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Year : 2014  |  Volume : 57  |  Issue : 1  |  Page : 127-129
Cutaneous amyloidosis at the site of insulin injection with coexistence of acanthosis nigricans

1 Department of Pathology, St. John's Medical College, Bengaluru, Karnataka, India
2 Department of Dermatology, St. John's Medical College, Bengaluru, Karnataka, India

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Date of Web Publication17-Apr-2014


Skin is one of the important organs affected by amyloidosis which is characterized by extracellular deposition of fibrillary proteins having homogenous, eosinophilic on routine staining with distinct tinctorial properties. Nodular cutaneous amyloidosis is rare and may affect dermis, subcutis and also vascular walls. Nodular amyloid deposits in the deeper dermis occurring at the site of insulin injection are a rare observation, which is described here. This description indicates that cutaneous amyloidosis may be associated with local subcutaneous injections of insulin and may clinically mimic a neoplasm or lipodystrophic lesion.

Keywords: Acanthosis nigricans, birefringence, cutaneous amyloid, insulin

How to cite this article:
Nandeesh BN, Rajalakshmi T, Shubha B. Cutaneous amyloidosis at the site of insulin injection with coexistence of acanthosis nigricans. Indian J Pathol Microbiol 2014;57:127-9

How to cite this URL:
Nandeesh BN, Rajalakshmi T, Shubha B. Cutaneous amyloidosis at the site of insulin injection with coexistence of acanthosis nigricans. Indian J Pathol Microbiol [serial online] 2014 [cited 2022 Sep 26];57:127-9. Available from:

   Introduction Top

Amyloid deposits have varied origins and clinical association. Amyloid in a diabetic patient has been described in pancreatic islet with the precursor protein being islet amyloid polypeptide. Clinically, significant primary cutaneous localized amyloidosis with nodular amyloid deposits at the site of insulin injection is very rare and co-existence of these deposits with acanthosis nigricans like change of the overlying epidermis is extremely rare. The present report intends to document one such unique presentation.

   Case Report Top

The case report is about a 54-year-old male patient who presented to the dermatology clinic with a periumbilical pigmented warty lesion of 2 year duration. The patient was on treatment for type 2 - diabetes mellitus since 28 years. He was on oral hypoglycemic drugs for more than 20 years with a poor glycemic control. From the past 5 years, he was on insulin therapy (recombinant human insulin). His general and systemic examinations were within the normal limits except that he was obese. The local examination revealed an ill-defined, hyperpigmented, hyperkeratotic verrucous plaque in the periumbilical region measuring 5 cm 4 cm in size [Figure 1]a. The lesion was nodular on palpation, with a soft to firm consistency. A clinical diagnosis of seborrheic keratosis versus acanthosis nigricans was made. However, the clinicians wanted to rule out verrucous porokeratosis, verrucous carcinoma, large verruca vulgaris, squamous cell carcinoma and melanoma in view of the nodularity with pigmentation. The fasting and postprandial blood sugar levels at the time of admission were 347 and 446 mg/dl respectively with a hemoglobin A1c level of 15.5. A biopsy was taken and on microscopy, the epidermis displayed acanthosis with papillomatosis and compact orthohyperkeratosis [Figure 1]b. The epithelial cells showed increased pigmentation in addition to changes resembling Acanthosis Nigricans. The deep dermis showed nodular, perivascular and interstitial eosinophilic homogenous deposits [Figure 2]a. There were a few histiocytes and a few multinucleated giant cells surrounding these deposits [Figure 2]b. There was no associated fibroblastic proliferation. There were no deposits around the adnexae. These deposits were metachromatic on crystal violet stain [Figure 2]c and stained salmon pink with Congo red [Figure 2]d, which exhibited an apple green birefringence [Figure 2] e and f] on polarized microscopy. This confirmed the amyloid nature of the deposits. They were also highlighted by periodic acid-Schiff stain. On eliciting history in retrospect, it was recognized that the patient would inject his insulin around the same areas. Further work-up (serum protein electrophoresis) to exclude a systemic cause of amyloidosis was done and no signs of systemic amyloidosis were detected.
Figure 1: (a) Photograph showing a hyperpigmented, hyperkeratotic verrucous plaque in the periumbilical region. (b) Microphotograph showing the epidermal changes with acanthosis, papillomatosis, compact orthohyperkeratosis and increased pigmentation (H and E, ×100)

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Figure 2: (a) Microphotograph showing deep dermal nodular, perivascular and interstitial eosinophilic homogenous deposits (H and E, ×200). (b) Microphotograph showing eosinophilic deposits with multinucleated giant cells (H and E, ×200). (c) Microphotograph demonstrating the metachromatic nature of the deposits (Crystal violet, ×200). (d) Microphotograph showing positive staining (orange to salmon pink color) of the deposits with Congo red (Congo red, ×200). (e and f) Microphotograph displaying the characteristic apple green birefringence (arrows) of the Congo red stained deposits on polarized microscopy (Congo red, ×200)

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   Discussion Top

Amyloidosis is typified by extracellular deposition of fibrillary proteins which appears homogenous, eosinophilic on routine staining and has distinct tinctorial properties. It can be systemic or localized (limited to a single organ). The signs and symptoms are dependent on the organ system involved. Skin is one of the important organs affected by amyloidosis. Several types of primary cutaneous amyloidosis have been described. [1],[2] The three main forms of primary cutaneous amyloidosis are lichen (or papular) amyloidosis, macular amyloidosis and nodular amyloidosis. [3],[4] In the first two forms, amyloid fibrils are deposited in the papillary dermis and are keratin derived. Nodular cutaneous amyloidosis is rare and may affect dermis, subcutis and also vascular walls. [3] The precursor protein for this nodular subtype is immunoglobulin light chain.

In patients with diabetes, amyloid deposits are known to occur in the pancreatic islets and localized amyloid deposition elsewhere is unusual. Although numbers are limited, a few diabetic patients have been described in literature, with cutaneous amyloidosis arising at the site of (repeated) subcutaneously administered insulin. [5] The present case is one such example, where in, there were nodular amyloid deposits in the deeper dermis. It was situated at the site of insulin injection with overlying skin exhibiting changes similar to acanthosis nigricans. This combination of dermatological changes at the site of insulin injection is extremely rare and an extensive literature search has shown only one report with such a coexistence. [6] Clinically, the overlying epidermis appeared keratotic and pigmented, simulating seborrheic keratosis and a verrucous lesion/neoplasm. In the present case, the pigmentation with a nodular elevation also made the clinician consider the less likely possibility of a melanoma in the differential diagnosis. Local insulin-derived amyloid tumors remain principally a differential diagnosis of skin tumors in insulin-dependent diabetic patients. [5],[7] This also indicates that the dermatopathic changes secondary to insulin can be quite varied. In several cases, insulin (fragments) could be demonstrated in the amyloid tumors. In the previous reports/cases, amyloid formation was associated with the use of non-human insulin products, particularly those of porcine origin. [1],[7],[8] It is speculate that amino acid differences between endogenous and injected insulin may have contributed to the development of amyloidosis. [7] In the present case, the association was with the use of human recombinant insulin, which has been very rarely documented. [5] Histology revealed multinucleated giant cells and macrophages around the amyloid depositions. Such inflammatory reactions and refractoriness of insulin peptides to digestion by macrophages may possibly contribute to the amyloid fibril formation. [9] During this process, accumulated insulin itself and other compounds related to insulin preparations resistant to digestion may be modified to insoluble fibrillar proteins. Alternatively, innate incapability to digest insulin may also play a role in amyloidogenesis. Accumulated insulin peptides in soft-tissues undergo aggregation with reactive fibrotic processes and finally result in amyloid fibrils. [10] Some of the previous reports have documented a good improvement in blood glucose control shortly after resection of the tumor or after the change of the injection site. The speculation is that presence of amyloid mass at the site of injection site may cause poor penetration of insulin and this may probably contribute to the insulin resistance or in other words, refractoriness of insulin treatment. [2],[11],[12] Other lesions at the site of insulin injection site, reported in the literature are insulin edema, lipoatrophy, lipohypertrophy. [1],[5],[8],[13] Amyloid lumps are typically harder and more discrete, than fatty lumps of lipohypertrophy. [7]

   Conclusion Top

Cutaneous amyloidosis may be associated with local subcutaneous injections of insulin, including human (recombinant) insulin and this may be one of the reasons for insulin resistance in poorly controlled diabetic patients. Hence, patients need to be educated about alternate use of insulin injection sites and to have regular check-up of injection site to avoid complications. This case also attempts to expand our knowledge about the local complications of insulin therapy and stresses that localized cutaneous amyloidosis is a likely differential when tumor-like lesions are noticed at sites of insulin injection.

   References Top

1.Dische FE, Wernstedt C, Westermark GT, Westermark P, Pepys MB, Rennie JA, et al. Insulin as an amyloid-fibril protein at sites of repeated insulin injections in a diabetic patient. Diabetologia 1988;31:158-61.  Back to cited text no. 1
2.Albert SG, Obadiah J, Parseghian SA, Yadira Hurley M, Mooradian AD. Severe insulin resistance associated with subcutaneous amyloid deposition. Diabetes Res Clin Pract 2007;75:374-6.  Back to cited text no. 2
3.Touart DM, Sau P. Cutaneous deposition diseases. Part I. J Am Acad Dermatol 1998;39:149-71.  Back to cited text no. 3
4.Sie MP, van der Wiel HE, Smedts FM, de Boer AC. Human recombinant insulin and amyloidosis: An unexpected association. Neth J Med 2010;68:138-40.  Back to cited text no. 4
5.Yumlu S, Barany R, Eriksson M, Röcken C. Localized insulin-derived amyloidosis in patients with diabetes mellitus: A case report. Hum Pathol 2009;40:1655-60.  Back to cited text no. 5
6.Kudo-Watanuki S, Kurihara E, Yamamoto K, Mukai K, Chen KR. Coexistence of insulin-derived amyloidosis and an overlying acanthosis nigricans-like lesion at the site of insulin injection. Clin Exp Dermatol 2013;38:25-9.  Back to cited text no. 6
7.Nagase T, Katsura Y, Iwaki Y, Nemoto K, Sekine H, Miwa K, et al. The insulin ball. Lancet 2009;373:184.  Back to cited text no. 7
8.Swift B. Examination of insulin injection sites: An unexpected finding of localized amyloidosis. Diabet Med 2002;19:881-2.  Back to cited text no. 8
9.Morten IJ, Gosal WS, Radford SE, Hewitt EW. Investigation into the role of macrophages in the formation and degradation of beta2-microglobulin amyloid fibrils. J Biol Chem 2007;282:29691-700.  Back to cited text no. 9
10.Uversky VN, Fink AL. Conformational constraints for amyloid fibrillation: The importance of being unfolded. Biochim Biophys Acta 2004;1698:131-53.  Back to cited text no. 10
11.Shikama Y, Kitazawa J, Yagihashi N, Uehara O, Murata Y, Yajima N, et al. Localized amyloidosis at the site of repeated insulin injection in a diabetic patient. Intern Med 2010;49:397-401.  Back to cited text no. 11
12.Endo JO, Röcken C, Lamb S, Harris RM, Bowen AR. Nodular amyloidosis in a diabetic patient with frequent hypoglycemia: Sequelae of repeatedly injecting insulin without site rotation. J Am Acad Dermatol 2010;63:e113-4.  Back to cited text no. 12
13.Van Hattem S, Bootsma AH, Thio HB. Skin manifestations of diabetes. Cleve Clin J Med 2008;75:772, 774, 776-7.  Back to cited text no. 13

Correspondence Address:
Bevinahalli N Nandeesh
Department of Pathology, St. John's Medical College, John Nagar, Bengaluru - 560 034, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.130920

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