Patient’s story

Last year, 8 July 2016, I started using Gilenya (fingolimod), this seemed to work ok, until about the end of 2016.

I was participating in a scientific study about fingolimod in which they are making MRIs every 6 months.

On the 20th of February, I had another scan made for this study. I was recalled to the hospital for a clinical scan following the oncology MRI protocol immediately the next day.

Since then a rollercoaster ride has started. They told me that evening that there were most certainly multiple lymphoma visible in my scan. With the largest one in the cerebellum (measuring 3.5cm). What followed was/is a long trajectory of exams that ended with a biopsy of the biggest lesion.
Because this has become such a complex story, I have kept a blog where I have written down my story. On this web page I have included all the diagnostic information.

It took more than two weeks for the very experienced pathologists at the VUmc to come up with something to say about the samples. What they see is very rare, atypical and abnormal, but there is no clear sign of lymphoma. The pathology report is included below.
Their hypothesis at the moment is that the fingolimod I was taking (8-7-2016 — 21-2-2017) somehow might have caused some kind of abnormal immune response (even though this has never been reported like this).

 

They think it might be B cell driven, but they can’t rule out that the T cells themselves are at fault. There is no definite conclusion about what to do yet, there will be more talks with the hematologists and neurologists.
We have spoken about Rituximab, which might treat both these strange masses, and my MS (which to me also seems very active on the scans). This might be one treatment option, but my neurologist wasn’t sure if, in case it is a T cell problem, this treatment might aggravate the symptoms.

After the successful brain biopsy, I have started taking dexamethasone. Symptoms have been improving since my admission (even before the Dexamethasone) and they continue to improve.
Judging from my symptoms (no headache or dizziness anymore) the masses are shrinking/disappearing (the MRIs of March 20 also show this). Of course, it was unclear whether this was due to time, the dexamethasone or the stopping with fingolimod. A new MRI scan of Friday the 7th of April after stopping with Dexamethasone, showed that the largest lesion increased in size again. Additional exams have been done, a lumbar puncture, a new eye exam. After these yielded nothing, a new brain biopsy was done on the 22th of April.

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A combination of registered T1 GD contrast scans of May 2016 (left) and February 2017 (right)

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Summary 13-3-2017

Dr. B. Platel was admitted to the hospital from 21-02-2017 until 28-02-2017, because of suspicion of cerebral lymphoma in the VUmc in Amsterdam.

History

October 2013 Relapsing-remitting multiple sclerose

Reason for admission

Abnormal MRI scan which was made for a scientific study of the use of fingolimod for relapsing remitting MS

Anamnesis

Since December complaints of dizziness. In particular, when looking up, also reported vomiting. Thought himself that it was MS exacerbation probably combined with the flu. Since mid-February symptoms have become better.

MRI brain (20-2-2017)

There are three new lesions left cerebellar, right in the thalamus and right high juxtacortical frontal cortical with the largest lesion located in the left cerebellum. This lesion presents sharply margined perifocal edema exorting mass force on the fourth ventricle and secondary liquor circulation disorder with widened aspect of the lateral ventricle and the third ventricle.
Differential diagnosis could be considered a paradoxical reaction with tumefactive be it demyelination multifocal lymphoma manifestation.
Further advice according to neuro-imaging oncology protocol.

MRI brain (21-2-2017)

(provisional) Multiple homogeneous staining cell-rich lesions supra and infratentorial, best suiting lymphoid tumor which is primarily thought to be non-Hodkin lymphoma.

PET-CT (23-2-2017)

With FDG-PET no detectable lymphoma localizations outside the cerebrum.

Discussion

A 39-year-old man familiar with RRMS was admitted because of suspicion multifocal cerebral lymphoma threatening cerebrospinal fluid circulation disorder. Patient was hospitalized for observation and because of the strong suspicion of a lymphoma, a biopsy was taken from the suspect tissue. Biopsy went without complications and patient could be discharged next day. Treatment with dexamethasone will follow as soon as the biopsy samples proof to be ok.

Conclusion

Suspicion multifocal cerebral lymphoma impending liquor circulation disorder

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Patient Information

Date of Birth: 6 February 1978
Allergies: None
Country of origin: The Netherlands
Current height: 200 cm
Current weight: 87 kg
Diagnosis: relapsing-remitting multiple sclerosis (since October 2013)
First symptoms occurred October 2013 (brainstem lesion, causing paroxysmal symptoms (right side of the face tingling and at the same time on the left side motoric difficulties in the arm and leg).
Final diagnosis was made in August 2014, since that time the disease has shown to be active on the MRI scans, mostly showing small GD enhancing lesions.

Current EDSS

3.0, evaluated on 13-6-2016

Past/present medical treatments and responses

• Tecfidera (dimethyl fumarate): 1 October 2015 — 24 December 2015 (no noticeable reduction in progression of clinical symptoms as well as continued new active MRI lesions)
• Rebif (interferon beta-1a): 31 December 2015 — 6 July 2016 (no noticeable reduction in progression of clinical symptoms as well as continued new active MRI lesions)
• Gilenya (fingolimod): 8 July 2016 — current

No. of relapses since diagnosis

No clear pronounced relapses since diagnosis, insidious degeneration with periods of worsening of symptoms and partial recovery months later.
First paroxysmal symptoms, that triggered the diagnosis, disappeared after half a year.

Blood Type

O-

Blood test

22-2-2017 08:30
Hb 9.3
Thrombo’s 225
Leuco’s 2.0 (PL)
Eo (microscopic) 0.00
Baso (microscopic) 0.00
Blasts 0.00
Promyelocytes 0.00
Myelocytes 0.00
Metamyelocytes 0.00
Staff 0.00
Segments 1.50
Lymfocytes (microscopic) 0.24 (PL)
Monocytes (microscopic) 0.26
anisochromasie +
anisoplanie +
Kreatinine 70
eGFR (MDRD) >90
LD 123
HBsAg Negative
Anti HBsAg Negative
HCV Ig total Negative
HIV Ag+As Negative

Co-morbidities

None

Family history

Father (Born 4 Nov 1949) has RRMS (diagnosed at age 29) which has progressed to SPMS
Sister (Born 18 April 1980) (only sibling) has RRMS (diagnosed at age 26)
Mother (Born a5 December 1953) has congenital myopathy, late onset (diagnosed at age 40) (expressed as rigid spine syndrome)
No other (distant) family members have any of these diseases

History of infection

None

Medications at admission

• Fingolimod 0.5 mg 1 dd (Gilenya) (Start date 8 July 2016)
• Fluticasone furoate 1x daily 1 inhalation (Start date 1 January 2011, indication: nose polyp)

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MRI files (DICOM ZIP)

Jeroen Bosch Ziekenhuis 30 October 2013
Jeroen Bosch Ziekenhuis 11 July 2014
Jeroen Bosch Ziekenhuis 17 February 2015
VUmc 23 September 2015
VUmc 11 May 2016
VUmc 28 July 2016
VUmc 21 February 2017
VUmc 20 March 2017

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Neurosurgery

Date of stereotactic biopsy: 27-2-2017.
Date of resignation: 28-2-2017.

Indication

suspected cerebral lymphoma

Case history

Since late December 2016 paroxysmal vertigo. This occurs mainly when looking upward, which made his eyes have rapid movements. This occurred several times a day and took in total about a day and then again days without complaints. Also, his walking balance has become less in recent weeks. Since early January 2017, he has a headache. No visual complaints. Symptoms have been reducing since the 16th of February.

Additional studies

Brain MRI 21-2-2017: multiple homogeneous enhancing cell-rich lesions supra and infratentorial, best fitting with multifocal lymphoid tumor in which a lymphoma is thought of in the first place.

Conclusion

A 39-year-old man with suspected cerebral lymphoma.

Operation

27-02-2017, Stereotactic biopsy

Postoperative

No complications, discharge 28-2-2017

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Pathology Report

Brain biopsy 27 February 2017, taken before start of steroid treatment (dexamethasone)

Clinical details

Suspicion of cerebral lymphoma left hemisphere. Familiar with MS since 2013, for which multiple immunomodulatory treatments have been administered. The latest one being fingolimod. MRI scan that was made for a research study showed multiple intracerebral lesions, that do not resemble MS lesions. Largest abnormalities in the cerebellum and basal ganglia, these lesions occupy space. Patient has limited symptoms.

Macroscopy

3 biopsies, maximal diameter 1.2 cm, 1 x t.i.

Microscopy

Cerebellar brain tissue containing many histiocytes (CD68 +) and a diffuse lymphocytic infiltrate in which many small cells and sometimes cells with slightly larger cores with a nucleolus. This infiltrate is strongly CD3 and CD5 positive with only a few CD20 and CD79a positive cells. EBER is negative. Further typing shows that the cells are CD2 positive. Assessment of CD4 is a bit tricky due to the many macrophages, but it seems clear to top the CD8.
The TIA-1 shows some positive cells, more or less corresponding to the CD8. The CD7 is negative.
/PVDV

It is a very dense T-cell infiltrate without a component B-cell (CD20, CD79a) and without EBER positive blasts. The T-cells are always small with some morphological variation and positive for CD2, CD3 and CD5. CD7 is almost entirely negative. The infiltrate consists of T-cell receptor alpha-beta positive cells with low gamma-delta positive cells and a large component of PD1 positive T-cells. There are only a few B-cells, and these are all small (CD20, PAX-5). However, there are recognizable CD30 positive blasts. The molecular biology research is rather multi-interpretable as oligoclonal or monoclonal in a polyclonal background.
The whole is extremely difficult to interpret. Thought to be an immune dysregulation, but this is more often seen with gamma-delta alpha-beta populations, therefore this would be less likely. The big component of PD1 positive cells is suggestive of having an immune deficiency related background with relatively small B-cells, but CD30 positive. This is maybe more likely.
/DDEJO

Molecular biological analysis (clonality analysis of T-cell Based on TCRG Gene Clonality Assay (IVS)): The TCRG gene reordering analysis shows reproducible prominent signals in
an incomplete polyclonal background (mix A blue (193bp), mix A green (224bp), mix B-blue (196bp), mix B Green (178bp)). The interpretation of this analysis with respect to the presence/absence of a monoclonal T-cell population has to be done in conjunction with the clinical and histological data.
/ Damh

Conclusion

Authorization date: 14-03-2017
Lesion biopsy left cerebellum with a lymphoid process, which in the context is extremely difficult to interpret. Most likely is a reflection or result of immunomodulation by fingolimod
be regarded as an immune deficiency related B-lymphoproliferative disorder ‘with a very limited CD30 positive component, negative EBER relatively small B-cells.
Alternatively, one can think of a primary T cell dysregulation.
For further interpretation, correlation with follow-up MRI is essential (after stopping with fingolimod).

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General Conclusion 14-3-2017

Based on the results of the biopsy the newly created lesions most correspond to an immune dysregulation most likely caused by B cells with a secondary response of T cells. Alternatively one can think of a primary T-cell dysregulation.
Possible that it originated as a response to immunomodulation by fingolimod. Fingolimod is stopped per the 21st of February, and the patient is using 8mg dexamethasone daily since the 1st March.
To evaluate the effect of the stopping with fingolimod and the administration of dexamethasone, a new MRI is scheduled for the 20th of March.
It should be realized that both these factors can have an effect on the lesions. After results of the MRI and consultation with hematology treatment policy will be determined.

Follow-up MRI 20-3-2017

The follow-up MRI of 20-3-2017 (DICOM link above) shows a  reduction of lesion sizes. Tapering and stopping Dexamethasone and follow-up MRIs will have to show whether the lesions will further shrink without the help of steroids, or whether they will grow again.

An MRI slice with contrast of 21st Feb (left) and 20th of March (right)

Epstein-Barr Virus

Epstein-Barr Virus VCA IgG (blood) Positive
Epstein-Barr Virus DNA PCR (blood) Negative

Lumbar Puncture

CSF cytology, the cell’s morphology appears normal

They also used something that I believe is called immunological marker analysis, to study the cell surface markers, to try and identify monoclonal (cancerous) cells, again this didn’t yield anything.

Overview 20-4-2017

Final addition

A second brain biopsy was made, which did not lead to new insights.

The doctors decided to treat for a primary central nervous system T-cell lymphoma.
The hematopathologist told me that the final-final diagnosis was secret option five: An even rarer “lymphoproliferative disorder with oligoclonal T-cell expansion”, you can read about it in my blog post of that day.

Treatment has started on the 16th of May and on the 29th of October I was released from the hospital after the last scheduled treatment. The next MRI scan is planned for the 12th of Januari 2018.

The first part took place in the Jeroen Bosch hospital in ‘s-Hertogenbosch, the second part took place at the Spaarne hospital in Hoofddorp, and the third took place in the VUmc in Amsterdam.