32yr old female with isolated splenomegaly and Pseudo

Gaucher cells

Swaminathan Murugappan MD, PhDHematology Oncology Fellow

University of WashingtonSeptember 24, 2010

32yr old caucasian female presented to the SCCA hematology clinic in

September 2009 for evaluation of her splenomegaly.

1. Left upper quadrant dull aching pain, constant with exacerbations. On going for a year.

2. Early satiety

3. Subjective fevers and chills

4. Night sweats requiring changing clothes at nights

5. Increasing fatigue and sleepiness

6. 20 pd weight gain in the last year (<10%)

7. Right metacarpophalangeal joint pain and stiffness for 3 weeks duration prior to her visit

8. History of frequent upper respiratory tract infections

Pertinent negatives:

1. No other GI complaints or loss of apetite

2. No rash, recent travel or sick contact

3. No other joint involvement

4. No easy bruising or bleeding

Past Medical History1. Splenomegaly of unknown etiology2. Anxiety/Depression

Social History:1. Smoking: 20pk year history2. Occasional alcohol intake3. Single and works in an office based environment4. No prior occupational exposure5. No IVDA or any recreational drug use

Family History:1. Father and mother have diabetes mellitus2. No known history of cancers

Medications:1. Zoloft 100mg daily2. Percocet as needed for pain3. OCP for menstrual pains

Physical Examination • General: comfortable, no acute distress. AAO X 3.

• Vitals: Temp 36.9, HR 82, RR 16, BP 114/80, Ht 162 cm, Wt 92kg.

• HEENT: No pallor/icterus noted. Oropharynx was clear with no lesions.

• NECK: No lymphadenopathy or thyromegaly.

• CHEST: Clear to auscultation bilaterally.

• CVS: S1 and S2 heard. Regular rhythm without any murmurs, gallops, or rubs. ABD: Obese. Tenderness on deep palpation on the left upper quadrant. Spleen felt 5 cm below the costal margin. No hepatomegaly noted.

• EXT: No clubbing, cyanosis, or edema was noted.

• MSK: No joint swelling or tenderness or any evidence of muscle atrophy is noted.

• NEURO: Grossly intact.

• SKIN: No ecchymoses/rash were noted.

• LYMPH: No cervical, axillary or inguinal lymphadenopathy noted.

Outside laboratory data• CBC March 2009: WBC 6.1, Hct 43, MCV 94 Platelet count 205. Normal differential counts. • ESR March 2009: 12 • Comprehensive metabolic panel including LFTs: Normal in March 2009. • Thyroid function testing March 2009: Normal• HIV and Hepatitis panel: Negative

Outside radiological studies• 1) Pelvic Ultrasound (02/23/09): Small uterine fibroid, splenomegaly • 2) CT abdomen/pelvis with contrast (02/26/09): Enlarged spleen at 15X6X15cm. No

adenopathy. Indistinct liver lesions too small to characterize. • 3) Ultrasound Abdomen (03/2009): Splenomegaly 16.8 cm. Normal splenic vein flow.

Outside pathology studies Bone marrow biopsy (03/2009): Reviewed at UW on 08/24/2009: • Normocellular marrow with trilineage hematopoiesis and no evidence of dysplasia,

leukemia, or lymphoma. • Flow cytometry revealed no abnormal myeloid blast population or abnormal B, T, or NK

cell population. • Cytogenetic studies revealed a normal 46XX female karyotype

32yr old female with significant splenomegaly, constitutional symptoms, normal

bone marrow and peripheral counts

Work-up at SCCA

Labs (09/2009):

WBC 8.12 Hct 43 MCV 93 Plt 188

Diff: ANC 4.39 Lymph 2.84 Mono 0.73 Eos 0.16 Baso 0.00

CMP: normal

LDH: 149

Uric acid: 5.2

ESR: 6

CRP: 4.9

ANA: negative

Blood cultures: No growth

Work-up (contd..)

CT chest/abdomen/pelvis (09/2009):• Slight interval decrease in size of spleen now measuring 15.0 cm

craniocaudally x 7.7 cm transverse by 10.4 cm AP, previously measuring 15.8 cm cranial caudal x 8.2 cm transverse by 10.4 cm craniocaudal. No focal splenic lesion seen. (Compared to the outside films).

• Stable tiny 0.2 cm low attenuation lesion is seen in the dome of the liver, which is too small to characterize.

• No enlarged mediastinal, hilar, axillary lymph nodes, intra-abdominal nodes.

Bone marrow biopsy 09/10/09

• Bone marrow with maturing trilineage hematopoiesis and scattered and focally clustered, increased number of histiocytes most consistent with pseudo-Gaucher cells.

• No histologic evidence of dysplasia, leukemia, lymphoma or abnormal plasma cells.

• Negative flow cytometry study for abnormal B, T, and plasma cells.

• Cytogenetics: 46XX.

Workup so far….

• Infectious: Negative for bacterial, AFB, HIV, Hepatitis B/C infections.

• Rheumatological: Negative.

• Hematological: Unclear still with the presence of Pseudo-gaucher cells.

• Congestive: Unlikely, given the CT findings.

• Infiltrative: Not tested for Gauchers disease.

Clinical Course…..

• Patient remained symptomatic with significant effect on her quality of life.

• Tests for Gaucher’s disease (peripheral blood leucocyte beta-glucocerebrosidase activity) was normal.

• Based on patients preference and need for additional diagnostic specimen, laproscopic splenectomy was performed on October 8, 2009. Vaccinations were administered prior to surgery.

• Immediate post operative course was uncomplicated. Patient had significant improvement in her symptoms post surgery.

Spleen biopsy report…..

• 204g of aggregate of splenic tissue was received by Pathology.

• Splenic architecture was preserved. No infiltrating lymphoid collections noted.

• Significantly increased number of histiocytes containing bubbly cytoplasm present in the red pulp. Some of the macrophages also have refractile, pigmented material. Cells were PAS stain positive.

• Flow cytometry was negative for abnormal B or T cell population. Microbiological cultures for bacterial, AFB and fungal infections were negative.

• Final diagnosis: Splenic red pulp with increased histiocytes suggestive of reactive changes. Conferred with Dr. Elaine Jaffe at NIH.

32yr old female with symptomatic splenomegaly, constitutional symptoms, normal

blood counts now with evidence of reactive Pseudo-gaucher cells in the marrow and spleen

Clinical course…..

• Patient remained asymptomatic for 6 months until March 2010.

• Started developing similar LUQ pains along with fevers, chills and night sweats. Also reports weight gain. Repeat CT chest/abdomen/pelvis in March 2010 was unchanged. No new masses. LDH ranged from normal to 427. ESR was normal. CRP increased to 12.4 but returned to normal.

• ID and Rheumatology consulted and had a full workup done including fungal and viral studies. All the studies negative and no additional studies was recommended. She was diagnosed with fibromyalgia and started on antidepressants.

• Given the patient’s symptoms from her underlying RES activation, she was started on prednisone 1mg/kg daily with a plan for slow taper.

Clinical course……• Patient responded to the steroids but had recurrent symptoms on the

lower doses of steroids.

• Repeat CT studies in May 2010 showed an evolving chronic thrombosis of the anterior segmental and sub segmental branches of the right portal vein. This was apparently noted in the March 2010 CT but not reported. CT from Sept 2009 was reviewed and did not show any thrombus. USG showed that her portal vein flow was normal. PET CT looking for an inflammatory focus was negative.

• No anticoagulation was started given it was chronic of unclear duration with no RUQ symptoms/systemic clotting events.

• As of Aug 2010, she has been weaned off steroids and is under surveillance. Reportedly, she is asymptomatic without abdominal pains and other constitutional symptoms.

Key Questions….

• What is her primary diagnosis? Source of the pseudo-gauchers cells?

• Is the portal vein thrombus related to her laproscopic splenectomy or her underlying disorder?

• Additional diagnostic workup? Further treatment options, if her symptoms recur?

32yr old female with…..

• Diffuse splenomegaly

• Fevers, chills and night sweats

• Pseudo-gaucher cells in the marrow and spleen

• Portal vein thrombosis (post-surgical versus primary disorder driven)

• Normal peripheral blood counts

Relative frequency of the causes of splenomegaly

• Liver disease (cirrhosis) – 33%

• Heme Malig (Lymphomas) – 27%

• Infection (AIDS, endocarditis) – 23%

• Congestion or inflammation – 8%

• Splenic vein thrombosis – 4%

• Other/Unknown – 5%

West J Med 1998 Aug;169(2):88-97

Causes of massive splenomegaly (crossing the midline or in the pelvis)

• Chronic myeloid leukemia

• Myelofibrosis, idiopathic or post-polycythemic

• Gauchers disease

• Lymphoma, usually indolent, including hairy cell leukemia

• Kala-azar (visceral leishmaniasis)

• Tropical splenomegaly syndrome

• Thalassemia major

• AIDS with Mycobacterium avium complex

Uptodate: Approach to adult patient with splenomegaly

CANCER June 1, 2001 / Volume 91 / Number 11

Splenectomies done between 1986-1995

in Washington University and Brigham and Womens Hospital

CANCER June 1, 2001 / Volume 91 / Number 11

CANCER June 1, 2001 / Volume 91 / Number 11

Lymphoma/Leukemia 57%

Carcinoma 11%

Cyst/Pseudocyst 9%

Benign/Malig vascular lesions 7%

Pseudo gaucher cells

• Reactive histiocytes or macrophages that have an eccentric lobulated nucleus with a voluminous cytoplasm that as a “crinkled paper” appearance.

• Increased pseudo-Gaucher cells probably reflects the increased load of leukocyte membrane-derived glucosylceramide presented to macrophages under conditions of high cell turnover when the normal pathways for its removal may be saturated.

• The cells are PAS stain positive but iron stain negative. This is in contrast to gaucher cells that is positive for PAS and iron.

Associations….

• MDS• CML (multiple case reports)• ALL• Hodgkins lymphoma• Non-Hodgkins lymphoma• Thalassemia intermedia• HbE disease• Monoclonal gammopathy of unknown significance (MGUS)• Multiple myeloma• Sickle cell anemia• Lymphoplasmacytic lymphoma• Mycobacterial infections

(Pubmed: Keyword “Pseudo gaucher cells”)

Portal Vein Thrombosis

Portal Vein Thrombosis

• 8 patients with idiopathic SVT had JAK2 mutation.

• JAK2 mutation was not seen in any of the patients with DVT.

• These 8 patients had no etiology or other conventional thrombotic risk accounting for SVT.

• All of them had normal peripheral blood counts.

• However, all 8 patients had abnormal bone marrow biopsies with evidence for hyperplasia.

• 3/8 patient went on to develop overt MPD. One died of other causes. The remaining 2 patients still have normal counts.

• Given that there are JAK2 negative MPDs, all patients with idiopathic splenic vein thrombosis need bone marrow evaluation to assess for latent MPD.

Comments and Questions….