North American Society of Head & Neck...

North American Society

of

Head & Neck Pathology

Leon Barnes, M.D.

Professor Emeritus

University of Pittsburgh

History

A 51 year old woman presented with a two week history of a 1.5 cm asymptomatic swelling of the left upper lip and cheek. There was no cervical lymphadenopathy. Past medical history included DJD, hypothyroidism, elevated platelet count, “pseudotumor of the brain” and an unknown pulmonary infection treated with tetracyline. Clinical impression was pleomorphic adenoma.

Pathology

The excised specimen consisted of a 1.5x1.3x1.0 cm firm,yellow-brown, poorly defined soft tissue mass. On cross section, it varied from grey-white to tan-yellow.

CSH CD-68

CSH

CSH CD1a

CSH

CSH

Diagnosis

Crystal storing histiocytosis, immunoglobulin variant , associated with a mild lymphoplasmacytic infiltrate exhibiting IgM lambda light chain restriction

CSH---Definition

• CSH---a rare condition in which crystalline material of immunoglobulin or non-immunoglobulin origin accumulates in histiocytes. May be localized or generalized.

• According to Schaefer, the first case was described by Glaus in 1917 under the term “granular myeloma”( Schaefer HE, Pathol Res Pract 1996;

92:1152-1162).

Classification According to Crystal

1. Immunoglobulin A. Type (1) Heavy chain

(2) Light chain

B. Clonality (1) Monoclonal

(2) Polyclonal

(3) Indeterminate

2. Clofazamine

3. Charcot-Leyden

4. Other A. Cystine

B. Silica

Cause or Associated Disease

1. Hematopoietic A. Multiple myeloma B. Extramedullary plasmacytoma C. Lymphomas

2. MGUS-Amyloid

3. Drug A. Clofazamine

4. Allergic-Autoimmune

A . Rheumatoid arthritis B. Eosinophilic colitis C. Mastocytosis D. Hypereosinophilic syndrome

5. Metabolic A. Cystinosis

6. Inflammatory-Reactive A. Pulmonary infections B. Plasma cell granuloma C. Crohn’s disease D. Helicobacter pylori

7. Other A. Silica

CSH

Immunoglobulin Variant

CSH---Pathology

Most range in size from microscopic to 4 cm.

Typically poorly defined and composed of sheets of epithelioid and/or spindled-shaped eosinophilic histiocytes with bland nuclei associated with a variable mixture of plasma cells and lymphocytes. The cytoplasm of the histiocytes ranges from opaque to striated to granular.

The immunoglobulin crystals are PAS-variable, do not polarize, and on EM may appear rhomboid, hexagonal, or elongated.

CSH---Pathology

• Immunoglobulin crystals may be monoclonal, polyclonal or indeterminate. Most are monoclonal of kappa light chain type without a constant association with a particular heavy chain.

• In some instances, crystals may not stain. Failure to stain may be related to: (1) altered molecular configuration of protein with decreased antigenicity, (2) antigen masking resulting from crystalline structure of the protein. (3) fixation issues, or (4) the crystals are not of immunoglobulin origin.

CSH---Clinical Features

N=80

Men 51% Ave age 59 yrs. (38-75)

Women 49% Ave age 61yrs. (17-81)

CSH--- Symptoms

• Symptoms vary according to site. Most present as an asymptomatic mass or swelling.

• Orbital CSH associated with ptosis, proptosis and ophthalmoplegia.

• Cardiac CSH resulted in recurrent atrial arrhythmias and dizziness.

CSH---Localized vs. Generalized

N=80

• 58% were localized and of these 35% occurred in the head and neck with the most common site being the eye-orbit.

• 42% were generalized. Besides the bone marrow which was involved in all but one case, the most frequent sites in G-CSH were the liver, lymph nodes, spleen and kidneys.

CSH--- Sites in Head and Neck

Eye-orbit Larynx

Lymph nodes Nasopharynx

Lacrimal gland Sinonasal tract

Skin Tongue-hypopharynx

Brain Parotid gland

Meninges Thyroid

CSH--- Non Head and Neck Sites

Bone marrow Pleura

Liver Bone

Spleen Skin

Lymph nodes Pancreas

Kidney Testes

G-I mucosa Heart

Mesentery Pericardium

Peritoneum Thymus

Lungs Bladder

Immunoprofile of 80 Cases

• The specific type of heavy chain was documented in 37 cases: 14 IgM, 10 IgG, 6 IgA, and 7 polyclonal.

• The light chain component was mentioned in 51 cases: 33 kappa, 8 lambda, and 10 polyclonal.

Diseases Associated With CSH

N=80 • Multiple myeloma 90% • Extramedullary plasmacytoma • Malignant lymphomas • MGUS

• Rheumatoid arthritis 8.8% • Plasma cell granuloma • Crohn’s disease • Pulmonary infections • Helicobacter pylori

• Unknown 1.2%

CSH---Pathogenesis

• Overproduction--abnormal secretion--or impaired excretion of paraprotein.

• Production of protein with abnormal sequence (structure) which promotes crystallization or adversely effects normal enzymatic degradation or both.

CSH---Pathology Issues

• Cytoplasm of histiocytes may be deeply eosinophilic and opaque obscuring any inclusions on H&E.

• Histiocytic component is usually dominant and may mask the neoplastic nature of any background plasma cells or lymphocytes.

• Exceptionally may be discordance between clonality of crystals and serum protein.

CSH

Non-immunoglobulin Variants

Examples

• Clofazimine Am J Surg Pathol 2000; 24:129-135

• Charcot-Leyden Am J Surg Pathol 2007; 31:481-485

• Cystinosis Arch Pathol Lab Med 2002: 126:1135

• Silica Cancer 1978; 42:2738-2743

CSH Workup

• Identify type of crystal

• History and physical exam (any underlying disease;

medications; additional CSH lesions; enlarged lymph nodes, liver, spleen)

• Additional studies 1. Serum and urine protein studies 2. Serum free light chain analysis 3. Bone marrow aspirate and biopsy 4. Skeletal survey (lytic –blastic lesions &/or osteopenia) 5. Possible lymph node biopsy

CSH---Diagnosis

• Although most cases of CSH occur in patients with a previous well established diagnosis of MM, LPL or MGUS, we identified at least 7 cases (9%) in which the diagnosis of CSH led to the discovery of a simultaneous previously unrecognized LP-PCD and/or paraproteinemia.

• In another 3 cases (4%), CSH preceded the diagnosis of a LP-PCD by “a few months”, 7 months, and 4 years.

CSH---Treatment and Prognosis

Depends on underlying cause

Current Case--- Evaluation

• CBC Normal

• Serum proteins Total proteins 8.2 g/dL (6.2-8.0 g/dL)

Gamma globulins 1.7 g/dL (0.6-1.6 g/dL)

Beta-microglobulin 3.32 mg/L (0.0-2.51 mg/L

• Blood no monoclonal protein

• Urine no monoclonal protein

• Bone marrow normocellular with few plasma cells

• Skeletal survey no blastic or lytic lesions or osteopenia

Current Case--- Diagnosis

• Histologic: Crystal storing histiocytosis, immunoglobulin type, associated with a mild lymphoplasmacytic infiltrate exhibiting IgM lambda light chain restriction.

• Clinical: Possible monoclonal gammopathy of undetermined significance (MGUS).

Current Case--- Follow-up

• Since the patient was otherwise asymptomatic, no treatment was recommended other than periodic follow-up.

• At last examination ( 8 months since her dx of CSH) there was no significant change in her physical condition or laboratory data.

• Attempts at additional follow-up has not been successful. We are told that she has consulted with multiple physicians and all have refused to see her again because she is so rude and obnoxious.

MGUS

MGUS is an age-related asymptomatic condition in which a paraprotein is found in the blood during standard laboratory tests.

1. A monoclonal paraprotein band less than 30 g/L ( >3 g/dL)

2. Plasma cells less than 10% on BM exam

3. No evidence of hypercalcemia, renal insufficiency , anemia or bone lesions related to paraprotein (CRAB)

MGUS

• Prevalence increases with age: 3.2% in individuals over 50 years

5.3% over 70 years

7.5% over 85 years

Prevalence double in African Americans than Caucasians

Prevalence lower in Japanese than Caucasians

• Causes Radiation at early age

Exposure to pesticides, fungicides, herbicides

Genetics

Diseases Associated With MGUS

• Multiple myeloma

• CLL

• Lymphoplasmacytic lymphoma

• Waldenstrom macroglobulinemia

• Amyloidosis

• Connective tissue disorders

MGUS

• Risk of progression to multiple myeloma or other similar entities is 1% per year or about 25% at 25 years.

• The interval from recognition of MGUS to diagnosis of MM or related disorder has ranged from 1-32 years (median 10.4 years).

MGUS---Risk Factors

• Type of serum monoclonal protein---IgM and IgA worse.

• Size of serum monoclonal protein---15g/L or higher.

• Abnormal free kappa:lambda light chain ratio of less than 0.26 (lambda involved) or greater than 1.65 (kappa involved).

MGUS---Risk of Progression

• 58% at 20 years when all 3 factors are present

• 37% when 2 factors are present

• 21% when I factor is present

• 5% when all 3 factors are absent

Rajkumar S, et al. Blood 2005; 106:812-817

MGUS

• No treatment is warranted.

• Yearly follow-up with at least a serum protein electrophoresis.

CSH Differential Diagnosis

• Rhabdomyoma

• Granular cell tumor

• Langerhans histiocytosis

• Fibrous histiocytoma

• Gaucher disease

• Malakoplakia

• Mycobac pseudotumor

• Rosai-Dorfman Disease

• Xanthogranuloma

• Inflam pseudotumor

ARM

ARM

ARM

GCT

GCT

S-100 GCT

LH

LH CD1a

Fibrous Histiocytoma

Gaucher Disease

CSH---Summary

• Rare entity with equal gender distribution.

• Occurs over a broad age range (17-81 yrs) with an average of about 60 yrs.

• May involve almost any anatomic site.

• May be localized (58%) or generalized (42%).

• When localized, 35% occur in head and neck (eye/orbit).

• 90% associated with a LP-PCD ( MM, LPL or MGUS).

CSH---Summary

• In a few cases CSH may precede the diagnosis of LP-PCD disorder. Need for follow-up.

• About 10% of cases associated with a variety of benign diseases, often with an inflammatory background.

• Not all cases are due to immunoglobulin deposition.

• Treatment and prognosis depend on underlying disease.

• Pathology: can be easily overlooked and may be confused with other entities (ARM, GCT, LCH, FH, Gaucher dx, etc).

Acknowledgements

Wilhelmina P. Cruz-Vetrano, MD Medical Director, Laboratory Services

Altoona Regional Health System

Altoona, Pennsylvania

Snjezana Dogan, MD Assistant Attending Pathologist

Memorial Sloan-Kettering Cancer Center

New York, New York