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Stem cell autopsy: clinical cases in lupus nephritis and multiple sclerosis

I continue to highlight pathological findings from autopsies and biopsies performed on patients underwent cell therapy procedures. I decide to make a new category – “Stem Cell Autopsy”. It doesn’t mean that I’ll highlight only stem cell transplant cases, but I’ll cover all cell therapies in general.

I believe that information from pathological findings will allow us to gain knowledge and avoid possible complications (sometimes fatal) in designing new clinical trials. To get a sense of how it is important, you can read:

Fatal complications of autologous cell therapy [1];
Clinical neurotransplantation of fetal tissues – analysis of histological findings [2];
Potential risk of tumor formation from adult stem cell therapy could be underestimated [3].

Today I’ll highlight 2 cases:

1. Angiomyeloproliferative kidney lesions following autologous stem cell therapy [4]

This news blew up in mass media last week. A woman, who suffered from severe lupus nephritis underwent autologous hematopoietic stem cell transplant (HSCT) into the kidney in a Thailand clinic and eventually developed fatal complications.

There was no improvement in renal function and the patient began hemodialysis 3 months after stem cell therapy. Six months after therapy, the patient presented with left flank pain and hematuria. Ultrasound and magnetic resonance imaging studies showed a 4.0-cm enhancing mass in the left renal pelvis, with smaller lesions in the left kidney, the liver, and right adrenal gland.

The clinical impression was urothelial cell carcinoma with metastatic spread to the right adrenal and liver. The patient underwent a left nephrectomy 11 months after stem cell therapy. The patient continued on hemodialysis over the next year but gradually deteriorated and died of sepsis after infection of the arteriovenous shunt.

The correlation between stem cell treatment and cause of death is unclear, because an autopsy was not performed. All conclusions were based on pathological examination of the removed kidney. So, we can’t claim “death caused by complications of stem cells treatment”.

Thus, the lesions in this patient showed both angioproliferative and myeloproliferative components, with an appearance not typical of any tumor or reactive condition. Given thatthere are multiple lesions in the left kidney and this patient received multiple injections of stem cells into this area, the logical conclusion is that these lesions are stem cell– derived or stem cell–induced. Because the exact number of injections is not known other than “multiple,” the number of lesions in the left kidney may or may not have exceeded the number of injections. We cannot rule out that one or more of the smaller lesions could have spread from the main lesion. Although the lesions in the liver and right adrenal were never biopsied, we postulate that these are the same as those in the left kidney. All injections were given blindly and the liver and right adrenal may have been injected instead of the right kidney, particularly because no lesions were detected in the right kidney.

Importantly, we can’t call these lesions a tumor, but should instead use the term proliferative disease.

Although the histology of these lesions appears to be benign, it is unknown if these are truly neoplastic or localized proliferations of normal stem cells. If they are stem cell -derived or -induced, the proliferative and recurrence potentials are unknown and the classic concepts of benign and malignant may therefore not apply.

My 2 final points:
– It is unclear whether these lesions arose from hematopoietic stem cells or more mature progenitors;
– it is unclear whether lesions were made of transplanted mobilized HSC or brand new cells migrate from bone marrow in site of tissue injury.

2. Neuroinflammation and demyelination in multiple sclerosis after allogeneic hematopoietic stem cell transplantation [5]

Authors examined the histopathological findings of 4 multiple sclerosis (MS) patients who received allogeneic HSC transplantation and died from different reasons.

Four patients with MS who died at a median of 4.5 months (range, 3-9 months) after allo-HSCT for a concomitant hematologic malignant neoplasm; 5 patients without MS who died at a median of 10.0 months (1-29 months) after allo-HSCT; and 5 control subjects without MS who did not undergo allo-HSCT

The present study is, to our knowledge, the first to examine CNS histopathological findings in MS patients after allo-HSCT. Despite the procedure, active demyelination and inflammation persisted, indicating the failure of allo-HSCT to halt the MS disease activity, at least during the follow-up period in these patients.

Although the non-MS brains that underwent allo-HSCT contained diffuse but mild inflammation, no obvious demyelination was identified in the present study.

In conclusion, the demyelinating and inflammatory activities of MS persist after allo-HSCT. The demyelinating activity is presumably due to the persistence of recipient immune cells in the MS brain, whereas the inflammatory activity is more likely the result of GVH reaction after allo-HSCT. The findings of the present small series of MS patients indicate that allo-HSCT fails to stop the demyelination and inflammation of MS.

This is a very well done study. The authors discuss possible mechanisms and compare with other autopsy-based studies, such as after autologous HSCT [6]. Unfortunately, pathological findings after both autologous and allogeneic HSCT confirmed the notion that we have no chance to fix a patient when severe demyelination and neurodegeneration in progressive MS occurs. We should focus on trials in inflammatory stages.