CED
CPD • Clinicopathological case
Clinical and Experimental Dermatology
Nodule on the upper arm M. Lam,1 A. N. Patel1 and I. H. Leach2 Departments of 1Dermatology and 2Histopathology, Nottingham University Hospitals, Queen’s Medical Centre Campus, Nottingham, UK doi: 10.1111/ced.12399
Clinical findings
(a)
A 2-year-old boy presented with a 3-month history of a small lesion on his left upper arm. The boy’s mother had noticed the lesion while she was applying emollients to the child’s skin. The child was systemically well. He had been delivered at term without any complications. He had no developmental problems, and was up to date with his National Health Service vaccination schedule, including vaccinations with boosters against polio (at the ages of 2, 3 and 4 months) and measles, mumps and rubella (aged 13 months), diphtheria, tetanus, and pertussis. On physical examination, a small, solitary, symmetrical, mobile firm, subcutaneous grey papule, 5 mm in size, were seen on the left upper arm. The lesion was excised under general anaesthesia.
(b)
Histopathological findings On histological examination of the lesion (Fig. 1a,b), a well circumscribed nodule was seen in the subcutis, comprising a necrobiotic granuloma with a central area of mainly amorphous eosinophilic material surrounded by palisading histiocytes and some plasma cells. Many of the histiocytes had slightly bluish granular cytoplasm. Stains for microorganisms (including diastase–periodic-acid–Schiff and Ziehl– Neelsen) were negative. What is your diagnosis? Figure 1 (a) A well-circumscribed necrobiotic granuloma with a
Correspondence: Dr Minh Lam, Department of Dermatology Nottingham University Hospitals, Queen’s Medical Centre Campus, Derby Road, Nottingham, NG7 2UH, UK E-mail: [email protected]
central area of amorphous eosinophilic material surrounded by palisading histiocytes; (b) many of the histiocytes had a bluish granular cytoplasm. Haematoxylin and eosin, original magnification (a) 9 25; (b) 9 200.
Conflict of Interest: the authors declare that they have no conflicts of interest. Accepted for publication 2 March 2014
844
Clinical and Experimental Dermatology (2014) 39, pp844–846
ª 2014 British Association of Dermatologists
D CP Clinicopathological case
Diagnosis Aluminium granuloma.
Discussion The histological (haematoxylin and eosin) findings indicated an aluminium granuloma related to an aluminium-adsorbed vaccine. The presence of aluminium was confirmed by solochrome azurine stain (Fig. 2). Aluminium salts are used as an adsorbant in a number of vaccines to prolong the immune response to an antigen. Aluminium-containing vaccines are received universally by all children as part of the UK vaccination programme. The US-licenced vaccines that contain aluminium adjuvants are listed in Table 1.1 A transient foreign body reaction resulting in a nodule at the injection site is well recognized. In rare cases, a subcutaneous nodule may develop weeks to months after the initial vaccination. This delay means parents will not always recognize the association with the vaccination. There are two proposed mechanisms for aluminium granuloma formation; firstly, a delayed hypersensitivity reaction to aluminium and secondly, a nonallergic reaction such as direct toxicity. Clinically, these granulomas present as erythematous subcutaneous nodules, which may be asymptomatic or pruritic in nature. Hyperpigmentation and hypertrichosis are also reported as local side effects. The differential diagnosis includes a wide spectrum of reactive conditions. Because of this diagnostic uncertainty, the diagnosis is often confirmed by histopathological analysis. Chong et al. described a diverse range of histological reaction patterns in 14 cases of aluminium granuloma.2
Figure 2 Presence of aluminium In the lesion (solochrome azu-
rine, original magnification 9 200.
ª 2014 British Association of Dermatologists
Table 1 Vaccinations containing aluminium adjuvants. Diphtheria–tetanus–pertussis (DTP) vaccine Diphtheria–tetanus–acellular pertussis (DTaP) vaccine Some but not all Haemophilus influenzae type b (Hib) conjugate vaccines Pneumococcal conjugate vaccine Hepatitis B vaccines All combinations of DTaP, Hib, or hepatitis B vaccines Hepatitis A vaccines Human papillomavirus vaccine Anthrax vaccine Rabies vaccine
These include panniculitis, pseudolymphomatous and granuloma annulare-like features. Many cases showed a mixed inflammatory cell infiltrate consisting of lymphocytes, histiocytes and plasma cells. The key histological feature observed in all cases was the presence of histiocytes with violaceous granular cytoplasm. Four of the fourteen cases showed histiocytes surrounding necrobiosis-like areas with an amorphous eosinophilic appearance, similar to our case. Aluminium can be confirmed using solochrome azurine stain, which stains the cytoplasm of histiocytes and aluminium fragments a bluish colour. Although not readily available in all centres, energy-dispersive spectrophotometry is a useful technique for identifying the metallic composition of various tissue specimens. A study of solochrome azurine staining compared with spectrophotometry in identifying aluminium in bone samples found a sensitivity of 90.6% for the former.3 Some studies have demonstrated a high proportion of positive patch testing to aluminium, supporting a delayed hypersensitivity mechanism in aluminium granuloma formation.4 However, other studies have not found such a strong correlation in this patient group.5 Reported cases suggest that most nodules are asymptomatic, and any associated features tend to resolve with time. Many are excised for diagnostic purposes, but there is no clear consensus on optimal treatment or follow-up. Aluminium-containing vaccines have been used safely worldwide for more than 75 years, and the benefits of these vaccines are felt to outweigh any potential complications.6 Because every child receiving vaccinations as part of the NHS vaccination programme will receive an aluminium-based vaccine, it is important for dermatologists to recognize aluminium granuloma as a complication.
Clinical and Experimental Dermatology (2014) 39, pp844–846
845
Clinicopathological case
Learning points
•
Almost all children in the UK will receive an aluminium-containing vaccine as part of the NHS vaccination schedule. • Transient injection site reactions are common, but the formation of delayed subcutaneous nodules is a relatively rare complication. • This latency can mean the association is not recognized by parents or clinicians. • The characteristic histiocytes with violaceous granular cytoplasm are a key histological feature of aluminium granuloma.
References 1 Baylor NW, Egan W, Richman P. Aluminum salts in vaccines-US perspective. Vaccine 2002; 20: S18–23.
846
Clinical and Experimental Dermatology (2014) 39, pp844–846
2 Chong H, Brady K, Metze D, Calonje E. Persistent nodule at injection sites (aluminium granuloma): clinicopathological study of 14 cases with a diverse range of histological reaction patterns. Histopathology 2006; 48: 182–8. 3 Ellis HA, Pang MM, Mawhinney WH, Skillen AW. Demonstration of aluminium in iliac bone: correlation between aluminon and solochrome azurine staining techniques with data on flameless absorption spectrophotometry. J Clin Pathol 1988; 1: 171–5. 4 Bergfors E, Bj€ orkelund C, Trollfors B. Nineteen cases of persistent pruritic nodules and contact allergy to aluminium after injection of commonly used aluminium-adsorbed vaccines. Eur J Pediatr 2005; 164: 691–7. 5 Netterlid A, Bruze M, Hindsen M et al. Persistent itching nodules after the fourth dose of diphtheria-tetanus toxoid vaccines without evidence of delayed hypersensitivity to aluminium. Vaccine 2004; 22: 3698–706. 6 Mitkus RJ, King DB, Hess MA et al. Updated aluminum pharmacokinetics following infant exposures through diet and vaccination. Vaccine 2011; 29: 9538–43.
ª 2014 British Association of Dermatologists
CPD • Clinicopathological case
Clinical and Experimental Dermatology
Nodule on the upper arm M. Lam,1 A. N. Patel1 and I. H. Leach2 Departments of 1Dermatology and 2Histopathology, Nottingham University Hospitals, Queen’s Medical Centre Campus, Nottingham, UK doi: 10.1111/ced.12399
Clinical findings
(a)
A 2-year-old boy presented with a 3-month history of a small lesion on his left upper arm. The boy’s mother had noticed the lesion while she was applying emollients to the child’s skin. The child was systemically well. He had been delivered at term without any complications. He had no developmental problems, and was up to date with his National Health Service vaccination schedule, including vaccinations with boosters against polio (at the ages of 2, 3 and 4 months) and measles, mumps and rubella (aged 13 months), diphtheria, tetanus, and pertussis. On physical examination, a small, solitary, symmetrical, mobile firm, subcutaneous grey papule, 5 mm in size, were seen on the left upper arm. The lesion was excised under general anaesthesia.
(b)
Histopathological findings On histological examination of the lesion (Fig. 1a,b), a well circumscribed nodule was seen in the subcutis, comprising a necrobiotic granuloma with a central area of mainly amorphous eosinophilic material surrounded by palisading histiocytes and some plasma cells. Many of the histiocytes had slightly bluish granular cytoplasm. Stains for microorganisms (including diastase–periodic-acid–Schiff and Ziehl– Neelsen) were negative. What is your diagnosis? Figure 1 (a) A well-circumscribed necrobiotic granuloma with a
Correspondence: Dr Minh Lam, Department of Dermatology Nottingham University Hospitals, Queen’s Medical Centre Campus, Derby Road, Nottingham, NG7 2UH, UK E-mail: [email protected]
central area of amorphous eosinophilic material surrounded by palisading histiocytes; (b) many of the histiocytes had a bluish granular cytoplasm. Haematoxylin and eosin, original magnification (a) 9 25; (b) 9 200.
Conflict of Interest: the authors declare that they have no conflicts of interest. Accepted for publication 2 March 2014
844
Clinical and Experimental Dermatology (2014) 39, pp844–846
ª 2014 British Association of Dermatologists
D CP Clinicopathological case
Diagnosis Aluminium granuloma.
Discussion The histological (haematoxylin and eosin) findings indicated an aluminium granuloma related to an aluminium-adsorbed vaccine. The presence of aluminium was confirmed by solochrome azurine stain (Fig. 2). Aluminium salts are used as an adsorbant in a number of vaccines to prolong the immune response to an antigen. Aluminium-containing vaccines are received universally by all children as part of the UK vaccination programme. The US-licenced vaccines that contain aluminium adjuvants are listed in Table 1.1 A transient foreign body reaction resulting in a nodule at the injection site is well recognized. In rare cases, a subcutaneous nodule may develop weeks to months after the initial vaccination. This delay means parents will not always recognize the association with the vaccination. There are two proposed mechanisms for aluminium granuloma formation; firstly, a delayed hypersensitivity reaction to aluminium and secondly, a nonallergic reaction such as direct toxicity. Clinically, these granulomas present as erythematous subcutaneous nodules, which may be asymptomatic or pruritic in nature. Hyperpigmentation and hypertrichosis are also reported as local side effects. The differential diagnosis includes a wide spectrum of reactive conditions. Because of this diagnostic uncertainty, the diagnosis is often confirmed by histopathological analysis. Chong et al. described a diverse range of histological reaction patterns in 14 cases of aluminium granuloma.2
Figure 2 Presence of aluminium In the lesion (solochrome azu-
rine, original magnification 9 200.
ª 2014 British Association of Dermatologists
Table 1 Vaccinations containing aluminium adjuvants. Diphtheria–tetanus–pertussis (DTP) vaccine Diphtheria–tetanus–acellular pertussis (DTaP) vaccine Some but not all Haemophilus influenzae type b (Hib) conjugate vaccines Pneumococcal conjugate vaccine Hepatitis B vaccines All combinations of DTaP, Hib, or hepatitis B vaccines Hepatitis A vaccines Human papillomavirus vaccine Anthrax vaccine Rabies vaccine
These include panniculitis, pseudolymphomatous and granuloma annulare-like features. Many cases showed a mixed inflammatory cell infiltrate consisting of lymphocytes, histiocytes and plasma cells. The key histological feature observed in all cases was the presence of histiocytes with violaceous granular cytoplasm. Four of the fourteen cases showed histiocytes surrounding necrobiosis-like areas with an amorphous eosinophilic appearance, similar to our case. Aluminium can be confirmed using solochrome azurine stain, which stains the cytoplasm of histiocytes and aluminium fragments a bluish colour. Although not readily available in all centres, energy-dispersive spectrophotometry is a useful technique for identifying the metallic composition of various tissue specimens. A study of solochrome azurine staining compared with spectrophotometry in identifying aluminium in bone samples found a sensitivity of 90.6% for the former.3 Some studies have demonstrated a high proportion of positive patch testing to aluminium, supporting a delayed hypersensitivity mechanism in aluminium granuloma formation.4 However, other studies have not found such a strong correlation in this patient group.5 Reported cases suggest that most nodules are asymptomatic, and any associated features tend to resolve with time. Many are excised for diagnostic purposes, but there is no clear consensus on optimal treatment or follow-up. Aluminium-containing vaccines have been used safely worldwide for more than 75 years, and the benefits of these vaccines are felt to outweigh any potential complications.6 Because every child receiving vaccinations as part of the NHS vaccination programme will receive an aluminium-based vaccine, it is important for dermatologists to recognize aluminium granuloma as a complication.
Clinical and Experimental Dermatology (2014) 39, pp844–846
845
Clinicopathological case
Learning points
•
Almost all children in the UK will receive an aluminium-containing vaccine as part of the NHS vaccination schedule. • Transient injection site reactions are common, but the formation of delayed subcutaneous nodules is a relatively rare complication. • This latency can mean the association is not recognized by parents or clinicians. • The characteristic histiocytes with violaceous granular cytoplasm are a key histological feature of aluminium granuloma.
References 1 Baylor NW, Egan W, Richman P. Aluminum salts in vaccines-US perspective. Vaccine 2002; 20: S18–23.
846
Clinical and Experimental Dermatology (2014) 39, pp844–846
2 Chong H, Brady K, Metze D, Calonje E. Persistent nodule at injection sites (aluminium granuloma): clinicopathological study of 14 cases with a diverse range of histological reaction patterns. Histopathology 2006; 48: 182–8. 3 Ellis HA, Pang MM, Mawhinney WH, Skillen AW. Demonstration of aluminium in iliac bone: correlation between aluminon and solochrome azurine staining techniques with data on flameless absorption spectrophotometry. J Clin Pathol 1988; 1: 171–5. 4 Bergfors E, Bj€ orkelund C, Trollfors B. Nineteen cases of persistent pruritic nodules and contact allergy to aluminium after injection of commonly used aluminium-adsorbed vaccines. Eur J Pediatr 2005; 164: 691–7. 5 Netterlid A, Bruze M, Hindsen M et al. Persistent itching nodules after the fourth dose of diphtheria-tetanus toxoid vaccines without evidence of delayed hypersensitivity to aluminium. Vaccine 2004; 22: 3698–706. 6 Mitkus RJ, King DB, Hess MA et al. Updated aluminum pharmacokinetics following infant exposures through diet and vaccination. Vaccine 2011; 29: 9538–43.
ª 2014 British Association of Dermatologists
