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Year : 2021  |  Volume : 12  |  Issue : 4  |  Page : 524-527

Injection site acanthosis nigricans in type 1 diabetes mellitus and hepatocellular carcinoma: A case report

Department of Endocrinology, Gandhi Medical College and Hospital, Secunderabad, Hyderabad, Telangana, India

Date of Submission26-Feb-2021
Date of Decision31-Mar-2021
Date of Acceptance10-Apr-2021
Date of Web Publication12-Jan-2022

Correspondence Address:
Dr. Vijay Sheker Reddy Danda
Department of Endocrinology, Gandhi Medical College and Hospital, 3rd Floor, Gandhi Hospital, Musheerabad, Secunderabad 500003, Hyderabad, Telangana.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jod.jod_25_21

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Many injection site cutaneous complications such as lipohypertrophy and atrophy are known to occur in type 1 diabetic individuals. Acanthosis nigricans (AN) with insulin injection is a rare complication described in few case reports. It is also described as a paraneoplastic manifestation of malignancies such as hepatocellular carcinoma (HCC). Here we describe a case of injection site acanthosis in a type 1 diabetic with underlying HCC. This case report highlights the importance of knowledge on proper injection technique to prevent such unfortunate complications. High degree of suspicion of underlying malignancies is warranted in atypical presentation of AN.

Keywords: Acanthosis nigricans, cutaneous complications, hepatocellular carcinoma, type 1 diabetes mellitus

How to cite this article:
Reddy DS, Thaduri KR, Paidipally SR, Danda VS. Injection site acanthosis nigricans in type 1 diabetes mellitus and hepatocellular carcinoma: A case report. J Diabetol 2021;12:524-7

How to cite this URL:
Reddy DS, Thaduri KR, Paidipally SR, Danda VS. Injection site acanthosis nigricans in type 1 diabetes mellitus and hepatocellular carcinoma: A case report. J Diabetol [serial online] 2021 [cited 2022 Sep 25];12:524-7. Available from: https://www.journalofdiabetology.org/text.asp?2021/12/4/524/335583

  Key Messages: Top

This case report highlights the importance of knowledge on proper injection technique to prevent such unfortunate complications. High degree of suspicion of underlying malignancies is warranted in atypical presentation of acanthosis nigricans.

  Introduction Top

Insulin is the main modality of treatment in type 1 diabetes mellitus (type 1 DM). Subjects with type 1 DM require multiple injections and are prone to develop skin complications. Cutaneous complications associated with insulin injection include lipohypertrophy, lipoatrophy, allergic reactions, and amyloidosis.[1],[2] Acanthosis nigricans (AN) is a very rare cutaneous complication with insulin therapy.[3] It is also described as a rare paraneoplastic manifestation of hepatocellular carcinoma (HCC).[4] We report an interesting case of insulin-induced injection site AN in a patient of type 1 DM with HCC.

  Case History Top

An 18-year-old male diabetic presented to our department with uncontrolled glycemic parameters. He was diagnosed with type 1 diabetes at the age of 8 years. His treatment comprised human regular and neutral protamine Hagedorn insulin administered subcutaneously thrice daily for the past 10 years. Total insulin dose requirement was about 1.6 U/kg. Site of administration was predominantly on the posterior aspect of arms with poor site rotation. Glycated hemoglobin A1c at admission was 10.8% with multiple previous records of uncontrolled plasma glucose values. No hypoglycemic episodes were documented. He developed large dark pigmented, non-pruritic lesions at injection sites which were first noticed 2 years back [Figure 1]. Progression was insidious but the patient continued administration at the same site as the lesions were relatively painless. No medical attention was sought at that point of time. On examination, the lesions were approximately 8 × 6 cm in size over the posterior aspect of both arms which were raised, hyperpigmented, hyperkeratotic, and verrucous, consistent with morphology of AN [Figure 2]. AN was also noted over forehead. No other sites were involved. Further examination revealed generalized edema, hypertension, hepatomegaly of 4 cm, and distal symmetrical peripheral neuropathy of lower limbs. Rest of the examination was unremarkable.
Figure 1: Clinical image depicting injection site AN

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Figure 2: Clinical image showing hyperpigmented verrucous nature of AN

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  Investigations Top

Ascitic fluid analysis: Transudate, fundus examination — bilateral non-proliferative diabetic retinopathy, ultrasound abdomen — hepatomegaly with a mass of 6 × 6 cm, MRI abdomen — large well-defined T1 isointense lesion in left lobe with multiple lesions in both lobes which are hyperenhancing on arterial phase, suggestive of malignancy — multicentric HCC? [Figure 3], CT chest — normal, renal biopsy — diabetic nephropathy [Table 1].
Figure 3: MRI abdomen depicting hepatocellular carcinoma

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Table 1: Biochemical investigations

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Biopsy of skin lesion — hyperkeratosis, papillomatosis, acanthosis, consistent with AN [Figure 4].
Figure 4: Biopsy of skin lesion demonstrating hyperkeratosis, papillomatosis, acanthosis, consistent with AN

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The injection site was changed and was administered over abdomen. Meanwhile, he underwent surgery for hepatic tumor. Left lateral sectionectomy of segment 6 was done. Histopathology examination and immunohistochemistry (beta-catenin — negative, glypican — positive, Ki67 — low, CD34 — positive) were suggestive of well-differentiated HCC. Post surgery, there was poor wound healing, he developed acute chronic renal failure, anasarca, and succumbed 2 months later while on renal replacement therapy. There was no resolution of AN.

  Discussion Top

AN is a proliferative disorder of the epidermis and the dermal fibroblasts, appearing as a light to dark brown, thickened verrucous area on the skin with typical location on the neck, axilla, and other intertriginous areas.[4] Though first reported in 1969 by Erickson et al.[5] as a complication of insulin injection, very few cases have been reported till date. The mechanism involving pathogenesis of localized AN due to insulin is not clearly understood. High concentrations of subcutaneous insulin may activate IGF-1 receptors[6] on keratinocytes, thereby leading to proliferation of these cells and resulting in hyperkeratotic plaques. AN is also reported as a rare paraneoplastic manifestation of HCC. Its etiology is associated with tumor-produced substances like transforming growth factor (TGF-α) that stimulates keratinocytes through the epidermal growth factor receptor (EGF-1).[7] Sudden onset, rapid course, and extensive skin involvement are characteristics of malignant AN. In the present case, there was AN at injection site and forehead with indolent progression. Hence, malignant AN was not considered as first differential. PubMed search for articles using the terms acanthosis nigricans and insulin injections yielded 20 results. Among them, localized AN at insulin injection sites was described in 12 case reports. One observational study in a group of 500 diabetic patients reported localized AN[8] in two patients. Our patient developed AN 8 years after initiation of human regular and NPH insulin. Time for onset of acanthosis with insulin has been widely variable with some cases developing in the initial period and some developing after several years.[9] Earlier reports were associated with use of human insulins, and all the patients had poor site rotation. In our case, the lesions did not resolve after 2 months of change in site of administration. The time for resolution of lesions after change in the injection site was also variable in the literature ranging from few weeks to a year.[10] Unfortunately, in our case, we could not document resolution of lesions either with change in injection site or resection of tumor, as the patient succumbed in 2 months of post-operative period. Association of AN with insulin injection and HCC in type 1 diabetic individual was not reported previously. In the present case, whether insulin injection or HCC or both together playing their part in pathogenesis could not be concluded. Lack of patient education and improper administration techniques are a major setback in our population. Proper education of patients regarding injection techniques and regular follow-up can prevent such complications. Malignant AN as a differential diagnosis should always be borne in mind, especially when there is sudden, rapid course, and extensive evaluation of underlying malignancy is warranted.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Richardson T, Kerr D. Skin-related complications of insulin therapy: Epidemiology and emerging management strategies. Am J Clin Dermatol 2003;4:661-7.  Back to cited text no. 1
Ansari AM, Osmani L, Matsangos AE, Li QK. Current insight in the localized insulin-derived amyloidosis (LIDA): Clinico-pathological characteristics and differential diagnosis. Pathol Res Pract 2017;213:1237-41.  Back to cited text no. 2
Buzási K, Sápi Z, Jermendy G. Acanthosis nigricans as a local cutaneous side effect of repeated human insulin injections. Diabetes Res Clin Pract 2011;94:e34-6.  Back to cited text no. 3
Kamińska-Winciorek G, Brzezińska-Wcisło L, Lis-Swiety A, Krauze E. Paraneoplastic type of acanthosis nigricans in patient with hepatocellular carcinoma. Adv Med Sci 2007;52:254-6.  Back to cited text no. 4
Erickson L, Lipschutz DE, Wrigley W, Kearse WO. A peculiar cutaneous reaction to repeated injections of insulin. J Am Med Assoc 1969;209:934-5.  Back to cited text no. 5
Yahagi E, Mabuchi T, Nuruki H, Manabe Y, Ikoma N, Ozawa A, et al. Case of exogenous insulin-derived acanthosis nigricans caused by insulin injections. Tokai J Exp Clin Med 2014;39:5-9.  Back to cited text no. 6
Kubicka-Wołkowska J, Dębska-Szmich S, Lisik-Habib M, Noweta M, Potemski P. Malignant acanthosis nigricans associated with prostate cancer: A case report. BMC Urol 2014;14:88.  Back to cited text no. 7
Sawatkar GU, Kanwar AJ, Dogra S, Bhadada SK, Dayal D. Spectrum of cutaneous manifestations of type 1 diabetes mellitus in 500 South Asian patients. Br J Dermatol 2014;171:1402-6.  Back to cited text no. 8
Pal R, Bhattacharjee R, Chatterjee D, Bhadada SK, Bhansali A, Dutta P. Exogenous insulin-induced localized acanthosis nigricans: A rare injection site complication. Can J Diabetes 2020;44:219-21.  Back to cited text no. 9
Bomar L, Lewallen R, Jorizzo J. Localized acanthosis nigricans at the site of repetitive insulin injections. Cutis 2020;105:E20-2.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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