Background: The amyloidoses are a rare and heterogeneous group of disorders that are characterized by the deposition of abnormally folded proteins in tissues ultimately leading to organ damage. The deposits are mainly extracellular and are recognizable by their affinity for Congo red and their yellow-green birefringence under polarized light. Current classification of amyloid in medical practice is based on the amyloid protein type. To date, 36 proteins have been identified as being amyloidogenic in humans. Summary: in clinical practice, it is critical to distinguish between treatable versus non-treatable amyloidoses. Moreover, amyloidoses with a genetic component must be distinguished from the sporadic types and systemic amyloidoses must be distinguished from the localized forms. Among the systemic amyloidoses, AL continues to be the most common amyloid diagnosis in the developed world; other clinically significant types include AA, ALECT2, and ATTR. The latter is emerging as an underdiagnosed type in both the hereditary and wild-type setting. Other hereditary amyloidoses include AFib, several amyloidoses derived from apolipoproteins, AGel, ALys, etc. In a dialysis setting, systemic amyloid derived from β₂ microglobulin (Aβ2M) should be considered, although a very rare hereditary variant has also been reported; several amyloidoses may be typically associated with aging and several iatrogenic types have also emerged. Determination of the amyloid protein type is imperative before specific therapy can be implemented and the current methods are briefly summarized. A brief overview of the target organ involvement by amyloid type is also included. Key Messages: (1) Early diagnosis of amyloidosis continues to pose a significant challenge and requires the participation of many clinical and laboratory specialties. (2) Determination of the protein type is imperative before specific therapy can be implemented. (3) While mass spectrometry has emerged as the preferred method of amyloid typing, careful application of immune methods is still clinically useful but caution and experience, as well as awareness of the limitations of each method, are necessary in their interpretation. (4) While the spectrum of amyloidoses continues to expand, it is critical to distinguish between those that are currently treatable versus those that are untreatable and avoid causing harm by inappropriate treatment.

Context. —Amyloidoses are disorders of diverse etiology in which deposits of abnormally folded proteins share distinctive staining properties and fibrillar ultrastructural appearance. Amyloidosis ultimately leads to destruction of tissues and progressive disease. With recent advances in the treatment of systemic amyloidoses the importance of an early diagnosis of amyloid, and a correct diagnosis of its type, has been realized. Objective. —To summarize current recommendations for the diagnosis of amyloidosis. Data Sources. —Presentation given at the 4th Annual Renal Pathology Society Satellite meeting in Istanbul based on discussions and recommendations formulated during an interactive diagnostic session held at the XIth International Symposium on Amyloidosis in Woods Hole, Massachusetts. Conclusions. —Congo red stain is currently the gold standard for amyloid detection and the goal is to detect amyloid early. Diagnosis of the amyloid type must be based on the identification of amyloid protein within the deposits and not solely by reliance on clinical or DNA studies. However, the latter are recommended for confirmation of the amyloid type based on evaluation of the protein in deposits. Immunohistochemistry must be performed and interpreted with caution and inconclusive results must be evaluated further using the more sophisticated methods available in referral centers. An adequate amount and quality of tissue must be available for amyloid diagnosis and typing with emphasis on the use of fresh tissue and greater use of abdominal fat biopsy. The development of new technologies underscores the need for regular review of recommendations and standards for the clinical diagnosis of amyloidosis.

This review aims to summarize recent developments in the area of systemic amyloidoses with emphasis on pathologic diagnosis. In recent years, management of amyloidosis has shifted from a purely supportive approach to quite diverse, radical and aggressive treatments. The central issue is the understanding that treatment of systemic amyloidoses depends on the molecular type of the amyloid protein. In the United States and the Western world, AL-amyloidosis is the most prevalent type of systemic amyloidosis, but hereditary amyloidoses are being diagnosed with increasing frequency; genetics also plays a role in a subset of familial AA amyloidoses. The biggest challenge is in the diagnosis of AL-type with confidence and in differentiation of AL and hereditary amyloidoses. While careful clinico-pathologic correlation is recommended for all patients with amyloidosis, it is, in itself, not a substitute for amyloid typing. The diagnosis of the amyloid type ultimately depends on the examination of the amyloid protein within the deposits. The role of immunohistochemistry - the current standard of care in amyloid typing - is evolving with emergence of alternative biochemical methods. Amyloid, being essentially a protein disorder, presents an attractive venue for the application of proteomics methodologies, despite their inherent complexities.

Context. —In plasma cell dyscrasias, involvement of the distal tubules is frequent and well characterized. In contrast, proximal tubules have only rarely been reported to show diagnostic pathology such as intracytoplasmic crystals. Objective. —To look for additional morphologic features that might be helpful in the diagnosis of proximal tubulopathy associated with an underlying plasma cell dyscrasia. Design. —We examined patients presenting with nonspecific renal symptoms who were found to have light chain restriction limited to proximal tubular epithelium by immunofluorescence. We correlated these results with light microscopy, electron microscopy, and the clinical findings. Results. —By immunofluorescence, 5 patients had light chain restriction in proximal tubular epithelium. By light microscopy, only 1 patient had focal rhomboid crystals in the proximal tubular epithelium; all other biopsies failed to show any discernible pathology within the proximal tubules or elsewhere in the kidney. By electron microscopy, proximal tubules from 2 patients showed crystals with a latticelike structure, whereas the remaining 3 patients had only prominent phagolysosomes. However, by immunoelectron microscopy, the lysosomal content showed light chain restriction (in 2 cases studied). Post–kidney biopsy, all patients were diagnosed with multiple myeloma or plasma cell dyscrasia. One patient developed renal failure and had recurrence of crystals in the allograft. Conclusions. —Light chain proximal tubulopathy may be associated with the presence of crystals or with the presence of phagolysosomes with light chain restriction as the sole abnormality. Both κ and λ light chains may be involved. The prognosis is variable and the pathology may recur in transplants.

Context. —Cystic nephroma is a rare cystic tumor, which only recently has been recognized as an exclusively adult lesion. Mixed epithelial and stromal tumor of the kidney is also a rare, recently recognized, biphasic tumor composed of tubular and cystic elements embedded in grossly recognizable spindle cell stroma. The histogenesis of both lesions is unclear. Objectives. —To compare clinical phenotype, morphology, and immunohistochemistry in mixed epithelial and stromal tumor of the kidney and cystic nephroma in order to explore the relationship between these 2 lesions. Design. —Fifteen biphasic lesions (8 mixed epithelial and stromal tumors of the kidney and 7 cystic nephromas) were studied. All cases were reviewed and subjected to detailed pathologic studies, and the results were correlated with clinical findings. Results. —Mixed epithelial and stromal tumor of the kidney occurred exclusively in women aged 36 to 80 years (mean, 49.7 years), all of whom had a history of estrogen therapy and/or obesity. Cystic nephroma occurred in both sexes; patients were aged 22 to 71 years (mean, 50.4 years), and a history of hormonal therapy was present on occasion. All 15 lesions were benign. Lesions varied by size, the proportion of cystic component, and the amount and cellularity of stroma. However, in all lesions tested, the stroma was diffusely positive for smooth muscle actin, and smooth muscle differentiation was confirmed by electron microscopy. In mixed epithelial and stromal tumors of the kidney, the stroma was positive for estrogen and progesterone receptors in 4 of 5 lesions tested. In cystic nephroma, focal positivity for hormone receptors was seen in 2 of 7 tumors tested; both positive lesions were from women. The epithelial lining in both mixed epithelial and stromal tumor of the kidney and cystic nephroma lesions was variable with regard to shape, cytoplasmic appearance, and immunophenotype (with focal positivity for CD10, cytokeratin 7, high-molecular-weight keratin, and Ulex europaeus detectable in both lesions). This pattern suggests variable differentiation, which was confirmed by electron microscopic studies (performed in 1 case). Conclusions. —While mixed epithelial and stromal tumor of the kidney has a strong association with the female sex and hormonal milieu, cystic nephroma can affect both sexes and, on occasion, may also have hormonal associations. Morphologically, there is considerable overlap between both lesions, which suggests that they may represent opposite ends of the spectrum of the same process. Our studies also suggest that the tubules may be entrapped rather than comprising an intrinsic component of the tumor. However, further studies, including molecular studies, are needed to support this hypothesis.