Unexplained skin nodule

A skin nodule is a solid palpable lesion 1 cm or more in diameter lying in the dermis or subcutis, as distinct from a papule (under 1 cm) and a plaque (flat topped and wider than deep).

Depth. Epidermal and adnexal nodules arise from the surface or follicle. Dermal nodules are firm and fixed to skin. Subcutaneous nodules are deeper and move over the skin surface.

Number and arrangement. Solitary, multiple, grouped, linear, sporotrichoid (along lymphatics) or generalised.

Tempo. Acute painful nodules develop over days. Subacute nodules develop over weeks. Slow growth over months to years suggests benign lesions, though some cancers grow slowly.

Consistency. Soft and mobile (fat), rubbery (nerve or node), firm and tethered (fibrous), stony hard (calcium, urate or metastasis), tender (infection, inflammation, glomus tumour, neuroma, leiomyoma), and pulsatile (vascular).

Key distinctions. A central punctum suggests an epidermoid cyst. A dimple on lateral pinching suggests a dermatofibroma. A nodule that bleeds, ulcerates or grows quickly suggests carcinoma, melanoma or sarcoma. Nodules over bony prominences in an endemic area suggest onchocerciasis. Linear nodules along a limb suggest sporotrichosis, atypical mycobacterial infection, nocardiosis or leishmaniasis. A nodule over 5 cm or deep to fascia needs imaging before any biopsy.

History

• Duration, growth rate, change in size or colour, pain, bleeding, ulceration, discharge and itch. Number of nodules and the order they appeared.
• Trauma, injections, insect or tick bites, thorn injuries, freshwater or seawater exposure, animal contact, soil exposure and previous surgery at the site.
• Residence or travel in regions endemic for onchocerciasis, loiasis, mycetoma, Buruli ulcer, leishmaniasis, leprosy or cysticercosis.
• Fever, weight loss, night sweats, cough, bowel symptoms, joint pain, preceding sore throat, and abdominal or pelvic symptoms.
• HIV, immunosuppression, transplant, diabetes, prior cancer, prior skin cancer, sun exposure, radiotherapy and chronic wounds.
• Drugs: halogens (iodides and bromides), hydralazine, oral contraceptives and sulphonamides (erythema nodosum), insulin injection sites.
• Family history of neurofibromatosis, familial adenomatous polyposis, Cowden syndrome, familial melanoma and hypercholesterolaemia.

Examination

• Measure size, shape, colour, surface, edge, depth, consistency, mobility (skin and deep), tenderness, warmth, punctum, pulsation and transillumination. Check for dimple, slip and Darier signs.
• Full skin examination for other nodules, neurofibromas, café au lait macules, xanthomas and pigmented lesions.
• Regional and distant lymph nodes, hepatosplenomegaly, breast, thyroid, abdomen, testes, and umbilicus (Sister Mary Joseph nodule).
• Mouth and mucosae, eyes (uveitis), and joints.
• Dermoscopy for pigmented or vascular lesions.
• Signs of systemic infection or sepsis.

Red flags

• Rapid growth over weeks, size over 2 cm, location deep to fascia, fixation to underlying tissue, ulceration or bleeding.
• A new pigmented or amelanotic nodule, or a firm red or violaceous nodule on sun damaged skin.
• Recurrence after excision.
• Fever or sepsis with multiple nodules (bacteraemia, endocarditis, disseminated fungal or mycobacterial infection, nocardiosis).
• Nodules in a neutropenic or immunosuppressed patient.
• Lymphadenopathy, weight loss, night sweats or hepatosplenomegaly.
• Rapid growth of a long standing neurofibroma with pain or neurological deficit.
• Growing nodule in a child.
• Painful tender nodules with livedo, neuropathy or hypertension (polyarteritis nodosa).
• Ocular involvement (cysticercosis, onchocerciasis) or neurological symptoms with subcutaneous nodules (cysticercosis).

Special groups

• Children: epidermoid cyst, pilomatricoma, dermoid cyst, molluscum contagiosum, juvenile xanthogranuloma, infantile haemangioma, Spitz naevus, mastocytoma, infantile myofibromatosis, rhabdomyosarcoma and neuroblastoma metastasis.
• Pregnancy: pyogenic granuloma, haemangiomas, fibroepithelial polyps and growth of neurofibromas. Avoid ionising imaging where possible, and use ultrasound or MRI.
• Older adults: basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma, keratoacanthoma, lymphoma and metastasis.
• Immunosuppressed: atypical mycobacteria, nocardiosis, fungal infection, Kaposi sarcoma and aggressive skin cancers.
• Region specific: onchocerciasis, loiasis, mycetoma, Buruli ulcer, leprosy, leishmaniasis (including post kala azar dermal leishmaniasis), furuncular myiasis, tungiasis, cysticercosis, endemic Kaposi sarcoma, histoplasmosis, cryptococcosis and keloids.

Cysts and benign tumours

• Epidermoid and pilar cysts.
• Dermoid cyst and steatocystoma.
• Lipoma and angiolipoma.
• Dermatofibroma.
• Neurofibroma, schwannoma and traumatic neuroma.
• Leiomyoma and glomus tumour.
• Pilomatricoma and other adnexal tumours.
• Keloid and hypertrophic scar.
• Calcinosis cutis.
• Xanthoma.
• Rheumatoid nodule.
• Gouty tophus.
• Foreign body granuloma.
• Infantile haemangioma and pyogenic granuloma.
• Angiokeratoma.
• Digital mucous cyst and ganglion.
• Osteoma cutis.

Infective and infestation

• Furuncle and cutaneous abscess.
• Cutaneous tuberculosis (scrofuloderma, lupus vulgaris, erythema induratum).
• Leprosy (lepromatous and borderline).
• Buruli ulcer, nodular stage.
• Atypical mycobacterial infection, including Mycobacterium marinum.
• Sporotrichosis.
• Mycetoma (eumycetoma and actinomycetoma).
• Chromoblastomycosis.
• Cryptococcosis, histoplasmosis and penicilliosis.
• Nocardiosis and actinomycosis.
• Cutaneous leishmaniasis and post kala azar dermal leishmaniasis.
• Onchocerciasis and loiasis.
• Cysticercosis.
• Furuncular myiasis and tungiasis.
• Molluscum contagiosum, giant, in HIV, and warts.
• Cat scratch disease and bacillary angiomatosis.
• Tertiary syphilis (gumma) and yaws.
• Hydatid cyst and schistosomal granuloma.
• Orf and milker's nodule.

Inflammatory

• Erythema nodosum.
• Erythema induratum.
• Panniculitis (lupus profundus, pancreatic, alpha 1 antitrypsin deficiency, cold, factitial, post steroid).
• Cutaneous polyarteritis nodosa and nodular vasculitis.
• Sarcoidosis.
• Subcutaneous granuloma annulare.
• Prurigo nodularis.
• Hidradenitis suppurativa nodules.
• Pyoderma gangrenosum, early.
• Sweet syndrome.
• Injection site lipoatrophy and nodules.

Neoplastic

• Basal cell carcinoma, nodular.
• Squamous cell carcinoma and keratoacanthoma.
• Melanoma, nodular and amelanotic.
• Merkel cell carcinoma.
• Dermatofibrosarcoma protuberans.
• Atypical fibroxanthoma.
• Sebaceous, eccrine and apocrine carcinoma.
• Cutaneous lymphoma (mycosis fungoides tumour stage, primary cutaneous B cell and large cell lymphoma).
• Leukaemia cutis.
• Kaposi sarcoma and angiosarcoma.
• Leiomyosarcoma, liposarcoma and other soft tissue sarcoma.
• Cutaneous metastasis (breast, lung, colon, kidney, ovary, melanoma).
• Mastocytoma.
• Langerhans cell histiocytosis.

Other

• Amyloidosis, nodular.
• Cutaneous endometriosis.
• Umbilical hernia.
• Lymph node.
• Olecranon bursitis.
• Haematoma.
• Spitz naevus.

Step 1. Triage. Look for sepsis, immunosuppression, rapid growth, neurological or ocular features, and size or depth that needs sarcoma service assessment (over 5 cm, deep to fascia, growing).

Step 2. Bedside assessment. Classify by number, depth, tenderness, punctum, tempo and exposure. Use dermoscopy. Use high frequency ultrasound: epidermoid cysts are well defined and hypoechoic with posterior enhancement, lipomas are oval with parallel striations, abscesses show a hypoechoic centre with surrounding cobblestoning, and malignant lesions are irregular with disordered vascularity on Doppler.

Step 3. Blood tests

• Full blood count with differential (eosinophilia in helminth infection), ESR, CRP, urea, creatinine, liver tests, calcium, glucose and LDH (raised in melanoma and lymphoma).
• HIV test, syphilis serology, hepatitis B and C serology, and an interferon gamma release assay.
• ANA, ANCA, complement and cryoglobulins when vasculitis or connective tissue disease is possible. Serum angiotensin converting enzyme has limited value for sarcoidosis.
• Lipids (xanthoma), urate (tophus), serum protein electrophoresis (amyloid, myeloma), and ASO titre with throat swab for erythema nodosum.
• Pregnancy test before imaging or drugs.

Step 4. Tissue diagnosis

• Excisional biopsy with a 2 mm margin for lesions under 2 cm when melanoma is possible (do not shave a suspected melanoma).
• Incisional or deep punch biopsy (4 to 6 mm) for larger or ill defined nodules. Panniculitis needs a deep incisional wedge biopsy including fat, because a punch biopsy is inadequate.
• Core needle biopsy for deep or suspected sarcoma, lymphoma or metastasis. Fine needle aspiration helps for cysts, lymph nodes and metastasis but cannot grade most sarcomas.
• Soft tissue mass over 5 cm, deep to fascia or growing: MRI first, then biopsy through the planned excision track at a sarcoma centre. Unplanned excision of a sarcoma worsens outcomes.
• Send tissue for histology and immunohistochemistry (S100, SOX10 and HMB45 for melanoma, cytokeratin 20 for Merkel cell carcinoma, CD34 for dermatofibrosarcoma, CD30 and lymphoid panels), and for bacterial, mycobacterial and fungal culture when infection is possible. Send fresh tissue for flow cytometry and T cell receptor clonality when lymphoma is suspected.

Step 5. Infection specific tests

• Gram stain and culture, Ziehl-Neelsen stain, mycobacterial culture and nucleic acid amplification for tuberculosis, and fungal stains and culture of pus or tissue.
• Onchocerciasis: skin snips (2 mg bits in saline, read at 30 minutes and after incubation), with daytime blood film for Loa loa microfilariae (collected between 10:00 and 14:00) before any ivermectin.
• Leishmaniasis: slit skin smear, culture and PCR. Leprosy: slit skin smear from earlobes and lesions and biopsy. Buruli ulcer: IS2404 PCR.
• Mycetoma: direct microscopy of discharged grains (colour and size), culture, and ultrasound, radiograph or MRI for bone involvement.
• Cysticercosis: imaging of nodules, brain MRI or CT, and fundoscopy.
• Bartonella serology or PCR, cryptococcal antigen, and urine histoplasma antigen in HIV.

Step 6. Staging. Confirmed malignancy needs CT of chest, abdomen and pelvis (PET CT for selected cancers) and regional node ultrasound. Sentinel node biopsy is considered for melanoma with thickness over 0.8 mm or ulceration.

Limits. Punch biopsy misses deep disease and panniculitis. Fine needle aspiration cannot classify many lymphomas and sarcomas. Cultures are often negative after antibiotics. Benign appearance does not exclude malignancy.

Immediate. Sepsis or necrotising infection: resuscitation, blood cultures, broad spectrum antibiotics within 1 hour and surgical exploration. Suspected malignancy: urgent referral, and do not perform an incomplete excision. Neutropenic or immunosuppressed patient with nodules: admission, biopsy and culture, and specialist antimicrobial therapy.

Symptomatic care. Paracetamol 1 g orally every 6 hours (maximum 4 g daily; 3 g daily in hepatic impairment, chronic alcohol use or weight under 50 kg). Ibuprofen 400 mg orally three times daily with food for inflammatory nodules, maximum 1.2 g daily without specialist advice, avoided in kidney impairment, peptic ulcer and anticoagulation.

Benign nodules

• Epidermoid cyst: leave if asymptomatic. Infected cyst: incision and drainage, then excision of the cyst wall after 4 to 6 weeks of settling. Inflamed noninfected cyst: intralesional triamcinolone acetonide 2.5 to 10 mg/mL, 0.1 to 0.2 mL.
• Lipoma: observe. Excise if painful, growing, over 5 cm, deep or diagnostically uncertain. MRI before excision of any large or deep fatty lesion, because liposarcoma can resemble lipoma.
• Dermatofibroma: reassure. Excise if atypical or growing.
• Keloid: intralesional triamcinolone acetonide 10 to 40 mg/mL, 0.1 mL for each cm of lesion every 4 to 6 weeks, with silicone sheeting and cryotherapy for small lesions. Surgical excision needs adjuvant corticosteroid injection or radiotherapy.
• Pyogenic granuloma: curettage with cautery or excision, with histology.
• Infantile haemangioma needing treatment: propranolol 1 mg/kg daily in 2 to 3 divided doses with feeds, increased over 2 weeks to 2 to 3 mg/kg daily, started under specialist supervision with heart rate, blood pressure and glucose monitoring. Avoid in asthma and heart block.
• Gouty tophus: allopurinol 100 mg orally once daily (50 mg daily in chronic kidney disease), increased every 2 to 4 weeks to a serum urate under 300 micromol/L when tophi are present (maximum 900 mg daily; adjust to creatinine clearance), with colchicine 0.5 mg orally once or twice daily for 3 to 6 months as flare prophylaxis (reduce in kidney impairment; avoid with clarithromycin and ciclosporin). Test HLA B*5801 before allopurinol in high risk groups.
• Xanthomas: treat hyperlipidaemia.

Infective nodules

• Abscess and furuncle: incision and drainage. Add antibiotics for systemic features, cellulitis over 5 cm, difficult sites or immunocompromise: flucloxacillin 500 mg to 1 g orally four times daily for 5 to 7 days, or co-trimoxazole 960 mg orally twice daily for 5 to 7 days when MRSA is likely (halve the dose at creatinine clearance 15 to 30 mL/min; avoid under 15 mL/min).
• Erythema nodosum: identify and remove the cause. Rest, leg elevation, compression and ibuprofen 400 mg three times daily for 1 to 2 weeks. Streptococcal pharyngitis: phenoxymethylpenicillin 500 mg orally four times daily for 10 days. Persistent disease: potassium iodide 400 to 900 mg orally daily or colchicine 0.5 mg twice daily (specialist). Prednisolone 0.5 mg/kg daily for 2 to 4 weeks only after tuberculosis, streptococcal infection and fungal infection are excluded. Most episodes settle over 3 to 6 weeks.
• Cutaneous tuberculosis: the usual four drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol) under specialist care.
• Leprosy: multibacillary regimen of rifampicin 600 mg orally once monthly (supervised), clofazimine 300 mg once monthly and 50 mg daily, and dapsone 100 mg daily, for 12 months, after G6PD testing, with prednisolone 40 mg daily tapered over 3 to 6 months for reactions and neuritis.
• Buruli ulcer: rifampicin 10 mg/kg (maximum 600 mg) orally once daily plus clarithromycin 7.5 mg/kg (maximum 500 mg) orally twice daily, or moxifloxacin 400 mg daily, for 8 weeks, with wound care and surgery for large lesions.
• Sporotrichosis: itraconazole 200 mg orally once daily with food for 3 to 6 months, continued 2 to 4 weeks after resolution (monitor liver tests; avoid in heart failure; many CYP3A4 interactions; not in pregnancy).
• Mycetoma: eumycetoma needs itraconazole 200 mg orally twice daily for 9 to 12 months with surgical excision. Actinomycetoma needs co-trimoxazole 960 mg orally twice daily for months with intramuscular amikacin 15 mg/kg daily in 2 divided doses in 3 week cycles (monitor hearing and kidney function). Specialist care.
• Cutaneous leishmaniasis: sodium stibogluconate 20 mg/kg intravenously or intramuscularly daily for 20 days (monitor ECG, liver, pancreas and kidney), or miltefosine 2.5 mg/kg orally daily (maximum 150 mg daily) for 28 days (contraindicated in pregnancy; reliable contraception for 5 months), selected by species and region.
• Onchocerciasis: ivermectin 150 micrograms/kg orally as a single dose, repeated every 6 to 12 months for 10 to 15 years, after excluding high Loa loa microfilaraemia (risk of encephalopathy). Add doxycycline 200 mg orally daily for 4 to 6 weeks to kill adult worms (not in pregnancy or under 8 years). Nodulectomy for head nodules. Avoid ivermectin in pregnancy and children under 15 kg.
• Loiasis: specialist care. Diethylcarbamazine 8 to 10 mg/kg daily in 3 divided doses for 21 days when microfilarial load is low (under 2,500/mL). Higher loads need albendazole 200 mg orally twice daily for 21 days or apheresis first, because of encephalopathy risk.
• Cysticercosis: albendazole 15 mg/kg daily (maximum 800 mg daily) in 2 divided doses with food for 8 to 30 days, with corticosteroid and anticonvulsant cover as needed, after neuroimaging and fundoscopy. Isolated subcutaneous cysts often need no drug treatment.
• Furuncular myiasis: occlude the punctum with petroleum jelly and extract the larva when it surfaces, or remove surgically. Tungiasis: sterile flea extraction, tetanus immunisation check and topical dimeticone.
• Molluscum and warts: cryotherapy or curettage for molluscum, and salicylic acid 17 to 26% daily with paring or cryotherapy every 2 to 3 weeks for warts. Extensive molluscum in HIV needs antiretroviral therapy.
• Cat scratch disease: azithromycin 500 mg orally once, then 250 mg daily for 4 days. Bacillary angiomatosis: erythromycin 500 mg orally four times daily or doxycycline 100 mg twice daily for 3 months.
• Tertiary syphilis (gumma): benzathine benzylpenicillin 2.4 million units intramuscularly once weekly for 3 weeks. Yaws: azithromycin 30 mg/kg orally as a single dose (maximum 2 g).
• Disseminated cryptococcosis, histoplasmosis or penicilliosis: admission and specialist antifungal therapy (liposomal amphotericin B 3 to 5 mg/kg intravenously daily initially), with lumbar puncture in cryptococcosis.

Neoplastic nodules

• Basal cell carcinoma: excision with 4 mm margins for low risk lesions, or Mohs surgery for facial and high risk sites.
• Squamous cell carcinoma: excision with 4 to 6 mm margins, with nodal assessment for high risk lesions.
• Melanoma: wide excision margins by Breslow thickness (in situ 5 mm, under 1 mm 1 cm, 1 to 2 mm 1 to 2 cm, over 2 mm 2 cm), with sentinel node biopsy and oncology review.
• Merkel cell carcinoma and dermatofibrosarcoma protuberans: wide excision, sentinel node assessment and radiotherapy in Merkel cell disease, by specialist teams.
• Soft tissue sarcoma, lymphoma, Kaposi sarcoma (with antiretroviral therapy) and metastasis: oncology care.

Monitoring. Review at 2 to 4 weeks. Reassess the diagnosis and biopsy if the nodule grows, ulcerates or does not respond. Follow up histology within 1 to 2 weeks.

Referral and escalation. Dermatology or plastic surgery within 2 weeks for suspected skin cancer. Sarcoma centre for lesions over 5 cm, deep or growing. Same day surgery for abscess with systemic features. Infectious diseases for suspected mycobacterial, fungal, parasitic or disseminated infection. Rheumatology for vasculitis and connective tissue disease. Haematology and oncology for lymphoma or metastasis.

Admission criteria. Sepsis, necrotising infection, immunosuppression with disseminated nodules, neutropenia, suspected central nervous system involvement, and inability to take oral therapy.

Disposition. Most small benign nodules are managed in primary care. Safety net advice: return for rapid growth, bleeding, ulceration, new nodules, fever, weight loss, night sweats, neurological symptoms or visual change.