735893
case-report2017
IJSXXX10.1177/1066896917735893International Journal of Surgical PathologyTariq and Sharkey
Case Report
Leukocyte Cell-Derived Chemotaxin-2 Amyloidosis (ALECT2) in a Patient With Lung Adenocarcinoma: An Autopsy Report and Literature Review
International Journal of Surgical Pathology 1–5 © The Author(s) 2017 Reprints and permissions: sagepub.com/journalsPermissions.nav https://doi.org/10.1177/1066896917735893 DOI: 10.1177/1066896917735893 journals.sagepub.com/home/ijs
Hamza Tariq, MD1, and Francis E. Sharkey, MD1
Abstract Amyloidosis caused by deposition of leukocyte cell-derived chemotaxin-2 amyloidosis (ALECT2) is the most recently described form of systemic amyloidosis and has quickly emerged as a common and possibly underdiagnosed cause of slowly declining renal function, particularly in patients of Hispanic ancestry. We describe the autopsy findings in a 70-year-old Hispanic woman who died of metastatic lung adenocarcinoma and was incidentally found to have extensive amyloid deposition in the kidneys, liver, spleen, adrenal glands, small intestine, gallbladder, lungs, bilateral ovaries, and uterus. The type of amyloid was confirmed to be ALECT2 by mass spectrometry. The pattern of amyloid deposition in the kidneys and the liver was typical for what has been described for ALECT2. In addition, a unique pattern of amyloid deposition was observed in spleen, adrenal glands, small intestine, gallbladder, lungs, ovaries, and uterus. The pattern of amyloid deposition in ALECT2 is distinct from amyloid A and amyloid light-chain and needs to be recognized to avoid misdiagnosis as amyloid light-chain or amyloid A amyloidosis. After recognition, an accurate diagnosis by mass spectrometry and/or immunohistochemical staining is essential to guide treatment and avoid toxic therapies. Keywords amyloid, ALECT2, mass spectrometry
Introduction Amyloidosis is the abnormal deposition and accumulation of insoluble protein fibrils in the parenchyma of tissues leading to organ dysfunction and failure.1 Current amyloid fibril protein nomenclature by the International Society of Amyloidosis lists 30 human and 10 animal fibril proteins known to cause amyloidosis.2 Leukocyte cell-derived chemotaxin-2 amyloidosis (ALECT2) is the most recently described form and is being more often recognized as a common form of systemic amyloidosis in the United States. In 2 large retrospective studies, ALECT2 was found in up to 10% of all kidney biopsies containing amyloid, making it the most common type of amyloidosis after amyloid light-chain (AL) and amyloid A (AA) amyloidosis. The exact prevalence of ALECT2 is unknown, but it is an underdiagnosed cause of progressive renal failure since chronic kidney disease is not typically an indication for a renal biopsy. It predominantly involves kidneys and liver, but involvement of spleen, adrenal glands, and colon has also been noted.3,4 Systemic amyloidosis is rarely seen in association with nonhematologic malignancies. Secondary
amyloidosis (AA) occurs as a paraneoplastic syndrome in patients with renal cell carcinoma, and a few cases in patients with non–small cell lung carcinoma (NSCLC) have also been reported.5,6 ALECT2 occurring in association with NSCLC has never been reported before, and currently, there is no scientific evidence linking the two. We report the autopsy findings of a 70-year-old Hispanic woman who died of metastatic adenocarcinoma of the lung and was incidentally found to have extensive amyloid deposition in her kidneys, liver, spleen, adrenal glands, small intestine, gallbladder, lungs, ovaries, and uterus at autopsy. The type of amyloid was confirmed to be ALECT2 by mass spectrometry.
1
University of Texas Health Science Center at San Antonio, TX, USA
Corresponding Author: Hamza Tariq, Department of Pathology and Laboratory Medicine. University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229-3264, USA. Email: [email protected]
2
International Journal of Surgical Pathology 00(0)
Case Presentation The patient was a 70-year-old woman with a past medical history of hypertension, diabetes, and chronic renal insufficiency. She was diagnosed with stage IV adenocarcinoma of the right lung 3 months antemortem. Computed tomography scan of the chest showed bilateral pulmonary nodules as well as enlarged hilar and mediastinal lymph nodes, consistent with metastatic disease. She received a few rounds of paclitaxel and carboplatin but opted to discontinue the treatment due to poor tumor response. One week antemortem she developed severe intractable cough and shortness of breath. She was treated with antibiotics for pneumonia superimposed on her lung cancer but subsequently developed acute on chronic renal failure. Laboratory testing showed a serum creatinine of 7.1 mg/dL, serum blood urea nitrogen of 79 mg/dL, and serum lactate of 4.6 mmol/L. Her urine analysis showed 3+ proteinuria and a urine protein to urine creatinine ratio of 2.5. Two days antemortem, she developed vasopressor-resistant hypotension as well as severe metabolic acidosis and died. The autopsy revealed a large mass involving the entire right upper lobe. The right lower lobe and the entire left lung also showed multiple metastatic nodules. Microscopic sections of the lungs revealed a mixed adenocarcinoma with solid, glandular, lepidic, and micropapillary growth patterns, along with extensive necrosis and desmoplastic reaction. Lymphovascular invasion and metastases in the hilar lymph nodes were also seen. The only extra-thoracic site of metastasis was the right adrenal gland. Incidentally, she was found to have extensive amyloid deposition in multiple organ systems of the body. Congo red stain was performed on tissue sections taken from heart, bilateral lungs, liver, spleen, bilateral kidneys, pituitary gland, bilateral ovaries, uterus, thyroid gland, lumbar vertebral bone, small intestine, gallbladder, colon, pancreas, bilateral adrenal glands, and cerebral cortex. Amyloid deposition was seen in kidneys, liver, spleen, adrenal glands, lungs, small intestine, gallbladder, ovaries, and uterus. All sections showed red-green birefringence with polarized light, typical of amyloid. Mass spectrometry testing on the tissue blocks detected a peptide profile consistent with ALECT2. Grossly, both kidneys were atrophic (right: 90 g and left: 80 g) with extensive scarring of the cortex. Microscopic sections of both kidneys showed nodular glomerulosclerosis, but there was also extensive deposition of amyloid restricted to the interstitium and blood vessels of the cortex. The glomeruli and medulla were uninvolved (Figure 1). The liver was grossly unremarkable (weight: 1450 g) but microscopically showed globular amyloid deposits in the portal triads and around central veins, with no perisinusoidal deposition (Figures 2 and 3). The spleen was grossly
Figure 1. Microscopic section of kidney showing interstitial and vascular amyloid deposition by Congo red stain in the cortex, with sparing of the glomerulus.
Figure 2. Microscopic section of the liver showing characteristic globular amyloid deposition around central venule by Congo red stain, with no perisinusoidal deposition.
unremarkable (weight: 180 g) but microscopic sections showed extensive amyloid deposition. The amyloid was found in the walls of the branching arterial vessels; however, the surrounding lymphocytes and marginal zones of the white pulp were uninvolved. The red pulp showed almost complete obliteration of normal architecture due to sinusoidal and interstitial amyloid deposition. The splenic capsule was uninvolved (Figure 4). The adrenal glands also showed extensive vascular and interstitial amyloid deposition in both the cortex and the medulla, with sparing of the capsule (Figure 5). The small bowel showed diffuse amyloid deposition in the serosa
3
Tariq and Sharkey
Figure 3. Microscopic section of the liver showing characteristic globular amyloid deposition in the portal tracts by Congo red stain, with no perisinusoidal deposition.
Figure 4. Microscopic section of the spleen showing extensive amyloid deposition in the red pulp by Congo red stain. The arterioles also show some globular deposits of amyloid; however, the surrounding white pulp is uninvolved.
Figure 5. Microscopic section of the adrenal gland showing extensive interstitial amyloid deposition.
with occasional deposits in the submucosal blood vessels and connective tissue. The mucosa and muscularis externa were uninvolved. The gallbladder showed patchy vascular
Figure 6. Microscopic section of the lung showing extensive amyloid deposition in the alveolar septa.
involvement in the submucosa. The ovaries were atrophic and showed extensive cortical vascular and stromal amyloid deposition, whereas the hilum and the overlying mesothelium were uninvolved. The uterus showed prominent vascular amyloid deposition in the myometrium. The atrophic endometrium and the serosa were uninvolved. Sections of the lungs showed extensive amyloid deposition in the alveolar septa (Figure 6); however, no amyloid was seen within the tumor. Congo red stain on the pancreas showed rare amyloid deposits in the islets, which were negative for LECT-2 by LECT-2 immunohistochemical stain. Given the patient’s history of diabetes, the findings in the pancreas are most consistent with diabetes-associated amyloid deposition in the islets. The heart, pituitary gland, bone marrow, thyroid gland, colon, and cerebral cortex did not show any amyloid deposition.
Discussion Leukocyte cell-derived chemotaxin 2 (LECT2) is the latest addition to the list of proteins that can cause systemic amyloidosis. Understanding of this disease is still in the early stages of evolution. LECT2 is a 151-amino acid protein that is believed to be exclusively expressed in the liver. The physiologic functions include leukocyte recruitment, growth factor–mediated restructuring of cartilage, regulation of hepatocyte activity, and a number of immunomodulatory functions. The serum levels of LECT2 increase with acute liver damage, chronic active hepatitis, steatohepatitis, and hepatocellular carcinoma, but surprisingly are normal in patients with systemic LECT2 amyloidosis.7 In various studies, ALECT2 has shown a strong ethnic bias, mostly occurring in Hispanics. In addition to Hispanics, Punjabis, First Nations people in British Columbia, and Native Americans have also shown a high prevalence as compared with Caucasians and African Americans.1,8-10 In a recent retrospective autopsy study by Larsen et al, 16 cases of ALECT2 were identified among
4 520 Hispanics (3.1%) and 1 among 142 Native American Indians (0.7%). In contrast, only 1 case was identified among 318 Caucasians (0.3%).1 In 2 large retrospective studies, ALECT2 was found in up to 10% of all kidney biopsies with amyloid, making it the most common type of amyloidosis after AL and AA.3,4 The pattern of organ involvement in all major studies has been fairly uniform. Kidney involvement has been seen in all cases where the disease causes progressive renal insufficiency. The second most commonly involved organ is the liver, where the disease is almost always an incidental finding when the organ is sampled for other unrelated disorders or at autopsy. Other organs affected by deposition of LECT2 amyloid include adrenal glands, spleen, gallbladder, small bowel, and alveolar septa. At this time, the disease has only been found to manifest clinically in the kidneys in the form of proteinuria, bland urinary sediment, and slowly declining renal function.4,8,10-13 In our case, the patient was of Hispanic descent and showed similar clinical findings of long-standing progressive renal decline, which is attributed to a combination of ALECT2 deposition and diabetic glomerular disease. ALECT2 found in the liver, adrenal glands, spleen, ovaries, uterus, small intestine, gallbladder, and lungs did not cause any clinically apparent functional decline in those organs. The kidneys in our case showed the typical histological features described for renal ALECT2. Amyloid deposition was seen only in the blood vessels and interstitium of the cortex. Glomeruli and medulla were uninvolved (Figure 1). These aspects differentiate ALECT2 from other forms of amyloidosis with distinctive morphologic patterns, such as AA and AL, which primarily involve the glomerulus14; apolipoprotein A-IV amyloidosis, which has predominantly medullary involvement15; and fibrinogen α-chain amyloidosis, which typically shows florid deposition restricted to the glomeruli.16 ALECT2 is probably an underdiagnosed cause of endstage renal disease because bland urinary sediment, proteinuria, and slowly declining renal function are not typical indications for a renal biopsy. Furthermore, it has been shown that 38% of the patients with ALECT2 have diabetes.4 In most of these cases, the renal decline is clinically attributed solely to the diabetes, and ALECT2 is discovered only incidentally at autopsy, as in this case, illustrating that specific histologic findings are necessary to make an accurate diagnosis. Even though currently there is no specific treatment for ALECT2 amyloidosis, differentiation from AA and AL amyloidosis can guide clinical therapy and prognosis and avoid mismanagement. The prognosis for patients with renal ALECT2 amyloidosis is much better than for those with AL and AA amyloidosis because of the absence of substantial cardiac involvement.7 The liver also showed the unique pattern of involvement as has been described for ALECT2. There were
International Journal of Surgical Pathology 00(0) globular amyloid deposits in the portal tracts, periportal parenchyma, and around the central venules. Neither intraparenchymal nor intrasinusoidal deposition was seen (Figures 2 and 3). The characteristic globular pattern of LECT2 amyloid deposition contrasts distinctly with the perisinusoidal amyloid deposition pattern that typifies hepatic AL amyloidosis.12 Even though most cases of hepatic ALECT2 are found incidentally on biopsies taken for unrelated liver pathologies, the specific histologic pattern must be recognized in order to prompt investigation into the renal profile of the patient to ensure an early diagnosis. The exact pathogenesis of ALECT2 is unknown. In a case series conducted by Murphy et al the analysis of genomic DNA of the peripheral blood leukocytes of patients with ALECT2 amyloidosis revealed no mutations in the LECT2 coding sequences.11 The LECT2 gene, located on chromosome 5q31.1-32, consists of 4 exons that encode 151 amino acids and 3 introns. There is a G/A polymorphism involving nucleotide 172 in exon 3 that accounts for the presence of valine or isoleucine at position 40 in the mature protein. Interestingly, all of the patients were found to be homozygous for the G allele (G/G genotype). In principle, replacement of the buried isoleucine (A allele) side chain with valine (G allele) could destabilize the protein and possibly account for the amyloidogenic propensity of this LECT2 variant. Thus, it has been hypothesized that the presence of G/G genotype may be one factor in the etiology of LECT2 amyloidosis, though undoubtedly others are involved.11 Whether nonhematologic malignancies are a factor in triggering ALECT2 amyloidosis is obviously unclear, but AA amyloidosis has been described as a paraneoplastic syndrome in solid organ malignancies, occurring in 3% to 8% of the patients with renal cell carcinoma.17 A few cases of systemic amyloidosis (AA) have been seen in patients with NSCLC as well.5,6 Currently, there is no scientific evidence establishing NSCLC and other malignancies as a factor in triggering ALECT2 amyloidosis but further exploration into this hypothesis might be fruitful.
Conclusion Amyloidosis caused by deposition of ALECT2 is the most recently described form of systemic amyloidosis and is a common cause of slowly declining renal function, particularly in patients of Hispanic ancestry. The histologic picture of ALECT2 in kidney and liver biopsies is distinct from other forms of amyloidosis and needs to be recognized to avoid misdiagnosis as AL or AA amyloidosis. After recognition of the histologic pattern, confirmation of peptide pattern by mass spectrometry and/or immunohistochemical staining is essential to guide treatment and to avoid toxic therapies.
Tariq and Sharkey Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Larsen CP, Beggs ML, Wilson JD, Lathrop SL. Prevalence and organ distribution of leukocyte chemotactic factor 2 amyloidosis (ALECT2) among decedents in New Mexico. Amyloid. 2016;23:119-123. 2. Sipe JD, Benson MD, Buxbaum JN, et al; Nomenclature Committee of the International Society of Amyloidosis. Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid. 2012;19:167-170. 3. Nasr SH, Dogan A, Larsen CP. Leukocyte cell-derived chemotaxin 2-associated amyloidosis: a recently recognized disease with distinct clinicopathologic characteristics. Clin J Am Soc Nephrol. 2015;10:2084-2093. 4. Larsen CP, Kossmann RJ, Beggs ML, Solomon A, Walker PD. Clinical, morphologic, and genetic features of renal leukocyte chemotactic factor 2 amyloidosis. Kidney Int. 2014;86:378-382. 5. Richmond I, Hasleton PS, Samadian S. Systemic amyloid associated with carcinoma of the bronchus. Thorax. 1990;45:156-157. 6. Garthwaite EA, Sellars L, Bhandari S. Carcinoma of the bronchus presenting as renal failure secondary to amyloidosis. Nephrol Dial Transplant. 2003;18:1031-1032. 7. Dogan A. Amyloidosis: insights from proteomics. Annu Rev Pathol. 2017;12:277-304.
5 8. Dogan A, Theis JD, Vrana JA. Clinical and pathological phenotype of leukocyte cell-derived chemotaxin-2 (LECT2) amyloidosis (ALECT2). Amyloid. 2010;17:69-70. 9. Larsen CP, Ismail W, Kurtin PJ, Vrana JA, Dasari S, Nasr SH. Leukocyte chemotactic factor 2 amyloidosis (ALECT2) is a common form of renal amyloidosis among Egyptians. Mod Pathol. 2016;29:416-420. 10. Hutton HL, DeMarco ML, Magil AB, Taylor P. Renal leukocyte chemotactic factor 2 (LECT2) amyloidosis in First Nations people in Northern British Columbia, Canada: a report of 4 cases. Am J Kidney Dis. 2014;64:790-792. 11. Murphy CL, Wang S, Kestler D, et al. Leukocyte chemotactic factor 2 (LECT2)-associated renal amyloidosis: a case series. Am J Kidney Dis. 2010;56:1100-1107. 12. Mereuta OM, Theis JD, Vrana JA, et al. Leukocyte cellderived chemotaxin- 2 (ALECT2)-associated amyloidosis is a frequent cause of hepatic amyloidosis in the United States. Blood. 2014;123:1479-1482. 13. Said SM, Sethi S, Valeri AM, et al. Characterization and outcomes of renal leukocyte chemotactic factor 2-associated amyloidosis. Kidney Int. 2014;86:370-377. 14. Castano E, Palmer MB, Vigneault C, Luciano R, Wong S, Moeckel G. Comparison of amyloid deposition in human kidney biopsies as predictor of poor patient outcome. BMC Nephrol. 2015;16:64. 15. Nasr SH, Said SM, Valeri AM, et al. The diagnosis and characteristics of renal heavy-chain and heavy/light-chain amyloidosis and their comparison with renal light-chain amyloidosis. Kidney Int. 2013;83:463-470. 16. Hamidi Asl L, Liepnieks JJ, Uemichi T, et al. Renal amyloidosis with a frame shift mutation in fibrinogen alphachain gene producing a novel amyloid protein. Blood. 1997;90:4799-4805. 17. Palapattu GS, Kristo B, Rajfer J. Paraneoplastic syndromes in urologic malignancy: the many faces of renal cell carcinoma. Rev Urol. 2002;4:163-170.
case-report2017
IJSXXX10.1177/1066896917735893International Journal of Surgical PathologyTariq and Sharkey
Case Report
Leukocyte Cell-Derived Chemotaxin-2 Amyloidosis (ALECT2) in a Patient With Lung Adenocarcinoma: An Autopsy Report and Literature Review
International Journal of Surgical Pathology 1–5 © The Author(s) 2017 Reprints and permissions: sagepub.com/journalsPermissions.nav https://doi.org/10.1177/1066896917735893 DOI: 10.1177/1066896917735893 journals.sagepub.com/home/ijs
Hamza Tariq, MD1, and Francis E. Sharkey, MD1
Abstract Amyloidosis caused by deposition of leukocyte cell-derived chemotaxin-2 amyloidosis (ALECT2) is the most recently described form of systemic amyloidosis and has quickly emerged as a common and possibly underdiagnosed cause of slowly declining renal function, particularly in patients of Hispanic ancestry. We describe the autopsy findings in a 70-year-old Hispanic woman who died of metastatic lung adenocarcinoma and was incidentally found to have extensive amyloid deposition in the kidneys, liver, spleen, adrenal glands, small intestine, gallbladder, lungs, bilateral ovaries, and uterus. The type of amyloid was confirmed to be ALECT2 by mass spectrometry. The pattern of amyloid deposition in the kidneys and the liver was typical for what has been described for ALECT2. In addition, a unique pattern of amyloid deposition was observed in spleen, adrenal glands, small intestine, gallbladder, lungs, ovaries, and uterus. The pattern of amyloid deposition in ALECT2 is distinct from amyloid A and amyloid light-chain and needs to be recognized to avoid misdiagnosis as amyloid light-chain or amyloid A amyloidosis. After recognition, an accurate diagnosis by mass spectrometry and/or immunohistochemical staining is essential to guide treatment and avoid toxic therapies. Keywords amyloid, ALECT2, mass spectrometry
Introduction Amyloidosis is the abnormal deposition and accumulation of insoluble protein fibrils in the parenchyma of tissues leading to organ dysfunction and failure.1 Current amyloid fibril protein nomenclature by the International Society of Amyloidosis lists 30 human and 10 animal fibril proteins known to cause amyloidosis.2 Leukocyte cell-derived chemotaxin-2 amyloidosis (ALECT2) is the most recently described form and is being more often recognized as a common form of systemic amyloidosis in the United States. In 2 large retrospective studies, ALECT2 was found in up to 10% of all kidney biopsies containing amyloid, making it the most common type of amyloidosis after amyloid light-chain (AL) and amyloid A (AA) amyloidosis. The exact prevalence of ALECT2 is unknown, but it is an underdiagnosed cause of progressive renal failure since chronic kidney disease is not typically an indication for a renal biopsy. It predominantly involves kidneys and liver, but involvement of spleen, adrenal glands, and colon has also been noted.3,4 Systemic amyloidosis is rarely seen in association with nonhematologic malignancies. Secondary
amyloidosis (AA) occurs as a paraneoplastic syndrome in patients with renal cell carcinoma, and a few cases in patients with non–small cell lung carcinoma (NSCLC) have also been reported.5,6 ALECT2 occurring in association with NSCLC has never been reported before, and currently, there is no scientific evidence linking the two. We report the autopsy findings of a 70-year-old Hispanic woman who died of metastatic adenocarcinoma of the lung and was incidentally found to have extensive amyloid deposition in her kidneys, liver, spleen, adrenal glands, small intestine, gallbladder, lungs, ovaries, and uterus at autopsy. The type of amyloid was confirmed to be ALECT2 by mass spectrometry.
1
University of Texas Health Science Center at San Antonio, TX, USA
Corresponding Author: Hamza Tariq, Department of Pathology and Laboratory Medicine. University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229-3264, USA. Email: [email protected]
2
International Journal of Surgical Pathology 00(0)
Case Presentation The patient was a 70-year-old woman with a past medical history of hypertension, diabetes, and chronic renal insufficiency. She was diagnosed with stage IV adenocarcinoma of the right lung 3 months antemortem. Computed tomography scan of the chest showed bilateral pulmonary nodules as well as enlarged hilar and mediastinal lymph nodes, consistent with metastatic disease. She received a few rounds of paclitaxel and carboplatin but opted to discontinue the treatment due to poor tumor response. One week antemortem she developed severe intractable cough and shortness of breath. She was treated with antibiotics for pneumonia superimposed on her lung cancer but subsequently developed acute on chronic renal failure. Laboratory testing showed a serum creatinine of 7.1 mg/dL, serum blood urea nitrogen of 79 mg/dL, and serum lactate of 4.6 mmol/L. Her urine analysis showed 3+ proteinuria and a urine protein to urine creatinine ratio of 2.5. Two days antemortem, she developed vasopressor-resistant hypotension as well as severe metabolic acidosis and died. The autopsy revealed a large mass involving the entire right upper lobe. The right lower lobe and the entire left lung also showed multiple metastatic nodules. Microscopic sections of the lungs revealed a mixed adenocarcinoma with solid, glandular, lepidic, and micropapillary growth patterns, along with extensive necrosis and desmoplastic reaction. Lymphovascular invasion and metastases in the hilar lymph nodes were also seen. The only extra-thoracic site of metastasis was the right adrenal gland. Incidentally, she was found to have extensive amyloid deposition in multiple organ systems of the body. Congo red stain was performed on tissue sections taken from heart, bilateral lungs, liver, spleen, bilateral kidneys, pituitary gland, bilateral ovaries, uterus, thyroid gland, lumbar vertebral bone, small intestine, gallbladder, colon, pancreas, bilateral adrenal glands, and cerebral cortex. Amyloid deposition was seen in kidneys, liver, spleen, adrenal glands, lungs, small intestine, gallbladder, ovaries, and uterus. All sections showed red-green birefringence with polarized light, typical of amyloid. Mass spectrometry testing on the tissue blocks detected a peptide profile consistent with ALECT2. Grossly, both kidneys were atrophic (right: 90 g and left: 80 g) with extensive scarring of the cortex. Microscopic sections of both kidneys showed nodular glomerulosclerosis, but there was also extensive deposition of amyloid restricted to the interstitium and blood vessels of the cortex. The glomeruli and medulla were uninvolved (Figure 1). The liver was grossly unremarkable (weight: 1450 g) but microscopically showed globular amyloid deposits in the portal triads and around central veins, with no perisinusoidal deposition (Figures 2 and 3). The spleen was grossly
Figure 1. Microscopic section of kidney showing interstitial and vascular amyloid deposition by Congo red stain in the cortex, with sparing of the glomerulus.
Figure 2. Microscopic section of the liver showing characteristic globular amyloid deposition around central venule by Congo red stain, with no perisinusoidal deposition.
unremarkable (weight: 180 g) but microscopic sections showed extensive amyloid deposition. The amyloid was found in the walls of the branching arterial vessels; however, the surrounding lymphocytes and marginal zones of the white pulp were uninvolved. The red pulp showed almost complete obliteration of normal architecture due to sinusoidal and interstitial amyloid deposition. The splenic capsule was uninvolved (Figure 4). The adrenal glands also showed extensive vascular and interstitial amyloid deposition in both the cortex and the medulla, with sparing of the capsule (Figure 5). The small bowel showed diffuse amyloid deposition in the serosa
3
Tariq and Sharkey
Figure 3. Microscopic section of the liver showing characteristic globular amyloid deposition in the portal tracts by Congo red stain, with no perisinusoidal deposition.
Figure 4. Microscopic section of the spleen showing extensive amyloid deposition in the red pulp by Congo red stain. The arterioles also show some globular deposits of amyloid; however, the surrounding white pulp is uninvolved.
Figure 5. Microscopic section of the adrenal gland showing extensive interstitial amyloid deposition.
with occasional deposits in the submucosal blood vessels and connective tissue. The mucosa and muscularis externa were uninvolved. The gallbladder showed patchy vascular
Figure 6. Microscopic section of the lung showing extensive amyloid deposition in the alveolar septa.
involvement in the submucosa. The ovaries were atrophic and showed extensive cortical vascular and stromal amyloid deposition, whereas the hilum and the overlying mesothelium were uninvolved. The uterus showed prominent vascular amyloid deposition in the myometrium. The atrophic endometrium and the serosa were uninvolved. Sections of the lungs showed extensive amyloid deposition in the alveolar septa (Figure 6); however, no amyloid was seen within the tumor. Congo red stain on the pancreas showed rare amyloid deposits in the islets, which were negative for LECT-2 by LECT-2 immunohistochemical stain. Given the patient’s history of diabetes, the findings in the pancreas are most consistent with diabetes-associated amyloid deposition in the islets. The heart, pituitary gland, bone marrow, thyroid gland, colon, and cerebral cortex did not show any amyloid deposition.
Discussion Leukocyte cell-derived chemotaxin 2 (LECT2) is the latest addition to the list of proteins that can cause systemic amyloidosis. Understanding of this disease is still in the early stages of evolution. LECT2 is a 151-amino acid protein that is believed to be exclusively expressed in the liver. The physiologic functions include leukocyte recruitment, growth factor–mediated restructuring of cartilage, regulation of hepatocyte activity, and a number of immunomodulatory functions. The serum levels of LECT2 increase with acute liver damage, chronic active hepatitis, steatohepatitis, and hepatocellular carcinoma, but surprisingly are normal in patients with systemic LECT2 amyloidosis.7 In various studies, ALECT2 has shown a strong ethnic bias, mostly occurring in Hispanics. In addition to Hispanics, Punjabis, First Nations people in British Columbia, and Native Americans have also shown a high prevalence as compared with Caucasians and African Americans.1,8-10 In a recent retrospective autopsy study by Larsen et al, 16 cases of ALECT2 were identified among
4 520 Hispanics (3.1%) and 1 among 142 Native American Indians (0.7%). In contrast, only 1 case was identified among 318 Caucasians (0.3%).1 In 2 large retrospective studies, ALECT2 was found in up to 10% of all kidney biopsies with amyloid, making it the most common type of amyloidosis after AL and AA.3,4 The pattern of organ involvement in all major studies has been fairly uniform. Kidney involvement has been seen in all cases where the disease causes progressive renal insufficiency. The second most commonly involved organ is the liver, where the disease is almost always an incidental finding when the organ is sampled for other unrelated disorders or at autopsy. Other organs affected by deposition of LECT2 amyloid include adrenal glands, spleen, gallbladder, small bowel, and alveolar septa. At this time, the disease has only been found to manifest clinically in the kidneys in the form of proteinuria, bland urinary sediment, and slowly declining renal function.4,8,10-13 In our case, the patient was of Hispanic descent and showed similar clinical findings of long-standing progressive renal decline, which is attributed to a combination of ALECT2 deposition and diabetic glomerular disease. ALECT2 found in the liver, adrenal glands, spleen, ovaries, uterus, small intestine, gallbladder, and lungs did not cause any clinically apparent functional decline in those organs. The kidneys in our case showed the typical histological features described for renal ALECT2. Amyloid deposition was seen only in the blood vessels and interstitium of the cortex. Glomeruli and medulla were uninvolved (Figure 1). These aspects differentiate ALECT2 from other forms of amyloidosis with distinctive morphologic patterns, such as AA and AL, which primarily involve the glomerulus14; apolipoprotein A-IV amyloidosis, which has predominantly medullary involvement15; and fibrinogen α-chain amyloidosis, which typically shows florid deposition restricted to the glomeruli.16 ALECT2 is probably an underdiagnosed cause of endstage renal disease because bland urinary sediment, proteinuria, and slowly declining renal function are not typical indications for a renal biopsy. Furthermore, it has been shown that 38% of the patients with ALECT2 have diabetes.4 In most of these cases, the renal decline is clinically attributed solely to the diabetes, and ALECT2 is discovered only incidentally at autopsy, as in this case, illustrating that specific histologic findings are necessary to make an accurate diagnosis. Even though currently there is no specific treatment for ALECT2 amyloidosis, differentiation from AA and AL amyloidosis can guide clinical therapy and prognosis and avoid mismanagement. The prognosis for patients with renal ALECT2 amyloidosis is much better than for those with AL and AA amyloidosis because of the absence of substantial cardiac involvement.7 The liver also showed the unique pattern of involvement as has been described for ALECT2. There were
International Journal of Surgical Pathology 00(0) globular amyloid deposits in the portal tracts, periportal parenchyma, and around the central venules. Neither intraparenchymal nor intrasinusoidal deposition was seen (Figures 2 and 3). The characteristic globular pattern of LECT2 amyloid deposition contrasts distinctly with the perisinusoidal amyloid deposition pattern that typifies hepatic AL amyloidosis.12 Even though most cases of hepatic ALECT2 are found incidentally on biopsies taken for unrelated liver pathologies, the specific histologic pattern must be recognized in order to prompt investigation into the renal profile of the patient to ensure an early diagnosis. The exact pathogenesis of ALECT2 is unknown. In a case series conducted by Murphy et al the analysis of genomic DNA of the peripheral blood leukocytes of patients with ALECT2 amyloidosis revealed no mutations in the LECT2 coding sequences.11 The LECT2 gene, located on chromosome 5q31.1-32, consists of 4 exons that encode 151 amino acids and 3 introns. There is a G/A polymorphism involving nucleotide 172 in exon 3 that accounts for the presence of valine or isoleucine at position 40 in the mature protein. Interestingly, all of the patients were found to be homozygous for the G allele (G/G genotype). In principle, replacement of the buried isoleucine (A allele) side chain with valine (G allele) could destabilize the protein and possibly account for the amyloidogenic propensity of this LECT2 variant. Thus, it has been hypothesized that the presence of G/G genotype may be one factor in the etiology of LECT2 amyloidosis, though undoubtedly others are involved.11 Whether nonhematologic malignancies are a factor in triggering ALECT2 amyloidosis is obviously unclear, but AA amyloidosis has been described as a paraneoplastic syndrome in solid organ malignancies, occurring in 3% to 8% of the patients with renal cell carcinoma.17 A few cases of systemic amyloidosis (AA) have been seen in patients with NSCLC as well.5,6 Currently, there is no scientific evidence establishing NSCLC and other malignancies as a factor in triggering ALECT2 amyloidosis but further exploration into this hypothesis might be fruitful.
Conclusion Amyloidosis caused by deposition of ALECT2 is the most recently described form of systemic amyloidosis and is a common cause of slowly declining renal function, particularly in patients of Hispanic ancestry. The histologic picture of ALECT2 in kidney and liver biopsies is distinct from other forms of amyloidosis and needs to be recognized to avoid misdiagnosis as AL or AA amyloidosis. After recognition of the histologic pattern, confirmation of peptide pattern by mass spectrometry and/or immunohistochemical staining is essential to guide treatment and to avoid toxic therapies.
Tariq and Sharkey Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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