Unusual Clinical Presentations of Cutaneous Squamous Cell Involving Distal Extremities in Four Patients: The Importance of Tissue Sampling

cSCC originates from the keratinocyte in the epidermis, where it may spread superficially or begin to infiltrate the dermis and beyond. Classically, cSCC appears as a firm “keratotic” or rough papule or plaque. It can sometimes ulcerate and appear as a nonhealing lesion that is easily friable and prone to bleeding.¹ Roughly 20% of all skin cancers in the United States are cSCCs, and death from cSCC can occur in a minority of cases. Lifetime incidence of cSCC in the United States ranges from 14% to 20% in the non-Hispanic White population.^2,3 Risk factors for cSCC include but are not limited to Fitzpatrick skin type I-III, advanced age, being genetically male, UV exposure, human papillomavirus, and immunosuppression. A meta-analysis of 36 studies showed that Breslow thickness greater than 2 mm, perineural involvement, invasion beyond subcutaneous fat, poor differentiation, and location on the temple were risk factors for recurrence, metastasis, and disease-specific death.⁴ Once cSCC is diagnosed by skin biopsy, standard excision is generally the treatment of choice, while Mohs micrographic surgery is often the treatment of choice for cancers in areas where excess tissue is limited. In instances where Mohs surgery is not practical, other treatments may be used, such as radiation, topical treatments (eg, 5-fluororacil), and immunotherapy (eg, PD-1 inhibitors).⁵ In order to facilitate treatment, it is best to diagnose cSCC early. Occasionally, however, this can be difficult, as the authors illustrate in the following cases.

The cases included all White patients of non-Hispanic or Latino descent. Of the 4 patients, 3 were male and 1 was female. The patients ranged from 45 to 78 years of age. Not all lesion sizes were mentioned, but documented sizes ranged from 6 cm to 10 cm in diameter. Of the 4 cases, 3 were initially diagnosed as nonhealing wounds, and 1 was initially suspected to be cellulitis.

Case 1

A 45-year-old male presented to the ED with worsening pain in the left hand (Figure 1). The patient reported a 3-year history of worsening hand function and a nonhealing wound. He had received a possible diagnosis of scleroderma several years prior and underwent several trials of antibiotics without improvement. His records also documented that an I&D of the left hand was performed 3 years prior that did not yield purulent fluid. He was subsequently lost to follow-up. On exam, a left-hand wound with suspected abscess formation and tracts at the surface of the skin was noted. The patient did not have palpable lymph nodes on exam. He was admitted to the hospital with plans for hand debridement. Prior to debridement, MRI was performed due to clinical suspicion of osteomyelitis and revealed a mass that was infiltrating bone. While awaiting the results of a PET scan to evaluate for potential malignancy, the surgical oncology team advised proceeding with debridement of the necrotic tissue and biopsy to confirm diagnosis. During debridement, frozen sections of tissue showed keratinizing SCC. The patient’s PET scan results showed active lymph nodes in the left axilla. Ultimately, a mid-left forearm amputation was performed as there was no residual function of his left hand. The patient also received a left axillary lymph node biopsy, which was negative for metastasis. Four months following amputation and lymph node biopsy, the patient was stable and had no complications.

Case 2

A 78-year-old male originally presented to a dermatology office for a nonhealing ulcer on his left hand (Figure 2). Three months prior, he had sustained an abrasion to the left index finger and developed a persistent ulceration at this site. Surface cultures of the wound grew streptococcal species and Escherichia coli. He was treated with ciprofloxacin, silver sulfadiazine cream, and Epsom salt baths, and followed up with wound care. Three months later, he was referred to an orthopedist due to decreased mobility of the index finger. The lesion appeared as a large ulcer over the second MCP joint on the left hand, with purulent, bloody, malodorous discharge. He had palpable axillary lymph nodes on exam. The orthopedist was concerned for possible neoplasm and obtained a tissue biopsy, which revealed SCC. A recommendation was made to amputate the second and third digits, but the patient sought a second opinion with a dermatologist. The lesion was deemed too large for Mohs surgery and ultimately the patient was treated with systemic immunotherapy. He received cemiplimab, which resulted in dramatic shrinkage of the tumor at the fifth of 8 cycles; as of the time of writing, the tumor continued to improve.

Case 3

A 67-year-old male presented to the ED for evaluation of a necrotic wound of the left hand. On initial evaluation, a large ulcerating hand wound with rolled, raised borders and purulent discharge was observed on the dorsal aspect of the second MCP joint. He also had an ulcerating lesion on the distal fourth finger of his right hand obliterating much of the nailbed, with necrotic tissue and purulent discharge present (Figure 3). During initial evaluation, the patient reported that the wound had worsened over the previous 2 to 3 months, which he attributed to a bite sustained while cleaning chicken coops. Meropenem and vancomycin were started, and he was admitted with a plan for debridement in the operating room. MRI prior to debridement showed no abscess or osteomyelitis. While admitted, infectious disease consulted dermatology for a biopsy of the wound, which showed SCC. The wound on the right hand was biopsied in late November and demonstrated atypical squamous cells, foreign plant material, and arthropod remnants. It was thought to be a chronic wound, but a second biopsy was recommended if there was no improvement at his follow-up. Two months after presentation, he underwent Mohs micrographic surgery for his left hand. Four months later, the patient required amputation of his distal right fourth digit with axillary lymph node dissection, which was positive for SCC. Following lymph node dissection, the patient received radiation therapy to the right axilla. The patient did well for 8 months, but subsequently developed a neuroendocrine tumor in his lungs, which later metastasized. The patient died shortly after diagnosis.

Case 4

A 64-year-old female presented to the ED with a suspected diagnosis of worsening cellulitis of the left lower leg that had started a month prior to presentation (Figure 4). The patient had a history of kidney transplant and was on immunosuppressive therapy consisting of cyclosporine, mycophenolic acid, and prednisone. She had previously received multiple courses of antibiotics to treat the suspected cellulitis, including doxycycline, ciprofloxacin, and intravenous meropenem. Upon examination, she was noted to have a violaceous, indurated, nodular plaque that encircled the left lower extremity. The primary concern was for atypical cellulitis in the setting of immunosuppression; as such, biopsies were obtained for routine pathology as well as bacterial, fungal, and mycobacterial culture. The biopsy showed SCC, and 6 scouting biopsies from within the field were subsequently performed that confirmed the diagnosis of cSCC. Two weeks later, she received an above-the-knee amputation with inguinal lymph node biopsy, which was positive for metastatic disease. Given the history of kidney transplant she did not start on immunotherapy, but rather weaned off mycophenolic acid in hopes of slowing the growth of the SCC. Four months after hospital discharge, a PET scan showed further inguinal metastasis. Lymphadenectomy of enlarged nodes was performed with evidence of persistent metastatic disease. Repeated PET scans in 1 year after presentation showed no further spread of metastatic SCC disease but did reveal the presence of a pancreatic mass subsequently diagnosed as a neuroendocrine tumor. As the patient was deemed a poor surgical candidate, she is being followed by the oncology team.

cSCC rarely presents in unusual ways. Herein the authors describe 4 cases of patients with extreme presentations of cSCC whose diagnoses were initially unclear or thought to be infectious. The delay between initial treatment as a wound or infection to diagnosis as SCC ranged from 2 months to 3 years. All 4 patients were given antibiotics, 3 patients subsequently underwent amputations of extremities or digits, and 2 of the cases resulted in metastasis. As prompt and correct diagnosis is always the goal, it is important to be aware of possible clues that could point towards cancer in the setting of presumed chronic wounds and infections. Any skin lesion thought to be infectious but not responding to treatment should undergo tissue sampling.

In all these cases, one shared atypical feature was the distribution on the distal extremities, where infection and other non-malignant ulcers commonly and reasonably enter the differential diagnosis. A second atypical feature was the large size of these tumors. Most routine SCCs present as scaly papules or at most small plaques; it is less common for SCCs to present as large lesions, which may account for the initial misdiagnosis of infection. Finally, all these tumors had a deep-seated, infiltrative growth pattern and were very advanced. Most tumors that the current authors see in their routine practice and laboratory are small. The unusual presentation of a deep infiltrative tumor can cause diagnostic confusion.

Several additional clinical features are also important to note. In 3 of the cases, patients did not show any improvement in their wounds or infections despite multiple courses of antibiotics. In all 4 of the cases, patients did not benefit from wound care. Following recommended practices, a wound that does not show improvement after 3 months of appropriate treatment should raise suspicion for an atypical cause and should prompt skin biopsy.⁶ Another unique finding in cases 1 and 2 was the evidence of mass effect. Though swelling can be present in infection, increase in size should cause suspicion of abscess or tumor. The patients from cases 1 and 4 were both on chronic immunosuppressive therapy; patient 1 was on chronic prednisone for scleroderma as well as other immune modulators, and patient 4 was taking several medications to prevent rejection of a kidney transplant. Patients on chronic immunosuppressive therapy are at an increased risk of malignancy, and in solid organ transplant recipients the risk of cSCC is increased by 65 to 250 times compared with the general population.⁷ While most non-melanoma skin cancers in patients who are immunosuppressed are similar to those who are non-immunosuppressed in respect to size and location, extreme presentations are much more common in the context of immunosuppression. Therefore, when evaluating a patient who is immunosuppressed and has a chronic wound or infection that is resistant to therapy, it is especially important to keep malignancy on the differential.

Imaging is occasionally important for assessing the extent of involvement with nearby structures or to confirm if tissue changes are simply the result of lymphedema, but it may not be able to provide a specific diagnosis. In the setting of non-specific imaging findings, tissue sampling is the next step.

Other unusual presentations of SCC also exist. For example, tissue sampling should strongly be considered in any chronic wound or scar that demonstrates new or rapid change, as SCCs are well known to also arise in the setting of a chronic wound (known as a Marjolin ulcer).⁸ When SCCs occur in a chronic wound or scar, they can be particularly aggressive.

Limitations of this study are that it is anecdotal, highlights isolated cases, and is not meant as a rigorous large-scale review. The authors’ experience at a large referral hospital may be subject to a selection bias, as the authors’ institution tends to see more complex and unusual cases. Similar cases may be encountered less frequently in community practice.

Malignancies may masquerade as chronic infections. This case series shows several instances where cSCC evaded early detection by resembling a chronic, nonhealing ulcer or antibiotic-resistant cellulitis. For patients with wounds that do not respond to treatment, tissue biopsy is indicated.