Localized AL amyloidosis of the colon: an unrecognized entity.

Virtually all patients who present with rectal bleeding and amyloid of the colon have evidence of systemic amyloidosis and require therapy. The small subset of patients with amyloidosis localized to the colon must be recognized and treatment avoided. We queried our file for patients who had amyloidosis of the colon but no evidence of systemic amyloidosis during long-term follow-up. We identified 3 patients who presented with rectal bleeding and who, on investigation, had primary amyloidosis of the colon but no evidence of systemic amyloidosis during a follow-up of 4.5 to 20 years. These patients had no evidence of a plasma cell dyscrasia and received no chemotherapy to prevent deposition of amyloid. It is important to recognize this rare subset and avoid treatment with alkylating agents or high-dose therapy followed by autologous stem cell transplantation. Alkylating agent therapy may be associated with myelodysplasia or acute leukemia. In addition, the cost, inconvenience, and morbidity of therapy are avoided by observation. Patients who present with rectal bleeding and a subsequent diagnosis of amyloidosis of the colon likely will be subjected to chemotherapy or transplantation. Such patients must be recognized and treatment avoided if there is no evidence of systemic amyloidosis because they remain stable for many years.     

Allogeneic bone marrow transplantation for systemic AL amyloidosis

Low-intensity chemotherapy is ineffective in most patients with AL amyloidosis, probably because clinical benefit requires regression of the amyloid deposits, and this occurs only very gradually after the underlying plasma cell dyscrasia has been suppressed. We report the first successful allogeneic bone marrow transplant (allo-BMT) for AL amyloidosis, which after 3 years was associated with complete clinical recovery. This supports the idea that there may be a brief window of opportunity in patients with AL amyloidosis during which dose-intensive chemotherapy is feasible and most likely to produce clinical benefit.     

Carfilzomib is an effective upfront treatment in AL amyloidosis patients with peripheral and autonomic neuropathy

Bortezomib is standard treatment in AL amyloidosis (AL), but is contraindicated in patients with significant neuropathy. Carfilzomib, a second-generation proteosomal inhibitor, results in a lower incidence of neuropathy than bortezomib, but data in AL is scant. We report a cohort of five AL patients treated with upfront carfilzomib. All had cardiac, peripheral and autonomic neuropathy at presentation. All achieved at least a very good partial haematological response. There was no worsening in cardiac function, peripheral or autonomic neuropathy. Carfilzomib is an effective upfront treatment option in AL patients with peripheral and/or autonomic neuropathy (without severe cardiac or renal involvement).     

Outcome of autologous stem cell transplantation for AL amyloidosis in the UK

High-dose chemotherapy with autologous stem cell transplantation (SCT) is widely used as a treatment for systemic AL amyloidosis, but its efficacy has not been proved and it has substantial toxicity in this setting. We report here the outcome of 92 patients evaluated at the UK National Amyloidosis Centre who underwent SCT for AL amyloidosis between 1994 and 2004 in various British centres. Median age was 53 years and median of two organs were affected by amyloidosis. All-cause day 100 mortality [treatment-related mortality (TRM)] was 23% for the entire cohort, although this was substantially greater for patients treated from 1994 to 1998 (15/47, 32%) than subsequently (6/45, 13%). Independent factors significantly associated with TRM on multivariate analysis were: number of affected organs, performance status, serum albumin and age. Response of the underlying clonal disease, defined by > or = 50% reduction in the aberrant serum-free light chain concentration, occurred in 83% of evaluable patients. Overall median survival was 5.3 years, and was 8.5 years among patients who survived beyond day 100. Despite recent refinements in patient selection, TRM remains substantial during SCT for systemic AL amyloidosis, and its place in the therapeutic armamentarium for this disease needs to be defined in randomised controlled clinical studies.     

AL amyloidosis with spontaneous hepatic rupture: successful treatment by transcatheter hepatic artery embolization

A 42-year-old male patient with primary AL amyloidosis experienced spontaneous hepatic rupture, producing diffuse widespread intrahepatic hemorrhage. Transcatheter hepatic artery embolization saved his life. Hepatic rupture infrequently develops in patients with systemic amyloidosis, but survival after this complication is rare because surgical treatments seldom succeed. Non-invasive emergent transcatheter embolization should be considered for hepatic rupture caused by massive deposits of amyloid.     

Marked shrinkage of amyloid lymphadenopathy after an intensive chemotherapy in a patient with IgM-associated AL amyloidosis

A male patient with primary AL amyloidosis who had been suffering from systemic lymphadenopathy with IgMκ-type M-proteinemia received two courses of VAD and high-dose melphalan with in vivo elimination of CD20⁺ cells using rituximab followed by autologous peripheral blood stem cell transplantation. Four years after complete hematological remission he showed marked reduction in size of the amyloid-laden lymph nodes. Deposits of AL amyloid may regress from the tissue if the chemotherapy succeeds in persistent inhibition of the production of amyloidogenic immunoglobulin light chains.     

Localized amyloidosis of the breast: a case series

We report on the clinical presentation and histopathology of a series of seven patients with localized amyloidosis of the breast. These patients were diagnosed by biopsy performed to rule out malignancy because of calcifications seen by mammography, and represented 0.5% of patients referred to the Amyloid Treatment and Research Program at Boston University Medical Campus in an 18-year period. The patients ranged in age from 35 to 75, median 63 years. None of these seven patients had evidence of a systemic plasma cell dyscrasia or amyloidosis in other organs, nor did systemic disease develop with a median follow-up of 6 years. Thus, other than excisional biopsy to exclude malignancy, no systemic therapy is indicated for this disorder.     

Nonsecretory immunoglobulin-derived amyloidosis of the heart: Diagnosis by immunohistochemistry of the endomyocardium

Primary amyloid light chain (AL) amyloidosis of the heart is a rare cause of congestive heart failure. Approximately 15% of patients with primary AL amyloidosis demonstrate no monoclonal proteins on serum or urine immunoelectrophoresis (so-called nonsecretory immunoglobulin-derived amyloidosis). The histologic findings of endomyocardial biopsy from these patients may be indistinguishable from those with senile cardiac amyloidosis. However, the AL type may respond favorably to chemotherapy while the latter type does not. The prognosis is also better in the senile cardiac amyloid type. The precise diagnosis in the present case was made by applying immunohistochemical techniques on cardiac tissues.     

Localized oral amyloidosis of the palate

Background.?Amyloidosis is a rare disease with multifactorial pathogenesis. Localized amyloidosis affecting the head and neck region is an uncommon and benign process, which has almost no clinical consequences. The most reported characteristic features of localized oral amyloidosis appear as multiple soft nodules of the tongue, lip and cheek.

Methods.?We report the case of a 68-year-old woman suffering from a primary localized amyloidosis presenting as a purple patch on the palate.

Conclusions.?The presence of systemic amyloidosis or underlying plasma cell dyscrasia have to be ruled out in patients presenting with a diagnosis of amyloidosis of the oral mucosa. If a primary localized amyloidosis is proven, the surgical therapy may be useful to eliminate a functional impairment.     

Perspectives in treatment of AL amyloidosis

Light chain (AL) amyloidosis is the most frequently diagnosed form of systemic amyloid in the western world. The historically poor prognosis of AL amyloidosis appears to be improving with currently reported median survival of c. 40 months compared to 13 months in the early 1990s when low-dose oral melphalan was the mainstay of treatment. Autologous stem cell transplantation (ASCT) achieves the highest rates of complete clonal response but is confounded by substantial treatment-related mortality in AL amyloidosis unless it is restricted to highly selected patients. Newer chemotherapy regimens appear to have a balance of better safety and respectable efficacy with overall outcomes nearly similar to ASCT, but which may be used more widely. There are few data comparing durability, depth of clonal response, rate of organ response and overall survival following ASCT or chemotherapy, but a recent small, randomized trial did not suggest superiority of ASCT to oral melphalan and dexamethasone. There is a compelling need for further and larger randomized trials in this context. At the same time, various new specific anti-amyloid drugs have shown (in early phase studies or animal models) some very promising results. This review attempts to highlight the challenges, controversies and progress in AL amyloidosis.     

Endoscopic and pathological manifestations of the gastrointestinal tract in familial amyloidotic polyneuropathy type I (Met30)

Yoshimatsu S, Ando Y, Terazaki H, Sakashita N, Tada S, Yamashita T, Suga M, Uchino M, Ando M (Kumamoto University School of Medicine; and Saiseikai Hospital, Kumamoto, Japan). Endoscopic and pathological manifestations of the gastrointestinal tract in familial amyloidotic polyneuropathy type I (Met30). J Intern Med 1998; 243 : 65–72.

Objectives

To evaluate the characteristic changes in the gastrointestinal tract in familial amyloidotic polyneuropathy (FAP) (Met30), both fibre gastroscopy and colonoscopy studies were performed in FAP (Met30) patients. Microscopic changes were also examined in autopsied and biopsied materials from patients with FAP, and compared with data from autopsied samples from patients with AL amyloidosis, and secondary amyloidosis patients.

Design

Endoscopic and histopathological study.

Setting

Kumamoto University Hospital, Kumamoto, Japan.

Subjects

Nine patients with FAP (Met30) underwent fibre gastroscopy and colonoscopy. Six autopsied and 23 biopsied gastrointestinal samples from FAP patients, four from autopsied amyloidosis (including two myeloma associated form), and two from autopsied secondary amyloidosis patients were examined for histopathological study.

Main outcome measures

Fibre gastroscopy and colonoscopy were employed for macroscopic study. Congo red and H-E staining were performed for histopathological study. Macroscopic changes in the gastrointestinal tract and microscopic differences in the amyloid distribution pattern were compared between the different types of amyloidosis.

Results

Fibre gastroscopy and colonoscopy for nine FAP patients revealed that four showed a fine granular appearance in the duodenum, three showed lack of lustre, and two showed mucosal friability in the gastrointestinal tract; however, no macroscopic abnormality was observed in four other FAP patients. Histopathological examination of tissue from FAP patients revealed that, although a small amount of amyloid was recognized in the submucosa perivascular layer, a significant amount of amyloid was seen in and around the nerves of the gastrointestinal tract, but very little in Auerbach's nerve plexus. In total, the amount of deposited amyloid in the tissues was small compared with that in other types of systemic amyloidosis, such as AL and secondary amyloidosis.

Conclusion

These results suggest that the major reason why FAP patients show such severe gastrointestinal symptoms, compared with other types of systemic amyloidosis, may be because of the deposition of a significant amount of amyloid in the nerves in the gastrointestinal tract.

     

Histological regression of amyloid in AL amyloidosis is exclusively seen after normalization of serum free light chain

Background

Histological regression of amyloid has not been studied systematically but is assessed by clinical parameters. We analyzed the change of amyloid deposition in fat tissue in patients with AL amyloidosis following chemotherapy and studied the relation with type of hematologic response.

Design and Methods

Between January 1994 and July 2007 all consecutive patients with AL amyloidosis were evaluated in whom fat tissue aspirate was obtained before and following chemotherapy. Patients were divided into three groups depending on response of serum free light chain: complete, partial or non-responders. Fat tissue was assessed using a validated semi-quantitative test (grading 0–4). A change of 2 grades of amyloid deposition in fat tissue was considered significant and used as event to construct Kaplan-Meier curves of the patients who were able to reflect such a change.

Results

One hundred and twenty consecutive patients were studied. Fifty-one patients fulfilled inclusion criteria. Thirty patients had a complete response of the amyloidogenic free light chain a median 0.5 year (range 0.3–2.9 years) following chemotherapy. Reduction of 2 grades of amyloid deposition in fat tissue was seen in 50% of these patients after 2.4 years and in 80% after 3.2 years. In contrast to complete responders, none of the patients with partial (n=9) and non-response (n=12) showed reduction of 2 grades (p=0.02) with median follow-up of fat tissue analysis of 1.3 and 0.8 years, respectively.

Conclusions

This study in a selected group of patients with AL amyloidosis shows significant histological regression of amyloid deposition in fat tissue exclusively after normalization of serum free light chain.     

Systemic AL amyloidosis due to non-Hodgkin's lymphoma: an unusual clinicopathologic association

Systemic AL amyloidosis (AL) is a disorder in which light chains form fibrillar deposits, leading to organ dysfunction and death. Rarely, AL has been associated with non-Hodgkin's lymphoma (NHL), although this association has not been well characterized. We report a series of six patients with AL associated with NHL, primarily lymphoplasmacytic lymphoma. Organ involvement was variable, with frequent bulky lymphadenopathy and visceral cavity deposits, but no cardiac involvement. Positron emission tomography scans were negative. Bone marrow and lymph node biopsies showed a mixed population of CD20+ lymphoid and CD138+ plasma cells. Serum free light chains were elevated, and correlated with response to therapy. Immunoglobulin light chain variable region (Ig VL) germline gene use was typical for AL, reflecting previously observed correlations between germline gene use and organ tropism. Five patients received rituximab-based therapies with two responses. Two patients underwent autologous stem cell transplantation with one complete haematological response. Four patients survive at 10-132 months from diagnosis. AL with NHL has distinctive clinical features but employs the same Ig VL gene repertoire as AL with clonal plasma cell dyscrasias. Serial serum free light chain levels are useful for tracking response to therapy. Treatments aimed at both lymphoid and plasma cell components appear warranted.     

Spontaneous rupture of the spleen in AL amyloidosis

The frequency of splenic involvement in AL amyloidosis is not precisely known. However, splenomegaly has been reported in 4-13% of patients. We report four cases of spontaneous splenic rupture in patients with AL amyloidosis. Splenic rupture was the initial manifestation of the disease in one of these patients. The other three experienced splenic rupture during or after high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT): one during stem cell mobilization with G-CSF prior to HDM/SCT and two after hematopoietic recovery following treatment. Two of the four patients had Factor X deficiency, the most common coagulation abnormality associated with AL amyloidosis. All four patients underwent splenectomy without significant postoperative complications. Splenic rupture in AL amyloidosis as a complication of aggressive treatment with HDM/SCT has not been reported previously.