once the decision to treat has been made, therapeutic options include radical prostatectomy, radiation therapy, androgen deprivation therapy (ADT), and chemotherapy. Since all treatment options may adversely affect the patient's quality of life, shared decision-making with the patient is strongly encouraged in all current guidelines. Symptomatic management may be preferable in patients with significant comorbidities or limited life expectancy, as further treatment is unlikely to be life-prolonging. Incidence: following skin cancer (i.e., melanoma and nonmelanoma combined) most common cancer in men in the US [1] Mortality: in 2020, second leading cause of cancer deaths in men in the US (after lung cancer) Advanced age (> 50 years) [1][2] Family history African-American descent Genetic disposition (e.g., BRCA2, Lynch syndrome) Advanced age is the main risk factor for prostate cancer. Sexual activity and benign prostatic hyperplasia (BPH) are not associated with prostate cancer. Symptoms Typically asymptomatic Early prostate cancers are typically detected during screening tests. Some prostate cancers are found incidentally (incidental prostate cancer). Patients may present with features of complicated lower urinary tract symptoms (LUTS), including: [5] Urinary retention Hematuria Incontinence Flank pain (due to hydronephrosis) Advanced prostate cancer can manifest with: Constitutional symptoms: fatigue, loss of appetite, clinically significant unintentional weight loss Features of metastatic disease; examples include: Bone pain (due to bone metastasis, especially in the lumbosacral spine) Neurological deficits (e.g., due to vertebral fracture causing spinal cord compression) Lymphedema (caused by obstructing metastases in the lymph nodes) Digital rectal examination (DRE) [6][7][8] A DRE should be performed in individuals with elevated serum PSA levels and as part of the comprehensive evaluation of male LUTS. DRE has a low positive predictive value for detecting prostate cancer and should not be performed as the sole screening modality. May be normal in early disease or if the cancer is located in areas of the gland that are not palpable on DRE [9] Features suggestive of prostate cancer include: Localized indurated nodules on an otherwise smooth surface Prostatomegaly, lobar asymmetry, obliteration of the sulcus Hard nontender nodules Most prostate cancers are located in the peripheral zone (posterior lobe) of the prostate. In contrast, BPH occurs in the transitional zone of the prostate. Even patients with advanced prostate cancer may have a normal DRE; if clinical suspicion is high, continue diagnostic evaluation for prostate cancer! Diagnostics Approach The following content is related to diagnosing prostate cancer in symptomatic patients or those with a positive screening test. Screening for prostate cancer in asymptomatic individuals is detailed separately. Suspect prostate cancer in patients with elevated PSA levels detected on routine screening and/or abnormal findings on DRE. Consider adjunctive PSA testing (e.g., free PSA:total PSA ratio, PSA density, urinary prostate cancer antigen 3 levels) before performing a biopsy. Confirm the diagnosis on image-guided prostate biopsy. Stage prostate cancer to determine the appropriate management and prognosis. Prostate-specific antigen (PSA) levels PSA is a serine protease produced only in the prostate gland and, therefore, is an organ-specific marker. It is not cancer-specific however, as levels may also be elevated in benign conditions. [10] Indications Suspected prostate cancer Monitoring for recurrence following treatment of prostate cancer Screening for prostate cancer (controversial). Interpretation [11][12] Total PSA levels PSA > 4 ng/mL: Prostate cancer is likely. [12] Free PSA (unbound) : Free PSA levels are lower in prostate cancer than in normal prostate tissue or benign disease. Other causes of elevated total PSA: BPH, UTI, prostatitis, prostatic trauma or manipulation (including DRE) [14] A PSA level ≤ 4 ng/mL does not exclude prostate cancer! 5-alpha reductase inhibitors (5-ARIs) can suppress PSA production, resulting in spuriously low PSA levels. This should be taken into consideration in patients on long-term 5-ARIs (e.g., for BPH). [15][16] Inflammation, manipulation of the prostate, and other malignant and benign prostate diseases may lead to a false-positive PSA result! Initial imaging mpMRI of the prostate [19][20] Becoming the preferred imaging modality for suspected prostate cancer [19][21] Transrectal ultrasound of the prostate: predominantly used to guide prostate biopsy if there is clinical suspicion of prostate cancer [22][23] Prostate biopsy Indication: clinical suspicion of prostate cancer after shared decision-making with a patient whose life expectancy is ≥ 10 years [8][24] Technique Prophylactic antibiotics to prevent prostatitis: recommended for transrectal biopsy; consider before transperitoneal biopsy Anesthesia: local anesthesia, nerve blocks, procedural sedation, or general anesthesia Under image guidance (TRUS-guided or MRI-guided), several biopsy cores are obtained from the prostate via the transperineal or transrectal approach. [28][29] Findings: adenocarcinoma [30][31] Gleason grade: depending on the degree of differentiation of tumor cells and stromal invasion, tumors are graded from 1 (well-differentiated) to 5 (poorly differentiated) Gleason score (ranges from 2 to 10): the sum of the two most prevalent Gleason grades [32] Gleason score and grade groups are used to grade the metastatic potential of prostate adenocarcinoma based on gland-forming differentiation. Evaluation of tumor extent [21][22][33] mpMRI provides information on local tumor extent (e.g., tumor size and volume). Additional imaging to assess for local tumor extent and metastasis to guide management: [21] Recommended in patients with intermediate or high-risk prostate cancer (i.e., patients with PSA > 10 ng/mL and an unfavorable grade group Not routinely recommended for patients with low or very low-risk prostate cancer (i.e., patients with PSA < 10 ng/mL, a favorable grade group, and low tumor burden in biopsy cores) Cross-sectional imaging (CT, MRI, or PET-CT scan) is recommended to identify: [34][35] The spread of cancer beyond the prostatic capsule Pelvic and distal lymph node involvement Hepatic and osseous metastasis Assessment of bone metastases Serum alkaline phosphatase may be elevated bone metastases. Bone scintigraphy (technetium-99m) is the standard study for detecting bone metastases. [22] PET scan is more sensitive than bone scintigraphy and may become the new standard. [22][36] X-rays (e.g., spinal x-ray) may be appropriate to evaluate undifferentiated bone pain or if pathological fractures are suspected. mpMRI is the preferred method for detecting local tumor extent (including recurrent prostate cancer) and PET-CT is preferred to evaluate for metastatic disease. [34][35] Skeletal metastases are the most common nonnodal sites of metastasis in prostate cancer. Vertebral metastases commonly occur due to the spread of malignant cells through the Batson vertebral venous system. Skeletal metastases are predominantly osteoblastic but osteolytic metastases can also occur. Staging The TNM staging system is based on American Joint Committee on Cancer recommendations (see "Grading and staging" in "General oncology"). Broadly, prostate cancer is divided into the following clinical stages. [21][37][38] Localized prostate cancer Tumor confined to the prostate (T1-T2) or tumor with extracapsular extension (T3a) And no evidence of lymph node involvement or metastasis (i.e., N0, M0) Locally advanced prostate cancer [39] Extension to the seminal vesicles (T3b) or adjacent periprostatic tissue (T4) Or regional lymph node involvement (N1) [38] And no evidence of distant metastases (M0) Metastatic prostate cancer Involvement of lymph nodes outside the true pelvis (M1a) Or spread to nonnodal regions (M1b-c) Most common site: bone (M1b), especially the vertebrae Less common sites: lungs, liver, and adrenal glands (M1c) Management Watchful waiting Indications: recommended approach if all of the following apply Limited life expectancy (≤ 5 years) Slow-growing tumor Asymptomatic or minimal symptoms Method Regular monitoring with scheduled DRE and serum PSA levels (less intensive follow-up than active surveillance). Initiate definitive management according to cancer stage only when symptoms occur. Active surveillance Indications Very low-risk and low-risk localized prostate cancers in patients with a life expectancy > 5 years Method Regular monitoring with scheduled DRE, PSA, prostate biopsies, and mpMRI Initiate definitive management according to cancer stage if disease progression is demonstrated. Androgen deprivation Androgen deprivation therapy (ADT) Definition: therapy designed to decrease testosterone production by the testes Indications Locally advanced and metastatic prostate cancer: primary treatment modality Options Medical castration: decreases pituitary stimulation of androgen production by the testes Gonadotropin-releasing hormone (GnRH) agonists (e.g., leuprolide) Gonadotropin-releasing antagonist (e.g., degarelix) GnRH receptor antagonist (e.g., relugolix) Surgical castration: bilateral orchiectomy Adverse effects: increased risk of osteoporosis and fractures Androgen synthesis inhibitors and androgen receptor antagonists Indication: adjunct to ADT in locally advanced and metastatic prostate cancer Androgen synthesis inhibitors Mechanism of action: inhibition of CYP17 gene products (including 17α-hydroxylase and 17,20-lyase) → inhibits androgen synthesis in the adrenal glands, testis, and tumor tissue Commonly used agent: abiraterone Specific adverse effects: Increased production of mineralocorticoids: hypertension, hypokalemia, cardiac arrhythmias Inhibition of glucocorticoid production: adrenal insufficiency Important consideration Glucocorticoids should be coadministered to avoid adrenal insufficiency. Glucocorticoids further increase bone fragility associated with androgen deprivation and aging. Androgen receptor antagonists (antiandrogen therapy) Mechanism of action: displaces androgens from androgen receptors Commonly used agents: apalutamide and enzalutamide (second-generation antiandrogens) Initiate prophylaxis against treatment-induced osteoporosis and fractures in all patients on androgen deprivation and/or glucocorticoids. First-generation antiandrogens (flutamide and bicalutamide) are used only for the short-term management of a testosterone flare. Radiation therapy Indications Localized prostate cancer: primary treatment option Metastatic prostate cancer, high-risk localized prostate cancer, local recurrence following prostatectomy: as an adjunct to androgen deprivation After prostatectomy: adjuvant therapy if adverse features are detected Options: brachytherapy and/or external beam radiation therapy (EBRT) Complications Radiation proctitis, enteritis (e.g., diarrhea), Cystitis, urethritis, and urinary incontinence Erectile dysfunction Increased risk of rectal cancer Radical prostatectomy Indications Localized prostate cancer in patients who are not candidates for active surveillance Following unsuccessful primary radiation therapy (salvage prostatectomy) [47] Technique Removal of the entire prostate gland, including the prostatic capsule, the seminal vesicles, and the vas deferens [21] Pelvic lymph node dissection may be performed during prostatectomy. Important consideration: PSA levels should drop to undetectable levels after a successful prostatectomy. Complications: erectile dysfunction , urinary incontinence , infertility [45] Radical prostatectomy involves the removal of the vas deferens, resulting in infertility. Chemotherapy [33] Indication: Consider as an adjunct to ADT in patients with metastatic prostate cancer. Commonly used agent: docetaxel (a cytotoxic agent) Management of bone health Prostate cancer patients are at an increased risk of skeletal features due to osteoporosis (treatment-induced and age-related) and bone metastases. [33] Supplement calcium and vitamin D. Advice lifestyle modifications (e.g., smoking cessation, weight-bearing exercise). Assess fracture risk: assessment of bone mineral density (e.g., DEXA scan), assessment of 10-year fracture risk (e.g., using tools such as FRAX®) Consider osteoclast inhibitors (e.g., bisphosphonates, denosumab) in patients at high risk of a skeletal-related event. Management of skeletal events Pain due to skeletal metastases: Consider EBRT. Acute skeletal pain: urgent x-rays to assess for pathological fractures New neurological symptoms: urgent MRI spine to identify spinal cord compression (see "Acute back pain" for details) Patients with known vertebral metastatic disease and new neurological symptoms must have an urgent MRI to rule out spinal cord compression. Screening Given the indolent nature of prostate cancer and the significant potential for treatment-related decline in quality of life, patients should be educated on the risks and benefits of participating in screening and undergoing treatment if cancer is detected. For patients with a limited life expectancy, neither screening nor treatment may be appropriate. [21][54] Screening recommendations Recommendations for screening are based on age and life expectancy. Screening is not recommended for patients with a life expectancy < 10 years

Chondrosarcoma

a malignant tumor arising from mesenchymal cells that produce cartilage Etiology Primary chondrosarcoma: unknown Secondary chondrosarcoma: e.g., osteochondroma, Paget disease of bone, radiation Epidemiology [9] Age: usually > 50 years Sex: ♂ > ♀ Localization: most common in the medullary cavity of the pelvis, ribs, proximal femur, and proximal humerus Clinical features Deep, dull pain (worsens at night, insidious progression over months to years) Local swelling Pathological fractures Neurovascular disturbances and/or limited range of motion Diagnostics [10] Conventional X-ray or CT Osteolysis with a moth-eaten appearance Calcifications (rings and arcs calcification, popcorn calcification) Endosteal scalloping and cortical breach with infiltration of soft tissue MRI: rim-like contrast enhancement Biopsy Malignant chondrocytes Lobulated appearance (hyaline cartilage nodules with peripheral calcification ) Grading [11] Grade I: low cellularity, mostly chondroid matrix Grade II: increased cellularity, decreased chondroid matrix with localized myxoid changes Grade III: high cellularity, prominent nuclear atypia, myxoid matrix Treatment Surgery (definitive resection) Chemotherapy and radiation therapy, possibly as adjuvant therapy or as palliative treatment Prognosis [12] Five-year survival rate of 50-85% (depending on the histological grading) Late recurrences are possible. Regular follow-ups for 10 years are required. • Adults • Pelvis, ribs, proximal femur and proximal humerus • Moth-eaten appearance • Endosteal scalloping • Intralesional calcifications • Surgery • 50-60%

Enchondroma

benign tumor arising from hyaline cartilage Epidemiology Most common type of hand tumor Peak incidence: 20-50 years (but may occur at any age) Clinical features Usually found in medulla of the long bones of the hands and feet (most often the metacarpals of the hand and phalanges of the fingers) Often painless Widening of the bone Pathological (spontaneous) fractures Subtypes and variants: enchondromatosis [3] Definition: A predominantly hereditary condition that manifests with multiple enchondromas. Epidemiology: peak incidence between 10 and 20 years Clinical features: often leads to skeletal deformities and stunted growth Prognosis: increased risk of malignant degeneration to chondrosarcoma Treatment Asymptomatic tumors do not require treatment and close monitoring suffices. Symptomatic tumors may require surgical curettage and subsequent bone grafting to prevent pathological fractures.

Chordoma

extremely rare malignancy of the spine and skull Epidemiology: typically develops in patients around 50 years Localization: sacral spine (∼ 50%) and skull base (∼ 35%) [13] Treatment: surgery Diagnostics Imaging General approach Detection and evaluation of possible primary bone tumors [15] Plain radiography (initial test of choice): fast and efficient overview, detection of bone lesions, indication of probable histological type (malignant or benign) CT Beneficial in areas with complex bony structures May be required to evaluate bone stability MRI: assesses the extent of soft tissue and bone marrow involvement Scintigraphy: measures the metabolic activity of bone lesions Detection of metastases: See "Secondary malignancies of the bone (bone metastasis)" below. Radiographic signs of malignant bone tumors [16] Margins of the lesion: The more poorly defined the margins of the lesion are, the more rapid is the tumor growth. [15] Type I: geographic Type II: moth-eaten appearance Type III: permeative Periosteal reactions: reactive periosteal bone synthesis as a result of bone destruction by a malignant process Types of periosteal reactions Continuous periosteal reactions Solid periosteal reaction Increased formation of new bone, with or without cortical destruction Indicates slow tumor growth Lamellated periosteal reaction Multiple layers of new bone (onion skin appearance) Indicates rapid tumor growth Spiculated periosteal reaction Spicules (new bone formations) that grow along Sharpey fibers (collagen fibers that anchor the periosteum to the compact bone) Indicates more aggressive tumor growth compared to the solid and lamellated types Hair-on-end appearance: spicules that extend perpendicular to the bone surface Sunburst appearance: divergent spicules that resemble a sunburst Interrupted periosteal reactions Occur if continuous periosteal reactions are themselves disturbed by tumor growth Indicate the presence of a particularly aggressive malignant process Codman triangle: develops as a result of the destruction and elevation of singular or multiple periosteal lamellae Biopsy Indications Confirmation of radiologic diagnosis Guidance of therapeutic procedures Techniques: open biopsy, needle biopsy (e.g., fine needle aspiration) Laboratory tests White blood count ESR Alkaline phosphatase LDH

Osteosarcoma

malignant, osteoid, and bone-forming tumor arising from mesenchymal stem cells (osteoblasts) located in the periosteum Etiology Primary osteosarcoma: unknown Secondary osteosarcoma: Paget disease of bone, radiation injury, bone infarction Increased incidence in individuals with retinoblastoma and Li-Fraumeni syndrome Epidemiology Incidence: bimodal distribution Primary osteosarcoma: in puberty/adolescence (peak incidence age 10-30 years) Secondary osteosarcoma: advanced age Sex: ♂ > ♀ Most common primary bone malignancy Localization Primary tumor: metaphyses of long bones (particularly distal femur and proximal tibia) Metastases: lungs , skeletal system, regional lymph nodes Clinical features Frequently first manifests with pain (progressive, worsens at night and with activity) Progressive swelling (tissue mass that is tender to palpation and accompanied by erythema) Pathologic fractures Limping, decreased range of motion Possible B symptoms Diagnostics [7] Imaging Conventional x-ray Sunburst appearance of lytic bone lesions and/or Codman triangles Signs of osteolysis adjacent to osteosclerosis (moth-eaten appearance) MRI: assesses the involvement of soft tissue, evaluation in cases of unclear radiographic findings Biopsy Pleomorphic, malignant osteoblasts that produce osteoid Osteosarcomas always feature woven bone matrix (compared to chondrosarcomas and fibrosarcomas) Laboratory ↑ Alkaline phosphatase ↑ LDH ↑ ESR Treatment Surgery (definitive resection) with neoadjuvant and adjuvant polychemotherapy (e.g., a combination of methotrexate, doxorubicin, cisplatin, and ifosfamide) Histological examination of the resected bone to evaluate the effect of neoadjuvant chemotherapy (major prognostic factor) Prognosis Aggressive course Primary osteosarcoma: five-year survival rate of ∼ 70% (usually responsive to treatment) Secondary osteosarcoma: poor prognosis (less responsive to treatment) • Primary: adolescents • Secondary: elderly individuals • Metaphysis of long bones • Sunburst appearance • Codman triangles • Moth-eaten appearance • Surgery • Polychemotherapy • ∼ 70%

Anal cancer

rare tumor. Risk factors include infection with human papillomavirus (HPV), immunodeficiency, and receptive anal intercourse. The most common clinical features are rectal bleeding (up to 45% of cases), pruritus ani, and tenderness or pain in the anal area. Anal cancer presents mainly as squamous cell carcinoma and in rare cases as adenocarcinoma or other non-epidermoid cancers. Depending on the exact localization and stage, it requires excision and/or radiochemotherapy. If the condition is treated in its early stages, the prognosis is favorable. Epidemiology Incidence: ∼ 8,000 cases diagnosed per year in the US [1] More common in HIV-positive individuals and men who have sex with men Etiology Risk factors Immunodeficiency (e.g., HIV) Receptive anal intercourse Smoking HPV infection (esp. types 16 and 18) Clinical features Rectal bleeding (most important initial symptom) A lump or tumor around the anus Pruritus ani Tenderness, pain in the anal area Fecal incontinence History of anorectal condyloma Diagnostics Physical examination Inspection Digital rectal exam Invasive procedures Anoscopy Biopsy for histology (small tumors are fully excised) Staging [2] Endosonography, abdominal CT, pelvic MRI, chest x-ray/CT, PET scan Women with anal cancer should also undergo a gynecologic examination for screening for cervical cancer. Pathology Histology: primarily squamous cell carcinoma; rarely adenocarcinoma or other non-epidermoid cancers Location Above the anal verge: anal canal tumors Below the anal verge: anal margin tumors Treatment Anal canal cancer [3] Treatment of choice: radiochemotherapy Recurrent cancers are treated surgically. Anal margin cancer If possible, local excision with safety margin Advanced tumor (Neoadjuvant) radiochemotherapy Subsequent resection depending on the size of the tumor In some cases, remission may be achieved with radiochemotherapy alone. Complications Metastasis Local invasion of adjacent organs Lymphatic spread (30% of patients): perirectal, paravertebral, inguinal, femoral Hematogenous spread (< 10% of patients): liver, bone, lung [4] We list the most important complications. The selection is not exhaustive. Prognosis Anal cancer of the dentate line: The 5-year survival rate after radiochemotherapy is > 80%. Anal cancer of the anal verge: The prognosis is favorable if complete local excision is possible. The 5-year survival rate after rectal amputation is approx. 50%.

Secondary malignancies of the bone (bone metastasis)

secondary bone tumors due to metastasis (predominantly hematogenous) of primary malignancies of other organs Etiology: primary malignancies (most commonly lung, breast, and prostate cancer, together comprising ∼ 80% of cases) Epidemiology More common than primary bone tumors (∼ 70% of all malignant bone tumors) Bones are the third most common site of metastases, after the lung and the liver. Localization: most commonly spine (∼ 40%) and pelvis (∼ 20%) [19] Classification: based on radiological findings [20] Osteoblastic metastasis New bone formation by osteoblasts outweighs osteolytic processes → increase in radiographic density Examples: prostate cancer, small cell lung cancer Osteolytic metastasis Osteolytic processes outweigh new bone formation → decrease in radiographic density Examples: multiple myeloma, thyroid cancer, kidney cancer, melanoma, non-small cell lung cancer Mixed metastasis: e.g., breast cancer, gastrointestinal cancer Clinical features Often no or few symptoms (incidental finding during routine staging of the primary tumor) Local pain and swelling [19] Pathologic fractures Spinal cord compression , and/or radicular symptoms Diagnostics Approach Imaging is generally only performed in patients with primary malignancies who have clinical signs or laboratory findings (e.g., elevated alkaline phosphatase, hypercalcemia) indicating metastatic bone disease. Biopsy is performed to confirm the diagnosis when imaging is insufficient or the patient has no known history of cancer. Laboratory Elevated serum calcium Radiographic imaging [20] Choice of imaging studies depends on: The location of the suspected lesion and the clinical presentation The most likely underlying primary tumor For suspected spinal lesions: Contrast-enhanced MRI (first-line modality ): used to detect tumor extension and possible spinal cord compression CT may be performed to assess vertebral bone integrity. For suspected extremity lesions: Conventional X-ray (initial test) Followed by CT or MRI if a pathological fracture is identified or suspected for operative planning [21] Whole-body skeletal imaging: indicated if a metastatic lesion is identified to detect additional, asymptomatic sites of metastasis Bone scintigraphy (bone scan): most commonly used test to detect metastases within the entire skeleton and indicate biological activity of lesions (osteoblastic, osteolytic) PET scan: useful to detect metastases and for staging, particularly for bone metastases from breast and lung cancer X-ray skeletal survey: primarily used for purely lytic metastatic bone disease (particularly multiple myeloma) Whole-body MRI or CT are less sensitive than bone scintigraphy or PET/CT. Biopsy Preferably taken from a soft tissue mass at the afflicted site, otherwise from an accessible bone where biopsy does not cause lasting impairment of motility or stability In the case of an isolated lesion, it should be presumed to be a primary tumor unless proven otherwise. Treatment The choice of treatment generally depends on the underlying primary malignancy and stage of the disease. [22] Pain management Systemic therapy Chemotherapy Osteoclast inhibitors (e.g., bisphosphonates): inhibit bone resorption Localized tumor radiation Surgery If pathologic fractures have occurred or are likely: stabilize and restore function If spinal instability or spinal cord compression has occurred or is likely: immediate decompression and stabilization

Torus palatinus

• Benign bony overgrowth of the hard palate • Peak incidence: young adults • Roof of the mouth (midline hard palate) • Usually asymptomatic and requires no treatment • If it interferes with speech or eating, surgery is an option.

Osteochondroma (cartilaginous exostosis)

• Bony exostosis with cartilage cap • Peak incidence: 10-30 years • Sex: ♂ > ♀ • Metaphysis of long bones • Most common primary benign bone tumor • Usually asymptomatic, but can be painful and palpable near the ends of long bones • X-ray: pediculated or sessile mass • Disease variant: hereditary multiple exostoses (malignant degeneration may occur) • Transformation into chondrosarcoma is rare Bony outgrowth (exostosis) with a cartilaginous cap on the surface of long bones adjacent to growth plates Contains a marrow space that is continuous with the underlying bone Epidemiology Most common primary benign bone tumor Peak incidence: 10-30 years [2] Sex: ♂ > ♀ Clinical features Typically located in metaphysis of long bones Usually asymptomatic, but can be painful and palpable near the ends of long bones Subtypes and variants: hereditary multiple exostoses Definition: autosomal dominant disorder with multiple exostoses Malignant degeneration to chondrosarcoma may occur (∼ 5% of cases). Diagnostics: x-ray shows pedunculated or sessile lesion on the surface of the metaphysis of long bones Treatment: excision of tumor in symptomatic cases Complications: Approx. 1% transform into chondrosarcoma.

Synovial chondromatosis

• Enchondral formation of cartilage as a result of metaplasia of synovial tissue • Peak incidence: 20-40 years • Most commonly the knee joint • Pain, effusion, knee locking • Radiographically visible loose bodies • Malignant degeneration to synovial chondrosarcoma in extremely rare cases cartilage formation as a result of metaplasia of the synovial tissue Epidemiology: peak incidence between 20 and 40 years Clinical features Most commonly located in the knees Pain, effusion, reduced range of motion, knee locking Diagnostics: x-ray shows radiographically visible (calcified) loose bodies Treatment: removal of loose bodies and synovial tissue Prognosis: extremely low risk of malignant degeneration to synovial chondrosarcoma

Ossifying fibroma (osteofibrous dysplasia)

• Fibrous bone tumor • Peak incidence: 1-5 years • Tibia and fibula • Localized swelling • Tibial bowing • Pathological fractures may occur. • X-ray: intracortical, osteolytic lesions with interspersed sclerosis fibrous benign bone tumor Epidemiology: peak incidence between 1 and 5 years Clinical features Most commonly found in tibia and fibula Localized swelling Tibial bowing Diagnostics: X-ray shows intracortical, osteolytic lesions with interspersed sclerosis. Treatment If asymptomatic, monitoring is sufficient. If symptomatic, surgical removal is preferred.

Nonossifying fibroma

• Fibrous growth in areas that normally ossify • Peak incidence: 10-20 years • Metaphyseal; very common in the distal femur and distal tibia • Usually an incidental finding • X-ray ◦ Marginal sclerosis ◦ Lobulated structures with translucent components growth of fibrous connective tissue into areas that normally ossify; a tumor-like lesion that is considered to be a nonneoplastic disorder of bone growth, rather than a true neoplasm Epidemiology: peak incidence between 10 and 20 years Clinical features Usually metaphyseal (predominantly in the distal femur and distal tibia) asymptomatic; usually an incidental finding [7][8] Diagnostics: x-ray Marginal sclerosis Lobulated structure with translucent components Treatment Usually self-limiting Bone grafting may be required for painful lesions or to prevent pathological fractures.

Langerhans cell histiocytosis

• Lytic lesion consisting of Langerhans and immune cells • Peak incidence: 5-10 years • Most commonly in the skull • Painful swelling • Pathologic fracture • X-ray: osteolytic lesions with or without marginal sclerosis • Typically, solitary lesions • May manifest with rash and recurrent otitis media with mastoid swelling • Lesions near the sphenoid, orbital, ethmoid, or temporal bones require treatment with vinblastine and prednisone. a rare disorder caused by clonal proliferation of Langerhans cells (antigen-presenting cells) [11] Epidemiology: peak incidence between 5 and 10 years Clinical features Osseous lesions (90%): pain and/or swelling, pathological fractures Localization: skull (most common site), femur, vertebra, mandible, ilium, ribs Can cause recurrent otitis media if the mastoid bone is involved Unifocal or multifocal Systemic manifestations (less common) Skin rash: brown to purple papules and/or eczematous rash Hepatomegaly and/or splenomegaly Lymphadenopathy Bone marrow infiltration Hypopituitarism that typically manifests as central diabetes insipidus Exanthema Diagnostics X-ray: osteolytic lesions with or without marginal sclerosis Normal calcium levels Biopsy (confirmatory test): proliferation of Langerhans cells (polygonal cells with coffee bean-shaped nuclei and eosinophilic cytoplasm) [12][13] Electron microscopy: Birbeck granules (tennis racket-shaped or rod-like structures) in the cytoplasm Immunohistochemistry: cells are positive for S100, CD1a, and/or CD207 Treatment Solitary bone lesions in low-risk anatomical regions Asymptomatic lesion: a wait-and-watch approach may be appropriate Symptomatic lesion: curettage and/or excision (as a part of biopsy) Bone lesions in high-risk anatomical regions (e.g., lesions involving the odontoid process or regions of the skull other than the vault), multifocal bone involvement, or systemic manifestation: vinblastine and prednisone

Aneurysmal bone cyst

• Mostly septated, blood-filled cysts • Peak incidence: 10-20 years • May affect any bone • Most common localizations: spine and metaphysis of the long bones • Predominantly affects the lower extremities • Local pain and swelling may occur. • X-ray: osteolytic lesion with definite margins; usually located in the metaphysis • MRI: multichambered lesion with fluid-fluid levels • High risk of recurrence Description Osteolytic lesions; usually septated, blood-filled cysts Idiopathic (primary aneurysmal bone cyst) or secondary to malignant or other benign bone diseases (secondary aneurysmal bone cyst) Epidemiology: peak incidence between 10 and 20 years Clinical features Common sites are the spine and the metaphysis of the femur and tibia. Usually asymptomatic; local pain and swelling may occur Pathological fracture: often the first sign Diagnostics X-ray: metaphyseal, osteolytic lesion with sclerotic margins MRI : septated, blood-filled lesions, with typical fluid-fluid levels. Treatment: surgical curettage and bone grafting Prognosis: high risk of recurrence

Fibrous dysplasia

• Normal skeletal tissue is replaced by fibrous tissue • Peak incidence: adolescence • Monostotic fibrous dysplasia: long bones, facial bones (∼ 70% of cases) • Often asymptomatic; may cause bone pain • X-ray ◦ Long bones: well-defined, lobulated lytic lesions with a thin cortex and a radiolucent, ground-glass appearance ◦ Facial bones: radiodense lesions with a leonine appearance Fibrous dysplasia is a benign, developmental disorder of bone that causes normal skeletal tissue to be replaced by fibrous tissue. Epidemiology Fibrous dysplasia accounts for approx. 5% of benign bone lesions Age of onset: most commonly presents during adolescence Sex: ♂ = ♀ Etiology: post-zygotically acquired, somatic, gain-of-function mutation in GNAS1 gene on chromosome 20q Pathophysiology GNAS1 codes for the α subunit of the Gs protein (Gsα). Mutation → constitutive activation of certain Gs-cAMP coupled pathways → inhibition of mesenchymal differentiation into osteoblasts → lack of osteocytes → skeletal lesions composed largely of mesenchymal cells → weak, imperfect bone with fibrous tissue Clinical features Disease phenotype Monostotic fibrous dysplasia (∼ 70% of cases) Polyostotic fibrous dysplasia (∼ 25% of cases) Common to all disease phenotypes Bone pain, bone deformities, and/or pathological fractures Entrapment neuropathies may occur as a result of expanding bone lesions Age at manifestation Monostotic fibrous dysplasia: 20-30 years Polyostotic fibrous dysplasia: < 10 years Diagnostics Laboratory tests ↑ Alkaline phosphatase (occasionally) Normal calcium, PTH, and 1,25-dihydroxyvitamin D levels Imaging: x-ray Long bones: well-defined, lobulated lesions with a thin cortex and a radiolucent, ground-glass appearance Facial bones: radiodense lesions with a leonine appearance Pathology: bone biopsy Therapy Bisphosphonates Management of precocious puberty: See "Peripheral precocious puberty." Prognosis The lesions do not heal spontaneously. Osteosarcomas occur in < 1% of cases. Syndromes associated with polyostotic fibrous dysplasia McCune-Albright syndrome Polyostotic fibrous dysplasia Café au lait spots with unilateral, ragged edges Most commonly peripheral precocious puberty Mazabraud syndrome Polyostotic fibrous dysplasia Intramuscular myxomas Jaffe-Lichtenstein syndrome Café au lait spots Polyostotic fibrous dysplasia

Osteoblastoma

• Predominantly cortical tumor larger than osteoid osteoma • Peak incidence: 10-20 years • Sex: ♂ > ♀ • Vertebrae (predominantly posterior column) • Severe chronic pain (not nocturnal) that is unresponsive to NSAIDs • X-ray: central lucent nidus with mild or absent perifocal sclerosis predominantly cortical tumor larger than osteoid osteoma (> 2 cm) Epidemiology Peak incidence: 10-20 years Sex: ♂ > ♀ Clinical features Typically involves the posterior elements of the vertebrae (vertebral arch) Severe chronic local pain (no nocturnal pain) that does not respond to NSAIDs Neurologic symptoms if the spinal cord is compressed Diagnostics: x-ray Shows tumor located in the cortical bone Central lucent nidus with mild or absent perifocal sclerosis Treatment Unresponsive to NSAIDs Surgical curettage and bone grafting preferred

Osteoid osteoma

• Small, predominantly cortical tumor (< 2 cm) • Peak incidence: 4-25 years • Sex: ♂ > ♀ • Metaphysis and diaphysis of long bones • Vertebrae • Severe nocturnal bone pain • Pain responds to NSAIDs • X-ray: radiolucent core (osteoid), surrounded by perifocal sclerosis • Surgery is necessary if pain becomes unresponsive to medication. Description Small tumor (< 2 cm) Predominantly located in the cortex of long bones Epidemiology Peak incidence: 4-25 years [5] Sex: ♂ > ♀ Clinical features Located in metaphysis and diaphysis of long bones (predominantly the proximal femur, tibia, and humerus) and vertebrae Constant, intense pain that worsens at night Pain is responsive to NSAIDs (e.g., ibuprofen, aspirin) Diagnostics X-ray or CT: radiolucent core (osteoid), surrounded by perifocal sclerosis (nidus) Scintigraphy: usually intense enhancement Double-density sign Intraoperative nuclear imaging using a probe to detect the tumor Treatment: NSAIDs or surgical removal if pain is unresponsive to medical treatment

Unicameral bone cyst

• Solitary, generally single-chambered bone cysts • Peak incidence: 5-15 years • Metaphysis of the long bones (predominantly the proximal humerus and proximal femur) • Pathological fractures • X-ray: osteolytic bone lesion with sharp margins and no sclerosis in the metaphysis of long bones • Aspiration and corticosteroid injection for larger lesions • Fallen fragment sign: characteristic radiological finding in which a bone fracture fragment appears within the cavity of a bone cyst solitary, single-chambered cyst Epidemiology: peak incidence between 5 and 15 years Clinical features Found in metaphysis of the long bones (predominantly the proximal humerus and proximal femur) Usually asymptomatic Pathological fractures Diagnostics X-ray: osteolytic bone lesion with sharp margins and no sclerosis in the metaphysis of long bones MRI: single-chambered, fluid-filled lesion Treatment: monitoring or aspiration and corticosteroid injection for larger lesions

Giant-cell tumour (osteoclastoma)

• Tumor arising from giant cells of the bone marrow • Peak incidence: 20-40 years • Epiphysis of long bones (usually around the knee) • Local pain and swelling • Pathological fractures • X-ray: multicystic osteolytic lesions (soap-bubble appearance) • Histopathology: multinucleated giant cells and mononuclear, RANKL-expressing cells • Locally aggressive tumor • Risk of malignant degeneration increases with age. benign but locally aggressive tumor composed of giant cells that arise from the bone marrow [1] Epidemiology: peak incidence between 20 and 40 years Clinical features Found in the epiphysis or metaphysis of long bones (especially knee region) Pathological fractures Local pain and swelling Limited range of motion Diagnostics X-ray: multicystic osteolytic lesions (soap-bubble appearance) Histopathology Mononuclear, RANKL-expressing cells (neoplastic) Multinucleated giant cells (are reactive and resemble osteoclasts) Treatment: curettage and bone grafting or en-bloc resection to minimize recurrence rate Prognosis: risk of malignant degeneration increases with age; may spread to the lungs

(Distal) enchondroma

• Tumor arising from hyaline cartilage • Peak incidence: 20-50 years • Medulla of the long bones of the hand • Usually asymptomatic • Possibly, local widening or pathological fractures • Variants: enchondromatosis ◦ Predominantly hereditary; multiple enchondromas ◦ Peak incidence: 10-20 years ◦ Often leads to skeletal deformities and stunted growth ◦ Increased risk of malignant degeneration into chondrosarcoma

Intraosseous hemangioma

• Vascular neoplasm • Peak incidence: 30-50 years • Most common benign tumor of the spine • Particularly involves the thoracic and lumbar vertebrae • Possible complications: compression fractures, spinal stenosis, bleeding resulting in spinal epidural hematoma • X-ray ◦ Vertically streaked vertebrae; ◦ Honeycomb appearance of lesions with definite margins vascular neoplasm [10] Epidemiology Peak incidence: 30-50 years Sex: ♂ < ♀ (1:2) Clinical features Most common benign tumor of the spine, particularly in the thoracic and lumbar vertebrae Usually asymptomatic; often an incidental finding Diagnostics: x-ray Vertical streaks visible in vertebrae Honeycomb appearance of lesion with sharp margins Treatment: usually no treatment required Complications Compression fractures Spinal stenosis Bleeding with subsequent spinal epidural hematoma

Chondroblastoma

• Very rare cartilage tumor • Peak incidence: 10-20 years • Epiphysis of the long bones • Joint pain and swelling benign cartilage tumor Epidemiology Very rare Peak incidence: 10-20 years Clinical features Located in epiphysis of long bones Joint pain (constant) and swelling Treatment: surgical curettage and bone grafting

Osteoma

• Well-defined solitary tumor, usually with a diameter < 1 cm that arises from osteoblasts • Peak incidence: middle age • Facial bones and cranial bones, especially paranasal sinuses • Long bones • Usually asymptomatic • A nasal sinus osteoma may result in obstruction of the ostium, with subsequent congestion and pressure headaches. • Associated with Gardner syndrome benign round bone tumor Epidemiology: most common in middle-aged individuals but may develop at any age Etiology: associated with Gardner syndrome Clinical features Usually affects facial bones and cranial bones (most commonly affects paranasal sinuses) In rare cases, long bones Often asymptomatic An osteoma of the paranasal sinus may lead to obstruction of the ostium, with subsequent congestion and pressure headaches. Associated with Gardner syndrome: extracolonic manifestation of familial adenomatous polyposis (FAP) that includes osteomas of the skull or mandible, hypertrophy of the retinal pigment epithelium, adrenal adenomas, desmoid tumors, dental abnormalities, and cutaneous lesions Treatment: Surgical removal may be required if expansive tumor growth leads to symptoms.