Primary Adrenal Lymphoma Presenting as Hemophagocytosis Lymphohistiocytosis Syndrome with CNS Involvement

1. Khushboo Gandhi, PGY2
Internal Medicine Residency Program
St. Luke’s Hospital
MORNING REPORT - 7
JUNE 1, 2017

2. 72 Year Old Caucasian
Female Presents With
Intermittent Fevers And
Generalized Weakness
For A Month

3. HPI:
 72 Year old Caucasian female presents with intermittent fevers and
generalized weakness for a month.
 Recently admitted 3/23/17-3/30/17 - diagnosed with viral bronchitis with
possible superimposed bacterial infection (Rocephin and Zithromax) –
discharged on Augmentin (completed course) and steroid taper.
 Initially improved after discharge – fatigued for past 2 days and this
morning she “could barely stand up” – went to PCP
 UA – showed 4+ RBC - sent to ED for further work up.
 Dry cough and SOB with exertion since march – discharged on 2L NC –
Weight gain of 8 Kgs
 Daily HA – throbbing and on top of her head – takes 4 ibuprofen daily since
discharge
 Lower extremity edema - started on HCTZ (day prior)
 Ulcers on tongue – Mycelex by PCP (day prior)
 Denies any sick contacts, recent travel outside of St Louis area, contact
with animals, long car or airplane trips

4. ROS:
Constitutional: Fever, Sweats, Weakness, Fatigue, Decreased activity, No chills.
Eye: No Discharge, No recent visual problem, No icterus, No blurring, No double vision,
No visual disturbances.
Ear/Nose/Mouth/Throat: Tongue ulcers, otherwise negative.
Respiratory: Shortness of breath, Cough, No sputum production, No hemoptysis, No
wheezing, No cyanosis, No apnea.
Cardiovascular: No chest pain, No palpitations, No syncope, Peripheral edema,
Orthopnea.
Gastrointestinal: No nausea, No vomiting, No diarrhea, No constipation, No heartburn,
No abdominal pain, No hematemesis.
Genitourinary: Negative.
Hematology/Lymphatics: Negative.
Endocrine/Immunologic: Negative.
Musculoskeletal: Generalized muscle weakness, No neck pain, No joint pain, No muscle
pain, No decreased range of motion, No trauma.
Integumentary: No rash, No pruritus, No abrasions, No breakdown, No burns, No
dryness, No petechiae, No skin lesion.
Neurologic: Alert and oriented X4, Headache, No confusion, No numbness, No tingling.
Psychiatric: Negative.

5. Past Medical/Surgical History:
HTN, Arthritis, Asthma, GERD, Schatzkis Ring, Cataract removal BL, Cesarean section,
tubal ligation, Open Fixation mid humerus fracture
Allergies:
Blue Dye – Hives
Lisinopril – Hives
Medications:
Albuterol Inhaler, Aspirin 81 mg, Montelukast, Prednisone 10 mg, Benadryl,
Omeprazole, Hydrochlorothiazide, Potassium Chloride, Calcium 500+d 500 Mg,
Cetirizine, Clotrimazole Troche, Dextromethorphan-guaifenesin, Fish Oil, Glucosamine
Chondroitin, Lactase, Multi-vitamin
Family History:
Sister – Breast Cancer, Asthma
Mother – CAD
Social History:
Lives with husband, has 3 grown up children, Never smoked, Never used recreational
drugs, Drinks alcohol socially, No IVDA
Prior to March, she was active, performed chores around the house and took care of
grandchildren

6. Physical Examination:
Vitals: BP: 115/63 mmHg, Pulse: 94 bpm, Temp: 98.8 °F (37.1 °C), RR: 18, SpO2: 93%
on 2 L, Ht: 5' 9" (1.753 m), Wt: 111.8 kg (246 lb 6.4 oz), BMI: 36.39 kg/m
General appearance: alert, cooperative, pleasant caucasian female in no acute
distress, ill appearing
Head: Normocephalic, without obvious abnormality, atraumatic
Eyes: Conjunctivae/corneas clear. PERRL, EOM's intact.
Ears: Normal external exam. Hearing grossly intact.
Nose: Nares normal. Septum midline.
Throat: white ulcers on tongue, no ulcers visible on mucosa of mouth or throat
Neck: Supple, symmetrical, trachea midline
Back: ROM normal. No tenderness
Lungs: clear to auscultation bilaterally, diminished breath sounds, not using accessory
muscles, no wheezes or crackles, Chest wall No tenderness
Heart: regular rate and rhythm, S1, S2 normal, no murmur. No rub or gallop, No JVD.
Abdomen: soft, obese, non-tender, without masses or organomegaly
Extremities: Normal, 2+ bilateral pitting edema most notable in lower leg/ankle
region, non-tender
Pulses: Radial pulses symmetrical, unable to palpate posterior tibial due to edema
Skin: Skin color, texture, turgor normal. No rashes or lesions
Lymph nodes: Cervical, supraclavicular, and axillary nodes normal.
Neurologic: AAOx3, CN II-XII focally intact, 5/5 strength in all extremities

7. Hemogram
WBC 10.1 H
RBC 3.84 L
Hemoglobin 10.5 L
Hematocrit 33.0 L
MCV 85.9
MCH 27.3
MCHC 31.8
RDW 15.5 H
Platelet 166
MPV 11.3
Differential Automated
Immature Gran %
Neutro % 73
Lymph % 12
Mono % 11
Eos % 2
Baso % 1
Neutro # 7.35 H
Lymph # 1.21
Mono # 1.14
Eos # 0.19
Baso # 0.05
General Chemistry
Sodium 135 L
Potassium 4.7
Chloride 97 L
Co2 23
Anion Gap 20
BUN 33 H
Creatinine 0.95
Glucose 87
Calcium 9.6
Protein, Total 6.2 L
Albumin 2.0 L
Alk Phos 182 H
Bilirubin, Total 0.5
AST 63 H
ALT 23
Phosphorus 0.5
Anion Gap 15
CRP 213.0 H
ESR 103 H
Lactic Acid 2.5 H
PROBNP 302 H
TROPONIN T 0.01
CKMB 1.0
CK 8 (L)
CK-MB REL. INDEX 12.5 H
D-DIMER 0.98 H
MRSA Neg
Respiratory PCR Neg

8. Urinalysis
Color Yellow
Clarity Clear
Specific gravity 1.029
PH 5.0
Leukocyte esterase Negative
Nitrite Negative
Protein Negative
Glucose Negative
Ketones Negative
Urobilinogen Normal
Bilirubin Negative
Blood 1 +
Wbc 6 - 10
Rbc 3 - 5
Bacteria 1+
Epithelial cells 0 - 5
Hyaline cast 3 - 5
 Chest X ray: Progression of bilateral lower lobe
predominant interstitial and alveolar infiltrates.
 EKG: No acute ST T wave changes, Normal Axis,
No hypertrophy
 Urine Culture - Enterococcus
 TSH - 0.15; T4 free - 0.39 – Subclinical
Hypothyroidism

9.  CT CHEST W CONT
• Bilateral subsegmental atelectatic changes, most notable in the lingula and
anteromedial right upper lobe.
• Subpleural nodule within the right base measuring 7 mm in diameter. This is not
clearly seen on the previous exam.
• Atherosclerotic calcifications in the left anterior descending coronary artery.
 CT ABDOMEN AND PELVIS
• Cholelithiasis with mild gallbladder distention. No evidence of gallbladder wall
thickening or pericholecystic fat stranding.
• Left adrenal mass measures up to 6.5 cm in craniocaudal length. Malignancy
cannot be excluded.
• Mild sigmoid diverticulosis. No evidence of diverticulitis.
• Mild free pelvic fluid.
 XR CHEST after 4 days:
• Worsening aeration of the lungs with increasing interstitial and airspace
opacities.

10. Hospital Course
• Started on Vanc and Zosyn for possible sepsis from pneumonia and UTI
• Surgery – Adrenal gland removal (biopsy of the mass could lead to
hypertensive crisis) – but because of sepsis it was postponed.
• Pulmonary edema – IV Lasix – Per pulmonology
• Echo: Normal systolic and diastolic function, EF 70%, No valvular
abnormalities, mild pulmonary HTN
• Continued to be hypotensive with increasing peripheral edema and
eventually anasarca (with intravascular volume depletion and extravascular
volume overload) – became hypoxic and hypotensive after BM biopsy -
transferred to ICU

11. 0
20
40
60
80
100
120
140
160
180
200
1 2 4 5 6 8 9 10 11 14 15 16 17 30
Platelets
Hospital Days
Platelets
Platelets

12.  ACTH Stimulation Test – Borderline adrenal insufficiency
 Cortisol, Baseline - 14.6
 Cortisol, 30 Minute - 17.9
 Cortisol, 60 Minute - 20.6
 Prealbumin <3
 UPEP: Negative
 SPEP: monocolonal gammopathy-IgM Kappa
 BM Biopsy: no evidence of leukemia/lymphoma
 Aspergillus and cryptococcus antibodies negative
 ADAMS13 – 55% only mildly low (TTP, HUS, DIC)
 Heparin induced platelet antibody - Negative
 Serotonin Release Essay - Negative
 Factor H and factor H antibody - Negative

13. Other:
INFLUENZA A AG Neg
NFLUENZA B AG Neg
Hepatitis B SAg Neg
Hepatitis B C IgM Neg
Hepatitis A IgM Neg
Hepatitis C AB Neg
Complement C 3 124 N
Complement C 4 6 L
IGG 993 N
IGA 542 (H)
IGM 122 N
IgE Elevated
FERRITIN: 1095.0  1101
1201
LDH: 1568 –> 1499  1724
Haptoglobin 342
HIV Test Neg
Other
ANA Neg
ANCA Neg
Anti CCP Ab Neg
Cryofibrinogen/Cryoglobuli
n
Neg
ASO titer WNL
DNAase B Ab WNL
Anti GBM ab Neg
Blastomyces ab Neg
Histoplasma ab Neg
24hr urine catecholamines WNL
24hr urine metanephrines WNL
Urine cr 158
Urine Na 21
Urine Urea 730
Urine osm 495
Urine eosinophil 1-15%

14. Other studies
IRON 11 L
TIBC 107 L
IRON % SATURATION 10 L
TRANSFERRIN 84 L
VITAMIN B12 1131 H
FOLATE, SERUM 9.2
RETICULOCYTES 4.2 (H)
IMMATURE RETIC
FRACTION
29.0 (H)
AMMONIA 48 N
PROTIME 26.9 (H)
INR 2.4 (H)
PTT 46.2 (H)
FIBRINOGEN 757 (H)
Heparin induced
platelet antibody
Negative
Other
CHOLESTEROL 168
TRIGLYCERIDE 563 (H)
HDL 6 L
NON-HDL
CHOLESTEROL
162 (H)
HbA1c 5.5
ADAMTS-13 activity - 55%
CSF Analysis:
Xanthochromic
WBC 2/uL
RBC 16/uL H
Neutrophils 2 % H
Lymphocytes 46 % L
Monocyte/Macr
ophage
48 % H
Glucose 158 mg/dl H
Protein 121.5 mg/dl H

15. • CT head for Acute encephalopathy - Motion artifact. No
definite gross abnormality.
• Encephalopathy continued – Intubated for airway protection
• MRI 4/17 showed multiple small bilateral areas of restricted
diffusion, patchy subcortical white matter disease
• MRA/MRV without occlusion and MRI pituitary unremarkable.
• LP preformed 4/17/1 showed xanthochromia, elevated
glucose, proteins and neutrophils - CSF cultures/PCR all neg
 TEE 4/19/17 : Normal systolic and diastolic function, Agitated
saline contrast study showed a very small right-to-left shunt,
following an increase in RA pressure induced by abdominal
compression.
 cEEG 4/20/17: Negative for epileptiform discharges

16. 0
2
4
6
8
10
12
1 2 4 5 6 8 9 10 11 14 15 16 17 30
Hemoglobin
Hospital Days
Hemoglobin
Hb

17. 0
2
4
6
8
10
12
14
1 2 4 5 6 8 9 10 11 14 15 16 17 30
WBCcount
Hospital Days
WBC
WBC

18. 0
1
2
3
4
5
6
7
1 2 4 5 8 9 11 15 16
LacticAcid
Hospital Days
Lactate
Lactate

19. 115
120
125
130
135
140
145
150
155
1 2 4 5 6 8 9 10 11 14 15 16 17
Sodium
Hospital Days
Sodium
Sodium

20. 0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
1 2 4 5 6 8 9 10 11 14 15 16 17
Creatinine
Hospital Days
Creatinine
Creatinine

21.  ADAMTS-13 activity 55% - Empiric Plasmapheresis for TTP
 Bronchoscopy lavage, cytology and cell block: No atypical cells, No PCP, No
significant number of hemosiderin-laden alveolar macrophages.
 MRI adrenal protocol not obtainable b/c of technical difficulties (has to
breath hold for at least 20 seconds).
 Decided to go for CT guided adrenal biopsy
 CSF paraneoplastic panel – negative
 Soluble CD25 (IL2 receptor Cd25) – Elevated
 Functional NK Cells (FC): Moderate decrease in the absolute number of
cytotoxic NK cells (CD16++CD56+)
 Diagnosed with HLH with CNS involvement – Dexamethasone and
Etoposide
 Ommaya reservoir placed for intrathecal MTX treatment
 LDH (873) and ferritinin (909) improved after Rx.

22.  Intraventricular catheter system that can be used for the aspiration of
cerebrospinal fluid or for the delivery of drugs (e.g. chemotherapy) into the
cerebrospinal fluid. It consists of a catheter in one lateral ventricle
attached to a reservoir implanted under the scalp.

23. On 20th day of Hospitalization - Adrenal mass biopsy - diffuse large B cell
lymphoma
 R-CEOP
 Repeat MRI – showed progression of lesions
 Severely pancytopenic after chemo – continued hemoptysis and dropping
Hb – repeated platelet and blood transfusions
 Recurrent prolonged right posterior quadrant (temporo-parieto-occipital)
electrographic seizures – Vimpat, Keppra and Versed
On 30th day of hospitalization
 Became hypoxemic with severe shock on maximum ventilator support,
presumed to be due to DAH
 All measures were continued except for No chest compressions
 Cardiovascular arrest and expired

24. Primary Adrenal
Lymphoma Presenting
As HLH With CNS
Involvement

25. Primary adrenal lymphoma (PAL)
 Extremely uncommon, <1% of all NHL
 < 50 cases have been reported in the literature
 2/3 cases – BL; Only 1/3 – Unilateral
 Sixth decade of life; Male:female ratio is 2:1 to 7:1
 Nonspecific symptoms - fever, weight loss, and abdominal/lumbar pain
 50% - symptoms of adrenal insufficiency (pigmentation of the skin and
mucous membrane, fatigue, anorexia, and constipation)
 Origin - Hematopoietic tissue rests in the adrenal gland akin to adrenal
myelolipoma
 The most common subtype is the diffuse large B-cell type.
 T-cell and angiocentric large cell lymphoma type B are the exception.
Treatment:
 Combination chemotherapy with or without surgery
 R-CHOP/CEOP - Cyclophosphamide, doxorubicin, vincristine, and
prednisone + monoclonal antibody rituximab (Rituxan)
 Median survival is less than 1 year

26. CNS Involvement In
Hemophagocytic Lympho-
histiocytosis

27. Hemophagocytic Lymphohistiocytosis
 Clinical syndrome of life-threatening hyper inflammation by activated macrophages
and lymphocytes.
 Genetic defects (primary HLH).
 Acquired with infectious, neoplastic, autoinflammatory, autoimmune, and
immunodeficiency etiologies (secondary HLH).
 Primary HLH is rare, with an estimated yearly incidence in Sweden of 0.12–0.15 per
100,000 children
 The incidence of primary HLH in adults or that of secondary HLH is not studied.
CNS-HLH
 Infiltration of activated lymphocytes and macrophages into the meninges and brain.
 Neuropathological stages:
 Stage I - leptomeningeal inflammation
 Stage II - perivascular infiltration
 Stage III - massive tissue infiltration, blood vessel destruction, and tissue necrosis -
induce devastating brain lesions - important cause of mortality and morbidity in
HLH
Blood. 2016;127:2672–81; Pediatric Blood Cancer. 2015 Feb;62(2):346–352; Hum Pathol. 1984;15:161–8; J Pediatr. 1997;130:358–65.

28. CNS involvement is a frequent finding - primary and secondary HLH (30–73%)
Carries key prognostic significance
Present with systemic HLH
May be the primary and only clinical presentation of HLH
Neurological symptoms and signs (Severe, sometimes life- threatening)
 Seizures are the most common sign of neurological dysfunction (30-83%)
 Mental status changes - irritability, disturbance of consciousness, and
encephalopathy (31-47%)
 Meningism
 Focal neurological signs - hemiparesis, cranial neuropathies, and ataxia (10-
20%)
Pathogenesis: Excessive activation of CD8+ T lymphocytes  Release of
cytokines TNF-α, IL-1β, IL-6, IL-8, and interferon-γ
Neuroinflammatory markers - Neopterin

29. CSF Analysis:
 Pleocytosis, moderately elevated protein levels (500 and 1000 mg/L)
 Protein levels higher than 2500 mg/L - associated with stage III abnormalities
Neuroimaging:
 MRI of the brain with gadolinium
 Multifocal and bilateral abnormalities seen on T2-weighted imaging are almost
universally present in primary HLH (89%), with a high rate of symmetric
involvement (53%)
 large, ill-defined, confluent lesions are seen in up to 2/3 of an HLH population.
 CNS hemorrhage was seen in 5/43 cases in one series of mixed primary and
secondary HLH.
 Chronic changes such as atrophy and calcifications - reported in some cases
 Nodular or ring like lesions
 Leptomeningeal enhancement

30. T2w image showing
bilateral hyperintense
lesions in the cerebellum

31. T2w image with
hyperintense signal and
edema in the left
posterior hemisphere and
abnormalities in the
brainstem

32. Diffusion weighted
imaging of the same
region as in b with lesions
imitating cerebral
infarction.

33. Treatment:
 High-dose dexamethasone
 Longer half-life in the CSF and better CSF penetration
 10-20 mg/m2/day
 Etoposide: (75–100 mg/m2/week)
 Intrathecal Mtx and steroids weekly x 3 doses - until all CSF indices
and CNS symptoms normalize
 Surveillance CSF analyses - 2–3 weeks afterwards
 Brain MRI’s are typically abnormal for months - should not be used
in isolation for guiding subsequent therapy, unless clearly indicative
of new or worsening problems.
 HSCT