Case Conference March 22, 2005

1
Case Conference March 22, 2005

• Steven Feinberg MD

2
Case Presentation

• 45-year-old female
• 3 month history progressive painless left
  cervical, supraclavicular, axillary
  lymphadenopathy
• Diffuse aches
• knees and lower back.
• insomnia and difficulty ambulating.
• No fevers or chills.
• Consult requested for biopsy

3
Case Presentation

• Multiple recent admissions
• FNA (1/05) left axilla
• benign lymphocytes
• no malignancy or organisms
• Bone marrow biopsy
• non-caseating granulomas
• no organisms or malignancy
• Open biopsy cervical and axilla
• small granulomas
• no organisms,
• normal flow cytometry

4
PMH

• Breast CA
• s/p mastectomy and chemotherapy,
• silicon implant
• Disseminated MAI
• Skin
• Lung
• Breast
• Histrionic personality disorder

5
PSH

• Cholecystectomy
• Mastectomy
• Bone marrow biopsy 11/04
• Removal ruptured breast implant 4/04
• Tracheostomy 1/04, status post decannulation
• Left upper lobectomy 1/04 due to massive
  hemoptysis
• Multiple bronchoscopies with KTP laser for
  obstructive LUL lesion
• Left axillary lymph node biopsy 12/03

6
Meds

• Ethambutol
• Rifampin
• Zyvox
• Avelox
• Restoril
• Naprosyn

7
Family History

• Leukemia
• Hypertension
• CAD

8
Physical Exam

• Multiple left cervical lymph nodes
• 1-2 cm in size
• levels 2-5
• mildly tender to palpation.
• No cellulitis
• Multiple left axillary lymph nodes
• No nasopharyngeal lesions

9
Workup

• CT chest
• bilateral hilar lymph nodes
• left axillary LAD
• precaval LAD
• soft tissue thickening of the left chest wall,
  trace bilateral pleural effusions
• RPR, HIV, legionella, bartonella and immunologic
  w/u negative
• Breast fluid - MAI 4/04
• Bronchial washings MAI
• blood cultures MAI

10
Differential Diagnosis

• VITAMIN-C
• Vascular unlikely
• Infectious
• MAI (and other atypical mycobacteria)
• Syphilis
• TB
• CocciodomycosisInvasive Fungal infections
• Histoplasmosis
• Blastomycosis
• Aspergillosis
• Legionella
• Cat scratch
• Brucellosis
• Toxoplasmosis
• Viral HIV
• CMV
• Infectious mononucleosis
• Nocardiosis

11
Differential Diagnosis

• VITAMIN-C
• Traumatic unlikely
• Autoimmune
• Rheumatoid arthritis
• Mixed connective tissue disease

12
Differential Diagnosis

• VITAMIN-C
• Metabolic
• Idiopathic
• Wegeners
• Sarcoid
• Langerhans cell histiocytosis

13
Differential Diagnosis

• VITAMIN-C
• Neoplastic
• Leukemias
• Lymphomas
• Metastatic breast CA
• Thyroid carcinoma
• Congenital
• Chronic granulomatous disease
• Branchial cleft cyst
• Lymphangioma
• Thyroglossal duct cyst

14
General Overview Granulomatous Inflammation

• Delayed type hypersensitivity
• Primarily response to chronic infections with
  persistent pathogens
• Acute infections (Salmonella, Listeria)
• Contains pathogen
• Chronic granulomatous inflammation ? damage and
  fibrosis
• Without inciting stimulus or clear benefit to the
  host (Sarcoid, Crohns, Wegeners, Rheumatoid
  arthritis)
• Foreign body reaction e.g. suture
• Hodgkins and non-Hodgkins lymphomas

15
General Overview Granulomatous Inflammation

• Granuloma formation
• complex and dynamic process
• diverse cell types
• Four phases of granuloma formation
• Initiation phase - macrophages attracted to
  persistent inflammatory stimulus, nucleate
  granulomatous lesion.
• Accumulation phase - CD4 T cells accumulate at
  the site and recruit other effector cells (T
  cells, macrophages, eosinophils).
• Effector phase - During the effector phase,
  various effector cells attempt to reduce the
  pathogen load through diverse mechanisms.
• Resolution Phase - once threat from pathogen is
  eliminated infiltrating cell population is
  reduced and the formation of scar tissue occurs.

16
General Overview Granulomatous Inflammation
A
B
C

• A Langhans type giant cell surrounded by
  epitheloid giant cells
• B granulomas with Langhans-type giant cells
  centrally,a surrouding lymphocytic infiltrate.
  Tuberculous meningitis.
• C - Numerous uniform, round granulomas within a
  lymph node in sarcoidosis

17
Sarcoidosis

• Systemic granulomatous disease
• unknown cause likely genetic predisposition
  with environmental trigger
• affects young and middle-aged adults
• African-Americans more frequently affected, more
  sever disease
• Bilateral hilar lymphadenopathy, pulmonary
  infiltrates, and ocular and skin lesions.
• Heart, liver,spleen, salivary glands,
  muscles,bones, kidneys, and central nervous
  system
• Otolaryngologic manifestations
• 10-15 of patients
• Cervical adenopathy high yield with FNA
• Parotid involvement
• Sinonasal manifestations

18
Sarcoidosis

• Diagnosis
• clinicoradiologic findings
• histologic evidence of noncaseating epithelioid
  granulomas
• exclusion of other granulomatous diseases.
• Prognosis - correlates with mode of onset, host
  characteristics, initial clinical course, and
  extent of disease.

19
Sarcoidosis

• Management optimal treatment has not been well
  defined.
• Corticosteroids - mainstay of treatment, but
  little evidence for the optimal initiation,
  dosage, or duration of therapy.
• Cytotoxic agents and immunomodulators - reserved
  for treatment of complex or refractory disease.
• methotrexate
• antimalarial agents are used frequently for skin
  lesions, limited success in the treatment of
  pulmonary disease.
• Lung and cardiac transplantation is reserved for
  end-stage disease.

20
Wegeners granulomatosis

• multisystem disease
• necrotizing granuloma of the respiratory tract,
• disseminated vasculitis
• glomerulonephritis.
• circumstantial evidence - autoimmune disease
• (c-ANCA) strongly associated with WG. (p-ANCA)
  less strongly associated with Wegeners

Granulomatous vasculitis
21
Wegeners granulomatosis

• Organ invovment
• Sinonasal
• most commonly involved
• Often misdiagnosed
• Edema, obstruction, rhinorrhea, ulcerations,
  crusting, epistaxis
• Saddle nose, perforation
• Otologic
• Serous otitis media
• Primary middle ear disease
• Pinna involvement
• Facial paralysis resembles relapsing
  polychondritis

22
Wegeners granulomatosis

• Oral and pharyngeal
• Mucosal ulcerations
• Strawberry gums
• Laryngotracheal
• Subglottic stenosis
• 16 of adults, 50 of kids
• Treatment intralesional steroids, trach,
  surgical reconstruction
• Only 20 diminish with medical therapy
• Others Renal, Ocular, Musculoskeletal, Skin,
  Neurologic, Genitourinary

23
Wegeners granulomatosis

• Diagnosis
• clinical features
• c-ANCA
• 90 sensitive for systemic disease
• 70 sensitive for localized disease
• 90 specific
• histopathologic confirmation
• Necrotizing granulomatous vasculitis
• Other tests ESR, UA, creatinine
• Treatment steroids, cyclophosphamide

24
Fungal Infections

• Histoplasmosis
• Histoplasmata capsulatum
• Endemic to Ohio, Mississippi river valleys
• Transmission airborn
• Symptoms
• usually asymptomatic,
• acute flu-like febrile illness.
• Physical examination unremarkable
• Imaging chest x-ray
• small scattered infiltrates
• hilar lymphadenopathy.

25
Histoplasmosis

• Outcomes of infection
• Spontaneous resolution
• Chronic disseminated disease
• Symptoms
• weight loss
• Fevers
• Fatigue
• Dysphagia
• Hoarseness
• gingival irrigitation
• painful mastication

26
Histoplasmosis

• Physical Exam
• Granulomatous lesions of lips, gingiva, tongue,
  pharynx, and larynx.
• Firm, painful ulcers, with "heaped-up" margins
• oropharyngeal involvement in 40-85 of adults
  with disseminated disease, 18 in children.
• Diagnosis swab specimen or biopsy from the
  center of an ulcerative lesion and culture on
  Sabourad's medium.
• Histology - growth of fungus within macrophages
  and granulomatous reactions in tissue
• Treatment - Amphotericin B or azoles

27
Fungal Infections

• Histoplasmosis is characterized by growth of
  fungus within macrophages and granulomatous
  reactions in tissue

28
Fungal Infections

• Blastomycosis
• Blastomycosis dermatitidis
• Southeast, Central and Mid-atlantic regions
• Less frequent than histoplasmosis
• Children and males age 40-60
• Usually asymptomatic.
• Acute or chronic infection may occur.
• Pneumonitis, cutaneous, osseous, and
  genitourinary involvement.
• Cutaneous lesions occur in 80 - proliferative
  and verrucous like.
• Larynx
• Hypopharynx
• Chest x-ray abnormal in 75
• obvious nodular infiltrates.
• Diagnosis
• sputum culture
• Skin scrapings
• Treatment amphotericin B.

29
Fungal Infections

• Blastomycosis histology
• combination of acute suppurative and
  granulomatous inflammation.
• lung
• widespread granulomatous inflammation with areas
  of abscess formation.
• Fungi are usually demonstrable at the edge of the
  abscess.
• Skin involvement
• pseudoepitheliomatous hyperplasia
• focal microabscesses in the papillary dermis.

30
Fungal Infections

• Cocciodomycosis
• Coccidiodes immitis
• Southwest USA and Mexico
• More virulent than other fungal pathogens
• Subclinical respiratory infection
• may disseminate to CNS, skin, soft tissue, bone
• Causes suppurative and granulomatous
  inflammation, with spherules and endospores seen
  on histology
• Head and neck involvment rare
• Usually limited to skin
• may involve tongue, larynx, thyroid,
  retropharynx, and lymph nodes
• Diagnosis histopathology, cultures, complement
  fixation assays
• Treatment amphotercin or fluconazole

31
Fungal Infections

• Rhinosporidiosis
• Rhinosporidium seeberi classified as fungus but
  controversial
• Endemic to South India and Sri Lanka, usually
  involves conjunctiva and nasal mucosa
• Histology spores seen within stroma of nasal
  mucosa (methanamine silver and PAS stains best)
• Cannot culture in laboratory

Spherical organisms surrounded by inflammatory
cells
32
Rhinosporidiosis

• Conjunctival rhinosporidiosis

33
Toxoplasmosis

• Protozoan parasite Toxoplasma gondii
• Immunocompetent host
• 90 asymptomatic
• lt 10 symptomatic
• Lymphadenopathy
• May mimic mononucleosis
• Painless, non-suppurative
• Most commonly cervical
• Inguinal
• Supraclavicular
• Congenital
• mental retardation, seizures, blindness,
  deafness, and death
• 75 of cases asymptomatic
• Delay of symptoms
• Transmission
• Ingestion of raw meat
• Ingestion of feces
• Transplacental

Brain Cyst
34
Toxoplasmosis

• Prevention
• serology for pregnant mothers
• educating pregnant women
• Dont eat kitty litter
• Dont eat raw meat
• Treatment
• Immunocompetent
• pyrimethamine and a sulfonamide (or clindamycin)
• Immunocompromised
• Same drugs,
• longer duration
• lifelong suppression therapy

35
Tuberculosis

• M. tuberculosis obligate aerobe, nonspore
  forming, rod
• Transmission respiratory route
• Mortality approaches 20 with multi-drug
  resistant pulmonary TB

36
Extrapulmonary Tuberculosis

• local manifestation of systemic disease
• Up to 15-20 of TB in immunocompetent
• Up to 50 of TB in immunosupressed
• Lymph nodes, pleural effusions most common
  locations
• Cervical lymph nodes
• Scrofula
• latin glandular swelling,
• French full necked sow

37
Extrapulmonary Tuberculosis

• Lymphadenitis
• In US majority of mycobacterial lymphadenitis
  caused by
• TB in adults,
• non-tuberculous mycobacteria in children
• Pathogenesis respiratory tract ? blood and
  lymphatic spread ? hilar and mediastinal
  adenopathy ? cervical lymphatics
• Oropharyngeal mucosa or tonsils ? lymphatics ?
  draining lymph nodes.
• Periadentitis ? matting ?necrosis ? sinus
  formation

38
Extrapulmonary Tuberculosis in the Head and Neck

• Lymphadenitis
• Diagnosis
• Skin testing PPD positive in 85
• Fine needle aspiration
• highly sensitive and specific in endemic areas
  (97-100 and 88-100)
• Poor sensitivity in non-endemic areas as low as
  25
• Higher sensitivity with PCR
• Cultures 6-8 weeks
• Smear presence of AFB
• Open Biopsies hazardous (spread disease, sinus
  formation)
• Treatment medical therapy
• Most common regimen 4 drugs (Rifampin,
  Isoniazid, Pyrazinamide, Ethambutol) until
  sensitivities back, then 2 drugs x 6 months

39
Extrapulmonary Tuberculosis in the Head and Neck

• Laryngeal
• Endemic countries majority with pulmonary TB,
  many sputum positive
• Non-endemic countries - pulmonary TB rarely seen
• May coexist with carcinoma
• Arytenoids, TVCs, FVCs.
• Symptoms hoarseness, cough, odynophagia, and
  globus sensation.
• In review of 15 cases of laryngeal TB from Japan,
  7 ulcerative lesions, 5 granulomatous lesions, 3
  non-specific inflammatory lesions. No site of
  predilection

40
Extrapulmonary Tuberculosis in the Head and Neck

• Oropharyngeal
• Rare
• usually secondary to laryngeal involvement
• Most common - palatine tonsil
• direct seeding of crypts from pulmonary disease
• Less common
• oral tongue, tongue base, palate, posterior
  pharyngeal wall

41
Extrapulmonary Tuberculosis in the Head and Neck

• Aural tuberculosis
• Profuse, painless otorrhea
• No response to abx
• Delayed diagnosis (e.g. 25 years)
• Findings
• pale granulation tissue
• perforation (multiple pathognmonic)
• preauricular adenopathy
• Complications similar to those of acute OM,
  draining post-auricular sinus
• Diagnosis
• requires high index of suspicion
• swab of pus 25 sensitive
• Biopsy 90 sensitive
• Treatment
• Anti-TB meds
• Surgery limited to removal of sequestrum,
  drainage of subperiosteal abscess

42
Non-tuberculous Mycobacteria

• At least 30 types of acid-fast mycobacteria that
  do not cause TB or leprosy
• Obligate aerobes, found in soil, water,
  vegetables, domestic animals, dairy products
• Runyon classification
• Group 1 Photochromogens (M. kansasii, M.
  marinum, M. simiae)
• Group 2 Scotochromogens (M scrofulaceum, M.
  szulgai, M. gordonae)
• Group 3 Nonphotochromogens (M malmoense, M
  xenopi, M avium-intracellulare)
• Group 4 Fast growers M fortuitum, M chelonae,
  M abscessus

43
Non-tuberculous Mycobacteria

• Pathogenesis
• bacteria gain entry via gingiva, oral mucosa,
  tonsils, salivary glands, or conjunctiva
• spread via regional lymphatics to lymph nodes

44
Non-tuberculous Mycobacteria

• MAC and M scrofulaceum
• lymphadenitis in immunocompetent patients
  localized disease.
• Usually children under age 5
• Submandibular nodes most commonly involved, while
  all nodes may be affected
• MAI most common species
• Unilateral, nontender, enlarged nodes with
  overlying erythema violaceous changes, eventually
  rupture with fistula formation
• Normal chest xray
• Pulmonary disease in immunocompetent patients
• Skin and soft tissue disease
• Disseminated in immunosupressed
• Portal of entry GI tract, lungs

45
Non-tuberculous Mycobacteria

• Diagnosis
• Sputum cultures may be misleading due to
  frequent colonization without clinical disease
• American Thoracic Society - at least 3 positive
  sputum cultures or 2 cultures with 1 positive
  smear
• Blood cultures special mycobacterial or fungal
  media. 5-12 d growth period, may take up to 12
  weeks
• Histopathology granulomatous inflammation,
  usually with casseating necrosis
• Skin tests none licensed in US for NTM, used in
  Europe. Highly sensitive (approx 88,
  sensitivity not well defined). PPD positive in
  25
• Disseminated MAC blood cultures, bone marrow
  biopsy, sterile fluid culture
• Bone marrow biopsy - hypocellularity, foamy
  histiocytes, stain and culture reveal MAC
• Imaging
• CXR classic radiograph mimics reactivation TB
  (patchy nodular infiltrates, no cavitation)
• Chest CT
• Abdominal CT HSM, retroperitoneal and
  periaortic LAD

46
Non-tuberculous Mycobacteria

• Treatment surgical excision of infected nodes
• ID may result in draining sinus
• FNA also associated with sinus formation
• May be adherent to marginal n.
• Antimicrobials
• Children with adenitis
• not well established, no controlled studies
• Anti-TB drugs ineffective
• Ideal antimicrobial treatment may be
  clarithromycin/rifabutin

47
Leprosy

• Hansens disease
• M. leprae droplet transmission
• Worldwide distribution, 200 cases in US annually
• Affected organs
• Skin
• Peripheral nerves
• Upper respiratory tract
• Saddle nose
• Epistaxis
• Chronic rhinorrhea
• Various subtypes
• Diffuse (Lepromatous)
• Tuberculoid
• Borderline

48
Leprosy

• Diagnosis
• Organisms infrequently detected in skin lesions
• Histology
• Tuberculoid leprosy - presence of non-necrotizing
  granulomas in the dermis and peripheral nerves
  with acid fast bacilli absent or few in number.
• Lepromatous leprosy - sheets of foamy macrophages
  in the dermis containing numerous acid fast
  bacilli, and absence of granulomas
• Treatment
• Depending on clinical variant, combinations of
  dapsone, rifampin, minocycline, and clofazamine
• 2-5 years

Lepromatous Leprosy
Tuberculoid Leprosy
49
Syphilis

• Oldest known STD.
• Treponema pallidum microaerophilic spirochete
• 3 stages
• Primary
• painless ulcer chancre
• appears after 3 weeks after spring break
• Secondary
• 3-6 weeks following resolution of primary
  syphilis
• Diffuse, nonpruritic rash, affects palms and
  soles
• Condloma lata
• Patchy alopecia
• Meningitis, optic neuritis, uveitis
• Tertiary
• 5-25 years after primary
• Cardiovascular syphilis, neurosyphilis, gummatous
  syphilis.
• Congenital
• Snuffles
• Rash
• Condyloma lata

50
Syphilis

• Otolaryngologic complaints
• Otologic
• Hearing loss
• Tinnitus
• Nystagmus
• Meniere-like, primarily due to vascular changes
• Tullios phenomenon
• Laryngitis
• Diffuse erythematous papules, edema, and ulcers
• mimic carcinoma or tuberculous laryngitis
• cervical lymphadenopathy are seen during the
  secondary stage.
• These may clear spontaneously within several
  weeks.
• Gumma formation during the tertiary stage leads
  to fibrosis, chondritis, and stenosis. Diagnosis
  
• RPR and VRDL
• FTA-ABS, MHA-TP
• Dark field microscopy
• Treatment
• PCN

51
Actinomycosis

• great masquereder
• Difficult to distinguish from malignancy
• gram-positive, anaerobic or microaerophilic
  bacterium, non-acid fast
• Actinomyces israeli most common
• commensal organism in the oral cavity and
  respiratory and digestive tracts.
• Sites of infection
• cervicofacial region (55)
• mandibular region most common
• Submandibular gland, Tongue, Palate, Parotid,
  TMJ, Mastoid, Skull, Nasopharynx
• abdominopelvic region (25)
• pulmonothoracic region (15)

52
Actinomycosis

• Pathophysiology
• Requires mucosal disruption
• Clinically variable
• Acute infection pus, sinus formation
• Chronic indolence, fibrosis
• Typical presentation
• slowly, progressively enlarging, fluctuant mass
  at angle of the mandible, hard, woody
• Violaceous skin changes
• pain, mild fever
• Histology
• organisms in a filamentous form with branching
  hyphae and characteristic sulfur granules (tiny
  microcolonies)

53
Actinomycosis

• Diagnosis
• Clinical findings
• Gram stain
• acid-fast characteristics
• histologic examination
• Difficult to culture
• Early open biopsy
• Treatment
• Debridement, excision, or both
• Adjuvant PCN for 6-12 months
• Consider HBO

54
Cat Scratch Disease

• 1992 Bartonella henselae
• fastidious gram-negative bacterium
• Immunocompetent hosts
• Typical (gt80) and atypical (5-20)
  presentations.
• Parinauds oculoglandular syndrome atypical
  presentation with granulomatous non-suppurative
  conjunivitis and ipsilateral preauricular
  adenopathy
• Neuroretinitis, endocarditis, aseptic meningitis,
  pneumonia, osteomyelitis
• Immunocompromised hosts
• Disseminated and systemic infections
• Fever
• Bacillary angiomatosis
• Vascular proliferative manifestation
• Dermal, mucosal lesions
• Peliosis hepatis

55
Cat Scratch Disease

• Cat is host
• Cat flea vector
• Flea to human transmisison
• All ages affected
• Kitten bite ? (3-10 days) ? nontender 1- to 10-mm
  red-brown papule develops ? (2 weeks) ? prolonged
  regional lymphadenopathy (80)
• Systemic symptoms (fever, malaise) in lt25
• Usually self-limiting with within 2 to 4 months.
  May last up to 2 years.
• Neck (43), axilla (38), groin (20), more than
  1 site (37). Parotid and deep space neck
  involvement may occur.

56
Cat Scratch

• Diagnosis
• Serological testing cornerstone in
  immunocompetent patients
• IgM antibodies seldom found early on, absence
  does not exclude cat scratch
• IgG levels may be low in early disease and
  present without disease
• PCR highest sensitivity, not widely available
• Histology HE or warthin starry stain.
• Treatment
• Not standard
• Macrolides, quinilones, sulfa, aminoglycosides
  thought to be effective, however resolution
  occurs without abx
• Surgical drainage or needle aspiration of
  suppurated lymph nodes in CSD is only necessary
  in selected cases.

57
Cat Scratch Disease

• Histology - inflammatory granulomas with
  microabsesses surrounded by histiocytes,
  occasional giant cells, lymphocytes, and
  fibrosis.

58
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