Clinicopathological Conference

1. Clinicopathological Conference Nadia Nasreen, PGY 3 Resident UIUC IMRP

2. Chief Complaint • Chest pressure for one month progressively worsened for 2 days • Weakness for 4 days • Non-productive cough for 1 week

3. History of Presenting Illness • A 64y old Caucasian female with past medical history of hypertension and CAD went to outside hospital with chest pressure which has been going on for one month with worsening for 2 days. Pain was in middle of the chest, retrosternal, 4/10, no radiation or shift, no aggravating or relieving factors, associated with non-productive cough for last 1 week. • Negative for hemoptysis and weight loss.

4. Past Medical and Surgical History • Hyperlipidemia, CAD, Hypertension • Appendectomy, Tonsillectomy, Nasal surgery • Medications • ASA, Atenolol, Allegra • Social History • 12 pack years, quit at 28yrs of age • Worked as spray painter in a boat manufacturing industry • No alcohol or drug use • FAMILY HX: • No hx of diabetes mellitus, pre-mature heart disease or cancers .

5. Physical Exam • Temp: 97.9 F, Pulse : 81/min, Resp: 18/min , BP: 118/69, SpO2 : 99% on 2L • GEN: AO x 3, no distress • HEENT : Non-contributory • NECK: No JVD, No lymph-adenopathy • Chest: Non tender on palpation, clear on auscultation B/L • Heart : Normal heart sounds, No murmurs heard • Abdomen: Soft, non-tender, no organomegaly,BS+ • Extremities: No edema, DP + • Neuro: Non-focal exam • Skin: No rashes , echymosis or purpura

6. Labs

7. Labs

8. Summary • 64 y/o caucasian female with PMH of HTN, CAD, presented with 1 month H/O retrosternal, non radiating 4/10, chest pressure, progressively worsening for last 2 days, weakness for 4 days, nonproductive cough for 1 week with no hemoptysis or weight loss. Remote H/O smoking , quit 36 years back and worked as a boat painter. • Lab- significant only for Mild normocytic anemia.

9. Additional History Required • Comprehensive review of systems- Fever or chill, night sweat, anorexia. • Any Associated SOB, dysphagia, odynophagia , hoarseness • Pain with deep breathing or coughing • Description of weakness- Focal or generalized, vs any UE s/s- numbness/paresthesia • Axillary, inguinal supraclavicular lymph node examination • Any Breast examination for lump/mass • Lateral CXR to evaluate the mediastinal location.

10. Imaging

11. Lung vsMediastinal Mass • The following characteristics indicate that a lesion originates within the mediastinum: • Mediastinalmass will not contain air bronchograms. • Mediastinallines (azygoesophageal recess, anterior and posterior junction lines) will be disrupted. • There can be associated spinal, costal or sternal abnormalities. • A lung mass abutts the mediastinal surface and creates acute angles with the lung, while a mediastinal mass will sit under the surface creating obtuse angles with the lung

16. Imaging

17. Imaging

18. Differential Diagnoses • Bronchogenic Carcinoma • Primary Lung cancer NSCLC vs SCLC • Metastatic neoplasms to Lungs • Sarcomatoid carcinoma • Lymphoproliferative disorders • NHL • Hodgkins lymphoma • Primary mediastinal large B cell Lymphoma • Primary Pulmonary Lymphoma • Extramedullaryplasmacytoma (primary pulmonary plasmacytoma) • Lymphomatoidgranulomatosis • Postobstructive pneumonia • Viral or bacterial pneumonia • Atypical/ Chronic Infections- • Pulmonary TB • Fungal – • Histoplasmosis • Aspergillosis, • Blastomycosis • Cryptococcal • coccidioidimycosis • Bronchial Carcinoid • Sarcoidosis • Collagen vascular disease- GPA( Wegners), SLE, RA • Asbestos associated Lung disease • Mediastinal involvement( Mainly posterior) • Esophageal Carcinoma • Neurogenic tumors- Schwannomas, meningocele, paraspinalGanglioneuroma

19. Bronchogenic Carcinoma • Lung cancer is the leading cause of cancer death in the United States, accounting for approximately 29% of all cancer deaths. • lung cancer is the second most common cancer in man and women • During 2008, approximately 213,380 new cases of lung cancer were diagnosed (114,760 among men and 98,620 among women).

20. Epidemiology • Age Distribution-predominately in persons aged 50-70 years. • Nearly 70% of patients are older than 65 years and fewer than 3% are younger than 45 years. • Sex- In the United States, the probability of developing lung cancer remains equal in both sexes until age 39 years It then starts to increase among men compared with women, reaching a maximum in those older than 70 years. • Prevalence-incidence rates are similar among African American and white women. • Approximately 45% higher among African American men than among white men • Current 5-year survival rates are estimated to be 16% among whites and 13% among non-whites

21. Etiology • Causes: • Smoking (90% of all Lung cancers)- • The risk of developing lung cancer for a current smoker of 1 ppd for 40 years is approximately 20 times that of someone who has never smoked. • Risk declines slowly after smoking cessation. The relative risk remains high in the first 10 years after cessation and gradually declines to 2-fold approximately 30 years after cessation. • Asbestos exposure- risk of Lung cancer is 5 times. Synergistic with smoking- 80-90 times greater risk than control population

22. Environmental toxins • - Radon , halogen , ether, arsenic atmospheric pollution • Chromium, nickel , Vinyl chloride • Radiation therapy —increase the risk of a second primary lung cancer in patients who have been treated for other malignancies. • Pulmonary fibrosis —The risk for lung cancer is increased about sevenfold patients with pulmonary fibrosis, Independent of Smoking • HIV infection — The incidence among individuals infected with HIV appears to be increased compared to that seen in uninfected controls • Genetic Exposure-. The ras gene mutations occur almost exclusively in adenocarcinoma and are found in 30% of such cases. • mutations in c-myc and c-raf among oncogenes and retinoblastoma (Rb) and p53 among tumor suppressor gene are found in NSCLC include

23. Classification Lung Cancer Small Cell Lung cancer- 10%-15%of Lung cancers Non-small Cell Cancer- 85%-90% of Lung cancers • Adenocarcinoma((including bronchioloalveolar carcinoma) — 38 percent • Squamous cell carcinoma — 20 percent • Large Cell Carcinoma - 5% • Other non-small cell carcinomas - • cannot be further classified (18 percent) • Others- Sarcomatoid, NE tumors- 6%

24. Adenocarcinoma • Adenocarcinoma, arising from the bronchial mucosal glands • The most frequent NSCLC in the United States, -35-40% of all lung cancers. • It usually occurs in a peripheral location within the lung. • Adenocarcinoma is the most common histologic subtype, and may manifest as a “scar carcinoma.” most commonly in persons who do not smoke. This type may manifest as multifocal tumors in a bronchoalveolar form. • Significant variation in architecture of neoplastic gland formation. • Variant Subtypes: - Acinar - Papillary - Bronchiloalveolar Carcinoma - Solid Adenocarcinoma with mucin production

25. Bronchiloalveolar Carcinoma • Bronchoalveolar carcinoma is a distinct subtype of adenocarcinoma with a classic manifestation as an interstitial lung disease on chest radiograph. • Bronchoalveolar carcinoma arises from type II pneumocytes and grows along alveolar septa. This subtype may manifest as a solitary peripheral nodule, multifocal disease, or a rapidly progressing pneumonic form. A characteristic finding in persons with advanced disease is voluminous watery sputum. • In the new classification scheme, these tumors have been renamed as adenocarcinoma in situ • has a propensity for intrapulmonary metastases and a more indolent course

26. Squamous Cell Carcinoma • 25-30% of all lung cancers. • Tends to occur centrally, with endobronchial lesions • Histologically : presence of keratin pearls detected with cytologic studies and has a tendency to exfoliate. It is the type most often associated with hypercalcemia. • Historically, most squamous cell carcinoma (60 to 80 percent) arose in the proximal portions of the tracheobronchial tree • A minority of cases occur peripherally and may be associated with bronchiectatic cavities or scars.Central and peripheral squamous cell carcinomas may show extensive central necrosis with resulting cavitation • The classic manifestation is a cavitary lesion in a proximal bronchus.

27. Large Cell Undifferentiated Carcinoma • only 10% of lung cancers. • Typically manifest as a large peripheral mass on chest radiograph • Histologically, this type has sheets of highly atypical cells with focal necrosis, with no evidence of keratinization (typical of SCC) or gland formation (typical of adenocarcinomas). • LCC is a diagnosis of exclusion intended to include all poorly differentiated NSCLCs that are not further classifiable by routine light microscopy.

28. Sarcomatoid Carcinoma • Represents a heterogeneous group of NSCLCs that contain a component of sarcoma or sarcoma-like elements: • Pleomorphic carcinoma • Spindle cell carcinoma • Giant cell carcinoma • Carcinosarcoma —defined by the presence of a typical carcinoma combined with sarcomatous elements (bone, cartilage or skeletal muscle). Typical sarcomatous components include rhabdomyosarcoma, osteosarcoma, and chondrosarcoma. • Pulmonary blastoma —biphasic malignancies that have an adenocarcinoma component that has the appearance of fetal adenocarcinoma and a stroma that resembles that seen in Wilms tumor. They are usually large at the time of presentation and are highly malignant

29. Pulmonary Neuroendocrine Tumors • Small cell carcinoma • large cell neuroendocrine carcinoma • Typical carcinoid, and atypical carcinoid • DIPNH- diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, a possibly preinvasive epithelial lesion • Typical and atypical carcinoids - similar to carcinoid lesions arising at other sites. • Small cell carcinomas and large cell neuroendocrine carcinomas more aggressive course and pathologically by a much higher mitotic activities.

30. Small Cell Lung Cancer • Small cell lung carcinoma (SCLC) accounts for approximately 15 percent of all bronchogenic carcinomas. • SCLC shows a strong correlation(>95%) with cigarette smoking and is extremely rare in persons who have never smoked. • SCLC is usually more aggressive than NSCLC . • Presents as a central lesion with hilar and mediastinal invasion along with regional adenopathy. • 65-70% of patients with SCLC have disseminated or extensive disease at presentation • The most common sites of metastasis of lung cancer are the bones, liver, adrenal glands, pericardium, brain, and spinal cord. • production of various peptide hormones leads to a wide range of paraneoplastic syndromes

31. Clinical presentations

32. Paraneoplastic Syndromes from lung cancers: • Hypercalcemia- Squamous cell carcinoma • Trousseau syndrome- Adenocarcinoma • Hypertrophic pulmonary osteoarthropathy- NSCLC • Clubbing – all types.

33. Paraneoplastic Syndromes Of SCLC

34. Diagnostic Imaging • CXR- may show the following: • Pulmonary nodule, mass, or infiltrate • Mediastinal widening • Atelectasis • Hilar enlargement • Pleural effusion • CT Scan -mediastinal lymphadenopathy. CT had a pooled sensitivity of 57%, a specificity of 82%, and a negative predictive value of 83%. • PET FDG- pooled sensitivity of 84% and a specificity of 89%, with a PPV of 79% and a NPV of 93%. • Combined positive predictive value and negative predictive value of CT scanning and PET-FDG were 83% to 93% and 88% to 95%, respectively. • PET-FDG is superior to CT scanning in the staging of disease in patients with mediastinal lymph node involvement.

35. Staging of SCLC • TNM system is generally not used in these patients. • The Veterans Administration Lung Study Group staging system is typically used, : as limited or extensive. • Limited-stage disease -limited to one hemithorax, with hilar and mediastinal lymphadenopathy that can be encompassed within one tolerable radiotherapy portal. • Extensive-stage disease consists of any disease that exceeds those boundaries. Most patients (60% to 70%) with SCLC present with clinically extensive-stage disease. significant differences in median and 5-year survival among these patients depending on the stages. Combination chemotherapy is the cornerstone of treatment for both limited-stage and extensive-stage SCLC.

36. Metastatic Neoplasm to Lungs • Approximately 10-30% of all malignant nodules resected from the lung are metastatic • Frequent sources of malignancy: • Head and neck • Colon • Kidney • Breast • Thyroid gland • Melanoma • In addition to solitary or multiple nodules, metastases of carcinoma to the lung include lymphangiitic, endobronchial, pleural, and embolic patterns. • Most common Clinical situation: multiple or innumerable nodules.

37. Lymphomatous proliferation involving Lungs • 3 different ways: • Haematogenousdissemination of Non-Hodgkinslymphoma (NHL) or Hodgkins disease • Contiguous invasion from a hilaror mediastinalsite of nodal lymphoma • Primary pulmonary involvement.

38. Non-Hodgkins Lymphoma • Epidemiology- Approximately 56,000 new cases (NHL) are diagnosed in the United States annually, with approximately 24,000 people dying from this disease each year. • The incidence of NHL increases exponentially with age and is greater in men than women and in whites than blacks. • Risk Factors: • Autoimmune disease and immunodeficiency states have a known association with NHL. • NHL may also be caused by viruses – EBV- Burkitts lymphoma, HTLV-1- Adult T cell leukemia- lymphoma, HHV-8- Body cavity lymphoma • Several chemicals, such as organochlorine agents (for example, DDT), have been weakly associated with an increased risk for NHL. • Farming - consistently shows an association with an increased risk for NHL, which is often thought to be related to the use of pesticides

39. WHO Classification Of Lymphoid Malignancy Lymphoid Neoplasms B cell neoplasms T- cell and NK -cell neoplasms Hodgkins Lymphoma Classification Criteria: Morphology Clinical features Genetic features Immunophenotype

40. 80%-85% of NHL in adults are B-cell in origin • Remainder – mostly T cell in origin • B cell Lymphomas- based on biology and natural history: • Indolent vs Aggressive vs Highly aggressive Groups

41. Clinical presentations • Aggressive NHLs - • acutely or subacutely with a rapidly growing mass, systemic B symptoms (ie, fever, night sweats, weight loss), and/or elevated levels of serum LDH and uric acid • 50% present with secondary extranodal disease, 10%-35% Primary extranodal lymphoma • - Most common EN site- GI tract then skin. Others – Testis, Bone, Kidney • potentially are curable with combination chemotherapy. • Indolent lymphomas • Are often insidious, presenting only with slow growing lymphadenopathy, hepatomegaly, splenomegaly, or cytopenias.. • Mostly present at advanced stage, incurable • Median survival 7-10years.

42. Chest and Lung NHL • Approximately 20 percent of patients with NHL present with mediastinaladenopathy on clinical examination or chest radiograph • Primary mediastinal large B cell lymphoma or part of diffuse Systemic disease • Cough, chest discomfort, or asymptomatic with abnormal CXR • 3%-8%- SVC syndrome • Other - include pleural and, less commonly, pericardial effusions. Chylothorax, alone or in combination with chylopericardium or chylousascites • Pleural disease is seen in up to 10 percent of all patients with NHL at diagnosis.

43. PA (upper panel) and lateral (lower panel) radiographs of a patient with a large right-sided mediastinal mass (arrows). The biopsy was consistent with diffuse large B-cell non-Hodgkin's lymphoma.

44. CT scan of Chest in NHL • Typical radiographic findings include alveolar opacities (consolidation, masses, or nodules) and peribronchialdisease. • parenchymal lung lesions can be seen with no evidence of mediastinal or hilar lymphadenopathy. Diagnosis: NCCN recommends- An excisional biopsy of an intact node - histologic, immunologic, and molecular biologic assessment Including flow cytometry and fluorescent in-situ hybridization or cytogenetics. Staging- CT chest abdomen, pelvis, PET scan, CBC, CMP, LDH, , Uric acid, BM Bx, Lumber puncture, Echocardiogram, NM scan

45. Diffuse Large B Cell Lymphoma • Most common Lymphoid malignancy. 25% of NHL • Caucasian Americans having higher rates than Blacks, Asians, and American Indian or Alaska Natives • male predominance ;approximately 55 percent of cases in men • Median age at presentation is 64 years. Younger for Blacks. • Typically presents as rapidly enlarging symptomatic mass, nodal enlargement- usually neck and abdomen • B-symptoms- 30% • BM – 30%, Extramedullary- 40% • tumors derived from germinal center B cells or post-germinal center B cells (also called activated B cells) • majority of DLBCL tumors demonstrate translocations or mutations that result in the increased expression of the B cell lymphoma 6 (BCL-6) gene.

47. Hodgkins Lymphoma • Arises from germinal or post-germinal center B cells. • Incidence- approximately 10 percent of all lymphomas in economically advanced countries. • Age and sex- Bimodal distribution- 1 peak in young adults (age 20 years) and one in older age (age 65 years); the majority of patients are young adults; male predominance • Based on the appearance and immunophenotype of the tumor cells: • Nodular lymphocyte predominant HL (NLPHL) • Classical HL • Classic HL is usually diagnosed by lymph node biopsy. • On light microscopy, the tumor contains a minority of neoplastic cells (Reed-Sternberg cells and their variants) in an inflammatory background. • The neoplastic cells typically express CD15 and CD30, variably express CD20, and do not express CD3 or CD45

48. Classical HL is further divided into the following four subtypes: • Nodular sclerosis classical HL • Mixed cellularity classical HL • Lymphocyte rich classical HL • Lymphocyte depleted classical HL • Clinical presentations include • Nontender lymphadenopathy in the neck or mediastinum • Incidental finding of a mediastinal mass on routine chest x-ray • Systemic symptoms - in less than 20 percent of stage I/II Hodgkin lymphoma • up to 50 percent of patients with more advanced disease. • Nonspecific symptoms- retroperitoneal LAD, cholestatic liver disease, alcohol-induced pain, skin lesions, neurologic symptoms, nephrotic syndrome, hypercalcemia, and abnormalities in blood counts. • Spread- via lymphatic channels before disseminating to distant nonadjacent sites and organs. • It is uncommon to have pulmonary disease at presentation without Hodgkin lymphoma being present within the hilar lymph nodes, usually on the ipsilateral side

49. Primary Pulmonary Lymphoma (PPL) • clonal lymphoid proliferation affecting one or both lungs (parenchyma and/or bronchi) in a patient with no detectable extrapulmonary involvement at diagnosisor during the subsequent 3 months • PPL is very rare; 0.5–1% of primary pulmonary malignancies, <1% of NHL • The current definition of PPL covers: • 1) lowgrade B-cell PPL (PPL-B), the most frequent form • 2) high-grade PPL-B • 3) lymphomatoidgranulomatosis(LG), a rare disorder.