Pathology of Plasma Cell Dyscrasia: How Much Can We Learn From Autopsy Studies?

In the August issue of the Archives, Herrera et al1 published an autopsy-based study of the morphologic spectrum of renal pathology seen in patients with plasma cell dyscrasia (PCD). Renal symptoms, either glomerular (typically proteinuria) or tubulointerstitial (renal failure) are not only present in the majority of patients with PCD, but also are frequently apparent before diagnosis of the underlying process is even considered.2 Consequently, the renal pathology associated with underlying PCD has been extensively studied, primarily in kidney biopsy material. There is a wide spectrum of lesions, some of which are a direct consequence of the circulating monoclonal protein, while others are secondary to the tumor burden and myeloid suppression.3 In most of these pathologies, the immunostains and electron microscopic studies that are routinely used for the evaluation of kidney biopsies have been critical in establishing a correct diagnosis. In particular, the recognition of light chain restriction by immunohistochemical methods has been pivotal in recognizing early changes. Consequent to increased awareness of the renal pathology accompanying early PCD, an increasing number of patients are being diagnosed at earlier stages and are being aggressively treated with various protocols.2 

What can be gained from autopsy studies in patients with PCD? Since the diagnosis has already been established, the treatment(s) has been tried, and (presumably) failed. Moreover, autopsy studies are perceived as providing suboptimal material due to autolytic changes and they are also hampered by the unavailability, in most instances, of immunofluorescence and electron microscopic studies.

However, let us keep in mind that the objectives of pathologic examination at the time of autopsy are very different from those at the early stages of PCD. For instance, we are no longer looking for the early diagnostic clues of PCD but, rather, for evidence of residual disease in patients who have undergone treatment. Also, as the spectrum of PCD expands and new therapies targeting these different disease types emerge, patient prognoses are changing. Thus, autotransplant-supported, high-dose therapy has improved the outcome for 65% of patients with “good” risk multiple myeloma—a survival rate of more than 10 years can be expected in 40% of these patients. As patient survival is extended and the aggressiveness of therapy increases, there is a clear need for studies of the pathology of these processes. For example, what is the efficacy of these new regimens? What is the pathology of relapse? How has the disease process been altered by the treatment? What are the short- and long-term complications, and what is the toxicity of these new treatments?

In the study by Herrera et al,1 interstitial manifestations and lesions were found to be more common than glomerular pathology. Light chain cast nephropathy and acute tubulopathy (acute tubular necrosis) were the most frequent findings. Thirty-five patients (45%) had more than one finding in renal tissue. Not detected in this series were the crystalline deposits of monoclonal light chain in the proximal tubular epithelium that are seen in acquired Fanconi syndrome or the recently described proliferative glomerulonephritis with monoclonal immunoglobulin G deposits. Also, the rate of amyloid and light chain deposition disease (LCDD) deposits was lower than previously reported. Interestingly, it has been suggested that acquired Fanconi syndrome and LCDD may be associated with a relatively “indolent” PCD and, therefore, a paucity of these pathologies may be expected in this patient population. Alternatively, however, this discrepancy may reflect underdiagnosis or patient-selection bias. Their patients do not represent the full spectrum of PCD but, rather, a select group with a performance status good enough to undergo stem cell transplantation.

Treatment-related pathology such as acute tubulopathy, thrombotic microangiopathy, and infections in the kidneys were present in more than 50% of patients studied. However, plasma cell tumor nodules in the kidneys were seen in less than 4% of patients. Although the data on renal pathology are interesting, one would like to see the remaining autopsy data. In particular, the incidences of residual disease and infections, which require multiorgan evaluation, most likely have been underrepresented in this study.

Autopsy, despite its shortcomings, offers a unique insight into the evaluation of systemic processes. As new treatment modalities are developed and tried, autopsy evaluation serves as an important quality assurance monitor of treatment efficacy and toxicity. One can only regret that more autopsy studies addressing these issues have not been forthcoming thus far. As we travel further into the realm of molecular pathology, let us not forget that a great deal can be learned from classical microscopy of autopsy material. Although it may not provide all the answers, it may yet give us information not otherwise available.