Abbreviations
amyloid A
amyloid immunoglobulin light chain
AL not otherwise specified
amyloid immunoglobulin light chain‐ κ
amyloid immunoglobulin light chain‐ λ
Annual of the Pathological Autopsy Cases in Japan
amyloid transthyretin
ATTR not otherwise specified
variant ATTR
wild‐type ATTR
amyloid β 2 ‐microglobulin
group for surveys and research of amyloidosis in Japan
liquid chromatography coupled with tandem mass spectrometry
INTRODUCTION
Clinical presentation of systemic amyloidosis differs among subtypes, and an accurate subtype classification is important for the selection of type‐specific therapeutics. 1 , 2 , 3 , 4 In the 1990s, amyloid A (AA) was the most common subtype of systemic amyloidosis among the immunohistochemically classified autopsy cases. 5 , 6 In the 2010s, a systematic investigation of biopsied cases revealed that amyloid immunoglobulin light chain (AL) was the most common subtype of systemic amyloidosis. 7 , 8 In 2018, the Group for Surveys and Research of Amyloidosis in Japan (GSRA‐J) started a nation‐wide pathology consultation of amyloidosis, 1 and amyloid transthyretin (ATTR) was found to be the most common subtype of systemic amyloidosis in Japan. 9 Tateishi et al. 10 reviewed autopsy cases in a single Japanese institution (Kyushu University) from 1990 to 2020 and found that ATTR is the most common subtype of cardiac amyloidosis, followed by AA.
The Annual of the Pathological Autopsy Cases in Japan (APAC‐J) edited by the Japanese Society of Pathology and published since 1960 ( https://pathology.or.jp/kankoubutu/autopsy-index.html ) lists all cases autopsied during the year at the hospitals registered in the Japanese Society of Pathology. APAC‐J lists autopsy cases of systemic amyloidosis in Japan during each 1‐year period. GSRA‐J selected 249 autopsy cases of systemic amyloidosis listed in APAC‐J, Volume 55 (published in 2012) and preliminarily analyzed the subtype frequency by a questionnaire survey. 11 The results showed that AL was the most common subtype (33.3%), followed by AA (16.5%), and ATTR (8.8%). Surprisingly, the subtype could not be determined in 38.2% of the cases. This survey revealed that in Japan, the subtypes are not correctly diagnosed in many cases of systemic amyloidosis, mainly because some laboratories are unable to diagnose the subtypes of systemic amyloidosis immunohistochemically. This result urged us to establish a nation‐wide pathology consultation system of amyloidosis. 1
In this study, we analyzed the systemic amyloidosis cases autopsied from January 1, 2017, to December 31, 2018, and listed in APAC‐J, Volumes 60 and 61. When the subtype was not clear, we performed a questionnaire survey, immunohistochemistry, and proteomic analysis to classify the subtype. We also determined the subtype frequency of systemic amyloidosis cases, in which systemic amyloidosis was the main cause of death. The dramatic change in the subtype frequency among autopsy cases during the last three decades is discussed.
METHODS
Study flow
In APAC‐J, the number and name of each registered institution is described at the top of each page, followed by a table of each case, which describes the case number, age/sex, clinical diagnosis, main clinical department, pathological diagnosis, and treatment of each patient (Table 1 ). The main cause of death was identified by autopsy and indicated in bold letters (Table 1 ). These data are available in print and as PDF files attached to the Annuals. The APAC‐J, Volumes 60 and 61 (published in 2019 and 2020, respectively) listed 21 412 autopsy cases from January 1, 2017 to December 31, 2018. First, we converted the PDF files of APAC‐J into Excel files and selected systemic amyloidosis cases by a keyword search (Figure 1 , Table 1 ). Next, we classified the systemic amyloidosis cases based on the criteria for the subtype classification (Table 2 ). When we needed additional minor information (e.g., κ or λ in AL cases; organ distribution in suspected ATTRwt cases), we sent a questionnaire survey to the corresponding institutions. When we could not classify the subtype based on the criteria or after the questionnaire survey, we asked the corresponding institutions to send us ten pieces of 4‐μm‐thick sections from formalin‐fixed paraffin‐embedded tissue of representative organs for Congo‐red staining and immunohistochemical analysis. When we could not classify the subtype after immunohistochemical analysis, we asked the corresponding institutions to send us block specimens for proteomic analysis. After subtype classification, we took photographs of each case and returned the results and specimens to each institution.
Table 1
Excerpts of amyloidosis cases from the Annual of the Pathological Autopsy Cases in Japan, Volume 61 (2020).
Note : This table indicates three amyloidosis cases autopsied at three different institutions. In the Annuals, the number and name of each registered institution is described at the top of each page, followed by the table of each institution's cases (not shown here). The main cause of death is identified by autopsy and indicated in bold letters. These data are available in print and as PDF files attached to the Annuals. M/F: male/female.
| Case number at each institution | Age/Sex | Clinical diagnosis [Main clinical department] | Pathological diagnosis | Treatments |
| 1997 | 70/M | Cardiac amyloidosis, Multiple myeloma [Cardiology] | Multiple myeloma (BJP‐λ type) (ribs, sternum) (1) Systemic amyloidosis (heart 470 g, kidney 140:110 g). (2) Pulmonary congestion with edema. (3) Gangrenous cholecystitis. (4) Left prostatic hypertrophy and right acute prostatitis. (5) Poststroke state. | Anticancer drug |
| 10774 | 86/M | Acute hepatic failure, Chronic heart failure [Internal medicine] | Senile systemic amyloidosis (heart, bilateral lungs, spleen, adrenal glands, liver, pancreas, esophagus, stomach, small intestine, tongue, thyroid gland, trachea, urinary bladder). (1) Fluid retention in body cavities (pleural effusion 1600:1400 mL, ascites 300 mL, pericardial effusion 400 mL). (2) Pulmonary edema (312:650 g) (3) Congestive hepatopathy + shock liver. (4) Colloidal bone marrow. (5) Aortic atherosclerosis (mild). | Antibiotic |
| 11815 | 75/F | Rheumatoid arthritis, Secondary amyloidosis [Palliative care] | Secondary amyloidosis (heart, lung, kidney, urinary bladder, spleen, liver, pancreas, and gastrointestinal tract). (1) Rheumatoid arthritis. (2) Gastrointestinal cytomegalovirus infection. (3) Drug‐associated lymphoproliferative disorder (mass formation in lung). (4) Bronchopneumonia (420:620 g). (5) Ascites (1200 mL). (6) Right pleural effusion (small amount). | Adrenal corticosteroid |
Table 2
Criteria for the subtype classification based on the description of the Annual of the Pathological Autopsy Cases in Japan.
Note : Each subtype was confirmed if A, B, or C was met. Abbreviations: AA, amyloid A; AL, amyloid immunoglobulin light chain; ATTR, amyloid transthyretin; ATTRv, variant ATTR, ATTRwt; wild‐type ATTR, Aβ2M, amyloid β 2 ‐microglobulin.
| Subtype | Criteria | |
| AL | A | One of the following is met. |
| 1. “AL amyloidosis” is described. | ||
| 2. “Primary amyloidosis” and “after chemotherapy” are described. | ||
| B | All the followings are met. | |
| 1. Multiple myeloma, plasmacytoma, lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia, monoclonal γ‐globulinemia, or “positive for urine Bence Jones protein” is described. | ||
| 2. Age less than 70 years old (exclusion of most ATTRwt cases). | ||
| 3. No description of rheumatoid arthritis or other diseases causing AA amyloidosis (exclusion of most AA cases). | ||
| 4. No description of “familial” or “isolated” (exclusion of most ATTRv and other hereditary amyloidosis cases). | ||
| 5. No history of long‐term hemodialysis (exclusion of most Aβ2M cases) | ||
| ATTRwt | A | “Systemic wild‐type transthyretin amyloidosis,” “senile systemic amyloidosis,” or “senile cardiac amyloidosis” is described. |
| B | All the followings are met. | |
| 1. “ATTR amyloidosis” is described. | ||
| 2. Age more than 80 years old. | ||
| 3. Typical organ distribution (heart, lung, vessel walls of systemic organs). | ||
| 4. No description of “familial” or “isolated” (exclusion of most ATTRv cases). | ||
| C | All the followings are met. | |
| 1. Age more than 80 years old. | ||
| 2. Typical organ distribution (heart, lung, vessel walls of systemic organs). | ||
| 3. No description of multiple myeloma, plasmacytoma, lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia, monoclonal γ‐globulinemia, or “positive for urine Bence Jones protein” (exclusion of most AL cases). | ||
| 4. No description of rheumatoid arthritis or other diseases causing AA amyloidosis (exclusion of most AA cases). | ||
| 5. No description of “familial” or “isolated” (exclusion of most ATTRv and other hereditary amyloidosis cases). | ||
| 6. No description of long‐term hemodialysis (exclusion of most Aβ2M cases). | ||
| ATTRv | A | “Mutant ATTR amyloidosis,” “familial amyloid polyneuropathy,” or “ATTR amyloidosis, solitary case” is described. |
| AA | A | “AA amyloidosis” is described. |
| B | All the followings are met. | |
| 1. Rheumatoid arthritis or other diseases causing AA amyloidosis is described. | ||
| 2. No description of multiple myeloma, plasmacytoma, lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia, monoclonal γ‐globulinemia, or “positive for urine Bence Jones protein” (exclusion of most AL cases). | ||
| 3. Age less than 70 years old (exclusion of most ATTRwt cases). | ||
| 4. No description of “familial” or “isolated” (exclusion of most ATTRv and other hereditary amyloidosis cases). | ||
| 5. No description of long‐term hemodialysis (exclusion of most Aβ2M cases). | ||
| Aβ2M | A | One of the following is met. |
| 1. “Dialysis‐associated amyloidosis” is described. | ||
| 2. “dialysis kidney (end‐stage atrophic kidney) + (secondary) amyloidosis” is described. | ||
| B | All the followings are met. | |
| 1. Chronic renal failure or history of dialysis is described. | ||
| 2. No description of multiple myeloma, plasmacytoma, lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia, monoclonal γ‐globulinemia, or “positive for urine Bence Jones protein” (exclusion of most AL cases). | ||
| 3. No description of rheumatoid arthritis or other diseases causing AA amyloidosis (exclusion of most AA cases). | ||
| 4. Age less than 70 years old (exclusion of most ATTRwt cases). | ||
| 5. No description of “familial” or “isolated” (exclusion of most ATTRv and other hereditary amyloidosis cases). |
We adopted the opt‐out protocol; the corresponding institutions downloaded the document for opting out from the homepage of GSRA‐J ( http://amyloidosis-research-committee.jp/ ), then it was uploaded on individual webpages or printed to display at each institution. This study was approved by the Institutional Review Board of the University of Fukui School of Medicine (20210007).
Immunohistochemistry
Formalin‐fixed, paraffin‐embedded tissue was sectioned at 4 µm thickness. Serial sections were immunostained by the streptavidin‐biotin‐peroxidase complex method. As primary antibodies, we used anti‐κ chain 116 – 133 , anti‐λ chain 118 –134 (rabbit polyclonal), 12 anti‐TTR 115 –124 (rabbit polyclonal), 13 anti‐AA (Dako) and anti‐β 2 ‐microglobulin (Dako) antibodies. 1 As antigen retrieval methods, formic acid (anti‐κ, anti‐λ, anti‐TTR) and autoclave at pH 6.0 (anti‐β 2 ‐microglobulin) were used. Subsequent procedures were performed using Histofine SAB‐PO (MULTI) kits (Nichirei). The immunohistochemical subtype was confirmed when serial sections were positive only for one antibody, and negative for other antibodies (Figure 2 ).
Proteome analysis
We performed protein extraction and proteome analysis using liquid chromatography coupled with tandem mass spectrometry (LC‐MS/MS) as previously described. 14 , 15 Briefly, laser capture microdissection (LMD7000; Leica Microsystems) was performed using the bright‐field setting to confirm the presence of amyloid deposits, which were placed into microcentrifuge tubes containing 10 mM Tris, 1 mM EDTA, and 0.002% Zwittergent 3–16. Collected tissue samples were heated at 98°C for 60 min. Samples were sonicated for 90 min and digested with 1.5 μL of 1 mg/mL trypsin (Promega) overnight at 37°C. Digested peptide mixtures were reduced with dithiothreitol at 95°C for 5 min and dried. Redissolved peptides in 40 μl of solution containing 0.1% trifluoroacetic acid and 2% acetonitrile, were analyzed using nano‐flow reversed‐phase LC‐MS/MS (LTQ Velos Pro; Thermo Fisher Scientific). We obtained the relative abundance of the identified molecules using the normalized spectral abundance factor. 16
RESULTS
Out of 21 412 cases listed in APAC‐J, Volumes 60 and 61, we found 481 (2.2%) systemic amyloidosis cases. Using the criteria for subtype classification (Table 2 ), we classified the subtypes of 163 cases (33.9%). Nine cases were ALκ, 18 cases were ALλ, 92 cases were ATTRwt, three cases were ATTRv, 18 cases were AA, and 23 cases were Aβ2M (Table 3 ). To classify the subtypes of the remaining 318 cases (66.1%), we asked the corresponding institutions either to respond to the questionnaire survey ( n = 127) or to send us ten pieces of 4‐μm‐thick sections from formalin‐fixed paraffin‐embedded tissue for histopathological analysis ( n = 191). The overall response rate was 78.0% ( n = 248), with 85.0% ( n = 108) for questionnaire survey and 73.3% ( n = 140) for histopathological analysis. In three cases, whose subtypes could not be determined by immunohistochemistry, we performed proteomic analysis.
Table 3
Patient demographics and the number of patients classified by APAC‐J description, questionnaire, immunohistochemistry, or proteomic analysis.
Note : In 21412 cases listed in APAC‐J, Volumes 60 and 61, male/female ratio was 14152:7235 with unknown cases of 25. Abbreviations: AA, amyloid A; AL, amyloid immunoglobulin light chain; AL NOS , AL not otherwise specified; ALκ, amyloid immunoglobulin light chain‐κ; ALλ, amyloid immunoglobulin light chain‐λ; APAC‐J, Annual of the Pathological Autopsy Cases in Japan; ATTR, amyloid transthyretin; ATTR NOS , ATTR not otherwise specified; ATTRv, variant ATTR; ATTRwt, wild‐type ATTR; Aβ2M, amyloid β2‐microglobulin. a Criteria of each subtype in Table 2 . b AL amyloidosis cases in which κ/λ was not determined. c ATTR amyloidosis cases in which ATTRv/ATTRwt was not determined. d ATTR deposition was incidentally found by immunohistochemistry.
| Subtype | Age (years old, mean ± S.D.) | Male/Female | Classification | |||||
| APAC‐J description | Questionnaire | Immunohistochemistry | Proteomic analysis | |||||
| A a | B a | C a | ||||||
| ALκ | 70.2 ± 7.6 | 37/23 | 9 | 0 | ‐ | 35 | 16 | 0 |
| ALλ | 71.9 ± 8.3 | 64/29 | 15 | 3 | ‐ | 40 | 32 | 3 |
| AL NOS b | 88.0 ± 4.0 | 2/0 | ‐ | ‐ | ‐ | 2 | ‐ | ‐ |
| ATTRwt | 88.3 ± 5.9 | 84/32 | 52 | 10 | 30 | 24 | ‐ | 0 |
| ATTRv | 79.3 ± 5.6 | 3/0 | 3 | ‐ | ‐ | 0 | ‐ | 0 |
| ATTR NOS c | 82.8 ± 6.8 | 46/12 | ‐ | ‐ | ‐ | 6 | 52 | 0 |
| AA | 71.5 ± 9.4 | 14/23 | 10 | 8 | ‐ | 1 | 18 | 0 |
| Aβ2M | 70.0 ± 5.7 | 11/13 | 21 | 2 | ‐ | 0 | 1 | 0 |
| ALλ + ATTR NOS d | 87.0 ± 3.5 | 2/2 | ‐ | ‐ | ‐ | ‐ | 4 | 0 |
| AA + ATTR NOS d | 78 | 0/1 | ‐ | ‐ | ‐ | ‐ | 1 | 0 |
| Aβ2M + ATTR NOS d | 74 | 0/1 | ‐ | ‐ | ‐ | ‐ | 1 | 0 |
Of the 411 cases available for analysis (85.4%), we could classify 399 systemic amyloidosis cases (Figure 3 , Table 3 ). The average age of these cases was 77.6 years old. ATTR was the most common subtype (44.4%, n = 177), followed by AL (38.8%, n = 155). AA and Aβ2M were 9.3% ( n = 37) and 6.0% ( n = 24), respectively. Three of the 155 AL cases were classified by proteomic analysis. Double deposition of amyloid was identified in 1.6% ( n = 6). The other 12 cases were either localized amyloidosis ( n = 6) or non‐amyloidosis cases ( n = 6).
In 168 systemic amyloidosis cases (42.1%), systemic amyloidosis was the main cause of death (Figure 4 ). Of these cases, AL was the most common subtype (47.6%, n = 80), followed by ATTR (41.1%, n = 69).
DISCUSSION
In this study, the subtypes of 399 cases of systemic amyloidosis listed in APAC‐J were classified using a questionnaire survey, immunohistochemistry, and proteomic analysis. The subtype frequency of systemic amyloidosis cases, in which systemic amyloidosis was the main cause of death was also determined. ATTR was the most predominant subtype among the current autopsy cases in Japan (Figure 3 ). As compared to the data in 1990's, the frequency of ATTR amyloidosis increased drastically (from 4.1%, 5 24.4% 6 to 44.4% in Figure 3 ). To the best of our knowledge, this is the first report of a multicenter study on the nation‐wide subtype frequency of systemic amyloidosis cases autopsied in the 21st century.
In the past decade, various new drugs were developed to treat each subtype of systemic amyloidosis, 1 , 3 and accurate subtype classification became essential for the selection of type‐specific therapeutics. 1 , 2 , 3 , 4 The nation‐wide pathology consultation of amyloidosis that was started in 2018 by GSRA‐J 1 revealed that (1) ATTR is the most common subtype of systemic amyloidosis in Japan; and (2) the approval of tafamidis and technetium‐scintigraphy raised the awareness of ATTR cardiomyopathy, leading to an upsurge in ATTR‐positive cardiac biopsy cases in Japan. 9 These data are compatible with our findings (Figure 3 ) and indicate that the subtype frequency of autopsy cases may precisely reflect the current situation of subtype distribution of systemic amyloidosis in Japan.
The dominancy of ATTR in autopsy cases can be explained as follows. First, aging of population with increased longevity in Japan may contribute to the increase in ATTRwt amyloidosis patients. As compared to the average age of subjects examined in 1990's 5 (64.9 years old), the average age of subjects examined in this study was 77.6 years old, indicating the aging of systemic amyloidosis patients in Japan. Although the average age of subjects examined in Strege et al. 6 was similar to this study (75.7 years old), the average age of ATTR patients was 88 years old, indicating the prevalence of ATTR amyloidosis in aged population.
Second, increased awareness to this disease 9 may also contribute to the increase in autopsied ATTRwt cases. As compared to the data obtained in the 1990's, the frequency of AA amyloidosis decreased precipitously (from 56.2%, 5 48.8% 6 to 9.3% in Figure 3 ), possibly due to the improvement in therapeutics of rheumatoid arthritis and other inflammatory diseases, 3 , 17 which further contributed to the relative increase in the frequency of ATTRwt amyloidosis.
According to the Cancer Statistics in Japan ( https://ganjoho.jp/reg_stat/statistics/data/dl/en.html ), the numbers of patients with multiple myeloma, an important background disease for AL amyloidosis, were 2896 in 1990, 4120 in 2000, 6356 in 2010, and 7765 in 2018 (2.7‐fold higher than in 1990). From these data, we may estimate the increase in the number of AL amyloidosis patients in Japan, but the incidence of AL was 38.8% (Figure 3 ) and similar to 32.2% in 1990's. 5 Because active myeloma is present only in approximately 10% of AL amyloidosis patients at the time of diagnosis, 3 we might not be able to detect the significant increase in the number of AL amyloidosis patients in Japan.
Major limitations of this study were as follows. First, the subjects analyzed in this study were autopsied individuals reported in APAC‐J, in which detailed information of each case was not available. Second, autopsy rate is now very low in Japan. According to the 2017 and 2018 annuals of the educational hospitals certified by the Japanese Society of Pathology ( https://e-learning.pathology.or.jp/course/view.php?id=54 ), a total of 668 172 patients died at these hospitals and 20 371 cases (3.0%) were autopsied. Finally, we applied the phenotypical criteria for subtype classification based on the pathological descriptions of APAC‐J (Table 2 ), because it was unrealistic to perform immunohistochemical analysis for all cases. The general pathology laboratories will need access to reliable commercial antibodies for ALκ, ALλ, and ATTR to accurately classify the subtypes of systemic amyloidosis. A robust consultation system to perform both immunohistochemical and proteomic analysis will also be necessary.
CONCLUSION
To reveal the latest subtype frequency of systemic amyloidosis among autopsy cases in Japan, we analyzed the systemic amyloidosis cases autopsied in 2017 and 2018 that were listed in APAC‐J. After conducting a questionnaire survey, immunohistochemistry, and proteomic analysis, we classified 399 systemic amyloidosis cases. ATTR was the most common subtype (44.4%), followed by AL (38.8%). In 168 cases (42.1%), systemic amyloidosis was the main cause of death. Of these cases, AL was the most common subtype (47.6%), followed by ATTR (41.1%).
AUTHOR CONTRIBUTIONS
Conception and design of the study : Aina Yamaguchi, Yukio Ando, and Hironobu Naiki. Acquisition and analysis of data : Aina Yamaguchi, Masayoshi Tasaki, Mitsuharu Ueda, and Hironobu Naiki. Drafting the manuscript or figures : Aina Yamaguchi, Masayoshi Tasaki, and Hironobu Naiki.
CONFLICTS OF INTEREST STATEMENT
Mitsuharu Ueda received research grants, honoraria, and non‐financial support from Alnylam and Pfizer. Yukio Ando received consulting fees from Alnylam, Pfizer, and Prothena. Hironobu Naiki received grant, and honoraria from Alnylam, Janssen, and Pfizer. Hironobu Naiki is an Editorial Board member of Pathology International and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication. The other authors declare no conflict of interest.
ACKNOWLEDGMENTS
The authors thank all the Japanese pathologists who participated in this study. Gratitude is also extended to N. Takimoto, H. Okada, and R. Nomura for excellent technical assistance. This work was supported in part by the Grant for surveys and research of intractable diseases from the Ministry of Health, Labour and Welfare, Japan (H29‐nanchitou(nan)‐ippan‐022 from 2017 to 2019; 20FC1022 from 2020 to 2022; P. I. Hironobu Naiki).
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