Clinicopathological ConferenceNadia Nasreen, PGY 3 Resident

UIUC IMRP

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

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.

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 .

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

Labs

Na 134 K 4

Cl 100 HCO3 24

BUN 9 Creatinine 0.7

Glucose 171 Ca 8.9

Total Bili 0.4 AST 20

ALT 17 Alk Phos 86

Total protein 8 ALB 4.6

LabsWBC 10.8 Hgb 11.9Hct 35.3 MCV 87.2

MCH 29.5 MCHC 33.8

RDW 14.9 Plt Count 188

Neut % 84.5 LYMPH % 9.9

Mono % 5.6 Eos % 0

Baso % 0

PT 10.6 INR 1

PTT 24.6

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.

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.

Imaging

Lung vs Mediastinal Mass

• The following characteristics indicate that a lesion originates within the mediastinum:

• Mediastinal mass will not contain air bronchograms.

• Mediastinal lines (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

Anterior Mediastinum Middle Mediastinum Posterior mediastinum

Structures included

Upper esophagus, trachea, thymus, aortic arch, and lymphatic vessels.

pericardium/heart, distal trachea, main bronchi, and lymph nodes

esophagus, descending aorta, sympathetic ganglia, and peripheral nerves.

Most common lesions/Masses

5Ts Thymoma/T carcinoma Thyroid or parathyroid

tumors Hodgkins disease orTcell

Lymphoma Teratoma( or G cell

tumors)

Metastatic LAD lymphoma, granulomatous disease

(sarcoidosis, fungal infections, pulmonary TB), Giant lymph node hyperplasia (Castleman disease

pericardial or bronchogenic cysts, vascular masses and enlargements, and diaphragmatic hernias.

Esophageal lesions: include leiomyomas, fibromas lipomas, Carcinoma

Neural tumors include neurofibroma and neurilemmoma (schwannoma).

Duplication cyst

Hiatus hernia

> 1 compartment

Infections, HemorrhageLung cancersHemangioma, lymphangiomaMediastinitis

Imaging

Imaging

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 Extramedullary plasmacytoma(primary pulmonary plasmacytoma) Lymphomatoid granulomatosis 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, paraspinal Ganglioneuroma

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).

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

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

• 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

Classification

Lung Cancer

Non-small Cell Cancer- 85%-90% of Lung cancers

Small Cell Lung cancer- 10%-15%of Lung cancers

Adenocarcinoma((including bronchioloalveolar carcinoma) — 38 percent

Squamous cell carcinoma — 20 percentLarge Cell Carcinoma - 5%Other non-small cell carcinomas -

cannot be further classified (18

percent)Others- Sarcomatoid, NE tumors- 6%

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

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

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.

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.

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

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.

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

Clinical presentations

• Paraneoplastic Syndromes from lung cancers:• Hypercalcemia- Squamous cell carcinoma• Trousseau syndrome- Adenocarcinoma• Hypertrophic pulmonary osteoarthropathy-

NSCLC• Clubbing – all types.

Paraneoplastic Syndromes Of SCLC

• Organ System Syndrome Mechanism Frequency

SIADH Antidiuretic homone

5%- 10%

Endocrine Ectopic sec of ACTH ACTH 5%Atrial Natriuretic factors

Eaton-Lambert reverse myasthenic syndrome

5%-6%

Neurologic Subacute cerebellar degeneration

Subacute sensory neuropathy

Limbic encephalopathy Anti-Hu, Anti-Yo antibodies

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.

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.

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.

Lymphomatous proliferation involving Lungs

3 different ways:

Haematogenous dissemination of Non-Hodgkins lymphoma (NHL) or Hodgkins disease

Contiguous invasion from a hilar or mediastinal site of nodal lymphoma

Primary pulmonary involvement.

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

• WHO Classification Of Lymphoid Malignancy

T- cell and NK -cell neoplasmsB cell neoplasms

Lymphoid Neoplasms

Hodgkins Lymphoma

Classification Criteria:Morphology

Clinical featuresGenetic features

Immunophenotype

• 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

Indolent Aggressive Highly Aggressive

Small Lymphocytic Diffuse large cell Burkett

Follicular Mantle Cell LymphoblasticMarginal AIDS relatedMALT

Splenic

Nodal

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.

Chest and Lung NHL

• Approximately 20 percent of patients with NHL present with mediastinal adenopathy 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 chylous ascites

• Pleural disease is seen in up to 10 percent of all patients with NHL at diagnosis.

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.

CT scan of Chest in NHL- Typical radiographic findings include alveolar opacities (consolidation,

masses, or nodules) and peribronchial disease.- 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

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.

PMLBL Systemic DLBL with mediastinal involvement

Younger women-3rd-4thdecade Older age at Dx- median age at Dx-7th decade

locally invasive anterior mediastinal mass with invasion of local structures ,(SVC, effusion)

Systemic B symptoms and elevated LDH levels are not uncommon.

Can spread to Supraclavicular and cervical LN later to Kidneys or CNS

If BM involvement or more distant LN spread then Dx is more likely DLBL

Immunophenotyping-express pan-B cell antigens, have weak expression of CD30, and only rarely express CD15

express pan B cell antigens (CD19, CD20, CD22, CD79a), as well as CD45

50%-75% of tumors express surface or cytoplasmic monoclonal (Ig), most often of the IgM isotype.

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

• 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

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 diagnosis or 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) lymphomatoid granulomatosis (LG), a rare disorder.

Low grade B-cell PPLBronchial MALT lymphoma

High grade PPL-B

58–87% of cases of PPL.90% of these cases correspond to MALT-

type NHLAge of onset is- 50–60 yrs (12–79 yrs)

The two sexes are equally affected

11-19% cases of PPLMALT type NHL coexists in ~50% of casesOften occurs in pts with underlying disorders HIV, Immunosuppresive medications. Sjogren’s.Median age- ~60yrs

50% are asymptomatic at Dx, With Incidental CXR

Usual CXR-50%- 90%Localized alveolar opacity with<5 cm diam

and associated with air bronchogram (50%)

CT- Bilateral and multiple appx 60%-70%, can- hilar or med LAD

<10%- B/L reticulonodular opacities, atelectasisor pleural effusion

Usually symptomatic, Resp s/s, fever or wt lossRadiology: Single pulmonary mass or atelectasis. Pleural effusionHIV- Multiple excavated opacities

Bronchial , Transbronchial or transthoracic biopsy

BX Blast like lymphoid cell with high mitotic activity

5 year survival rate >80%, Median survival time >10yrs

Prognosis is poor. Median survival 8-10yrs

Lymphomatoid Granulomatosis• Lymphoproliferative disorder in the family of Epstein-Barr virus (EBV)-

associated B cell lymphomas. Extremely rare• Age of onset- 30 and 50, Men are more commonly affected than women,

with an estimated male to female ratio of 2:1.• The lung is the most commonly involved organ; the skin and neurologic

system may be affected separately or concurrently.• most common presenting symptoms and signs include cough, fever,

rash/nodules, malaise, weight loss, neurologic abnormalities, dyspnea, and chest pain.

• CXR typically shows- multiple ill-defined nodular opacities. • Histolgy- triad of polymorphic lymphoid infiltrates, transmural infiltration of

arteries and veins by lymphoid cells ("angiitis"), and focal areas of necrosis within the lymphoid infiltrates

• clinical course is variable, ranging from remission without treatment to death within 2 years from malignant lymphoma.

Pulmonary Tuberculosis• Mycobacterium tuberculosis, an acid-fast–staining bacillus- inhaled into the

respiratory system by airborne droplets.• Prevalence in foreign-born U.S. residents is 9.7 times higher than that in U.S.-

born persons• In the AW- alveolar macrophages ingest the bacteria .Can not arrest the

multiplications- get destroyed

• Infected macrophages are carried to LN- Form Ghon complex- (localized parenchymal infection and lymph node involvement)- quiescent state- infection is recognized only by reactivity to tuberculin skin testing.

• Malnutrition, immunosuppressed states, and stress are risk factors for primary progression or reactivation of quiescent tuberculosis.

• In some patients, a pulmonary Ghon complex may reach significant size and calcification status to be visible on radiographs.

• Clinical menifestations:• pulmonary tuberculosis are often asymptomatic.• Constitutional symptoms, including anorexia, fatigue, weight loss, chills, fever, night

sweats, and local symptoms such as cough, may develop. • Hemoptysis and chest pain from pleural involvement indicate advanced disease.• HIV-infected or other immunocompromised patients - greater likelihood of

dissemination or extrapulmonary infection.

• Radiological findings:• Reactivation tuberculosis classically - lesions in the apical-posterior segments of

the upper lung and superior segments of the lower lobe. Cavitation may be present.

• Primary progressive tuberculosis may manifest as hilar lymphadenopathy or infiltrates in any part of the lung, similar to bacterial pneumonia.

• Atypical or absent radiologic findings commonly occur in in immunocompromised patients.

• Miliary tuberculosis may have the characteristic “millet seed” appearance. CT scans may identify abnormalities not yet visible on chest radiographs.

Pulmonary histoplasmosis• Most prevalent endemic mycosis in the United States. Most prevalent in the

midwestern and central states along the Ohio and Mississippi River valleys.

• H. capsulatum proliferates best in soil contaminated with bird or bat droppings, favoring sporulation of the organism.

• Exposure include excavation, construction, demolition, remodeling, wood cutting and gathering, and exploring caves.

• Majority of cases- Lungs provide portal of entry. Cause a localized or patchy bronchopneumonia.

• Most common syndrome following infection- Asymptomatic pulmonary histoplasmosis

• Symptomatic pulmonary histoplasmosis- typically presents as a subacute pulmonary infection weeks to months following exposure-productive cough, dyspnea, chest pain, fatigue, fevers, and sweats and

Radiographs typically show focal fibrotic apical infiltrates with cavitation and mediastinal or hilar lymphadenopathy.

• Following extensive exposure, - majority of patients develop acute diffuse pulmonary histoplasmosis within a week or two.

• Diffuse reticulonodular or miliary pulmonary infiltrates are noted and the disease can progress to respiratory failure or progressive extrapulmonary dissemination

Patients with underlying lung disease are at risk for the development of chronic pulmonary infection following exposure .

Shared similar findings as Sarcoidosis; Histoplasmosis must be excluded before treating patients with presumed

sarcoidosis with immunosuppressive medications

• Positive fungal stains or cultures and detection of antigen in urine or serum support a diagnosis of active histoplasmosis rather than sarcoidosis.

• Elevated titers of antibodies to H. capsulatum do not exclude a diagnosis of sarcoidosis .

Blastomycosis Aspergillosis

Blastomyces dermatitidis is a dimorphic fungus found primarily in the southeastern United States; around the Great Lakes.

lungs are the most common site of infection, followed by the skin, bones, and genitourinary tract.

C/F: Asymptyomatic in 50% cases, Acute or chronic pneumonia( Chronic more common)Extrapulmonary symptoms

Acute PNA- resembles- viral or bacterial CAPChronic- cases- often mimic malignancy or TB

Aspergillus is a ubiquitous mold found in soil and other moist environments throughout the world

Classically, the diseases caused by Aspergillus species are: Allergic bronchopulmonary aspergillosis. Invasive aspergillosis, Aspergilloma (fungus ball).

Risk factors- for invasive aspergillosis neutropenia, corticosteroid therapy,

HSC /solid organ transplantation, advanced AIDS, and chronic granulomatous disease.

Low grade fever, cough with productive sputum, chest pain, SOB, hemoptysis, with or w/o wt loss

EP features- Skin- 2nd most common- verrucous or ulcerative lesions,SQ nodules, OM next common

ABPA- is manifested by as persistent severe asthma, expectoration of brown sputum that contains Aspergillus organisms, pulmonary infiltrates, and fibrosis.Aspergilloma has been divided into chronic cavitary aspergillosis and single aspergilloma.

Blastomycosis Aspergillosis

Radiographic--Alveolar infiltrates with or without cavitation, mass lesions, and fibronodular infiltrates are most common . Tree in bud opacities More common in upper lobes.Small pleural effusion or thickening common. No hilar LAD

CT scan- The “halo sign” (nodules bordered by a ground-glass attenuation) is the classic finding

Dx- Culture of specimen Direct visualization yeast form in clinical specimens

Dx- culture from BAL, transbronchial biopsy, needle aspiration, and VAT biopsy. A definitive diagnosis requires histologic demonstration of the organisms in tissue. If not possible- Fungal Ag assay in blood, CSF, or urine

Galactomannan assays of blood or spinal fluid; and assays for (1-3)-β-D glucans.

Cryptococcal infections CoccidioidimycosisCommon opportunistic pathogen, associated mainly with HIV and, less frequently, transplantation.

The lungs are the presumed portal of entry, and pulmonary disease is one of the most common manifestations. (CNS) disease may also occur.

dimorphic fungus that lives in soil in parts of Arizona, California, New Mexico, west Texas, and parts of northern Mexico The disease is transmitted through inhalation of the arthroconidia, which are formed from the mycelia in soil

Subclinical primary infections are common and most are asymptomatic. Infection can persist in a latent state; if the host immune system becomes compromised organisms may be liberated from the granulomatous complexes and cause active infection. Symptomatic pulmonary cryptococcosiscan also occur in apparently immunocompetent patients.C/F - range from asymptomatic pneumonia to acute respiratory failure. The presentation of pulmonary cryptococcosis in patients with HIV is more acute and severe than in other hosts.

More than 50% of all infections are subclinical- C/F- acute or subacute pneumonia, w/wo pleural

effusions or empyema-

Xray- of acute disease may show infiltrates; pleural effusions or empyema; and cavitary lesions. Xray- in chronic infections may show findings consistent with COPD, fibrosis, infiltrates and thin-walled cavities.

Differential Diagnosis 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 Extramedullary plasmacytoma(primary pulmonary plasmacytoma) Lymphomatoid granulomatosis 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, paraspinal Ganglioneuroma

Bronchial Carcinoid Tumors• Low grade malignant neoplasm characterized by neuroendocrine differentiation

and indolent clinical behavior• 1%-2% of all lung malignancies, 20% of all carcinoids• Lung- 2nd most common site after GI tract• Typical vs Atypical Carcinoid• Average age of onset of typical B Carcinoid-45 years• Atypical carcinoid- appears approx 10 years later• 80% to 90% of tumors develop within a bronchus of subsegmental size or

greater.• 10% to 20% of tumors are located in the pulmonary periphery.• Atypical carcinoid tumors comprise about 10% of all pulmonary carcinoid

tumors.

• endodermal origin, arising from stem cells of the bronchial epithelium known as Kulchitsky cells.

• Secrets biologically active peptides and hormones; • serotonin, ACTH, ADH, melanocyte-stimulating hormone (MSH), and others.

• Excess serotonin production -Carcinoid syndrome. (constellation of symptoms, including tachycardia, flushing,bronchoconstriction, hemodynamic instability, diarrhea, and acidosis)

• Carcinoid syndrome much less frequent in pulmonary type than GI carcinoid. <2%.

• Cushing’s Syndrome: 1 to 2 percent of patients with bronchial carcinoid tumors and can be the initial reason for seeking medical attention. The onset is usually acute, and hypokalemia is often present.

• Clinical presentation: • Most of them centrally-located tumor & are symptomatic from the tumor mass

with coughing, hemoptysis, wheezing, or a recurrent postobstructive pneumonia.• Peripheral lesions present most often as an asymptomatic solitary pulmonary

nodule.• Atypical carcinoids present more often with hilar or mediastinal nodal

metastases and have a higher recurrence rate compared with typical carcinoids.

• Diagnosis: CT scan is the most useful imaging procedure,

• Generally confirmed either by bronchoscopic biopsy (for central lesions) or by transthoracic needle biopsy for peripheral lesions

Sarcoidosis• Multisystem, granulomatous, inflammatory condition of unknown cause that

occurs in young adults of both sexes.• 3-4 times more common in African American than White. 70%-90% of the cases

occur 10-40 years of age• Ranges from asymptomatic to acute systemic presentations with fever, erythema

nodosum, polyarthralgia, and hilar lymphadenopathy (Löfgren syndrome).• 90% of patients have pulmonary involvement at the time of presentation.• Typical Xray findings- B/L hilar LAD, Reticular opacities• Commonly involves the eyes and skin; the CNS, heart.GI tract are less

commonly involved.

• HRCT is not required in most patients, but findings can be characteristic -a pattern of reticulonodular abnormalities in a central distribution along the bronchovascular lymphatic vessels associated with bilateral hilar and mediastinal lymphadenopathy.

• Diagnosis: Elevated angiotensin converting enzyme (ACE) level and hypercalciuria. Pulmonary function tests - demonstrate a restrictive defect with impaired gas

exchange. Elevated CD4 to CD8 ratio may be detected by BAL. Noncaseating granulomas are the characteristic histopathologic abnormality. Classical Lofgren's syndrome and bilateral hilar LAD do not require biopsy . The diagnosis- requires compatible clinical and radiographic manifestations,

exclusion of other diseases that may present similarly, and histopathologic detection of noncaseating granulomas

Neurogenic tumors• 19 to 39 percent of all mediastinal tumors • Develop from mediastinal peripheral nerves, sympathetic and parasympathetic

ganglia, and embryonic remnants of the neural tube. • most frequent in the posterior compartment of the mediastinum• Benign and malignant tumors of peripheral nerve origin can occur• Schwannoma is the most common-affects patients of both sexes

predominantly in the third and fourth decade of life • Benign schwannomas are most often asymptomatic• signs of nerve compression and paralysis, Pancoast's syndrome, and

Horner's syndrome can occur.

• CT reveals a round, well circumscribed mass located in the paravertebral region or intercostal spaces. Focal calcifications and cystic changes are frequent.

• A characteristic clinico-radiological aspect -extension through an intervertebral foramen, resulting in dumbbell-shaped tumors, and neurologic symptoms of spinal cord compression.

Asbestos assciated Lung disease

• Risk factors- Cumulative exposure to the asbestos fiber.• construction industry, the automotive servicing industry, and the shipbuilding and

repair industry• Underlying factors- genetics, sex, ethnic origin, immune function, and fiber

clearance. Pleural plaques- most common sequelae . are focal, often partially calcified, fibrous tissue collections on the parietal pleura Typically develop bilaterally, with a latency of 10 to 20 years. Usually asymptomatic. Can be seen in CXR 50%-80% of times

Diffuse pleural thickening- more extensive fibrosis of the pleura .Obliterates the costophrenic angles. More likely to be associated with restrictive pulmonary physiology and may develop hypercapnic respiratory failure

Rounded atelectasis-(Shrinking pleuritis, Blesovsky syndrome, and folded-lung syndrome) is the result of infolding of thickened visceral pleura with collapse of the adjacent peripheral lung.

As single or multiple masses, which must be distinguished from a malignancy.

The classic Xray finding is a “comet tail” on chest CT scan extending from the hilum toward the base of the lung and then sweeping into the inferior pole of the lesion

Benign Pleural effusion: Asbestos-related pleural effusion is a diagnosis of exclusion Most patients are asymptomatic.Typically exudative and may be hemorrhagic.

Asbestosis Strictly the term refers only to bilateral interstitial fibrosis of the lung parenchyma caused by inhalation of asbestos fibers.

Asbestosis associated Lung Cancer well established Cigarette smoke and asbestos have a synergistic (multiplicative) effect

Differential diagnoses Bronchogenic Carcinoma Primary Lung cancer NSCLC vs SCLC Metastatic malignancy to Lungs Sarcomatoid carcinoma Lymphomproliferative disorders NHL Primary Pulmonary Lymphoma Postobstructive pneumonia Atypical/Chronic Fungal Infections Fungal –

Histoplasmosis Blastomycosis

Bronchial Carcinoid Sarcoidosis Asbestos associated Lung disease

Mediastinal involvement( Mainly posterior)

Esophageal tumors Neurogenic tumors- Schwannomas,

meningocele, paraspinal Ganglioneuroma

Final Differential Dx Bronchogenic Carcinoma- ( Primary vs Metastatic)

Lymphoma- most likely NHL

Atypical Fungal infection- ( Histoplasmosis vs Blastomycosis)

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