A 42-year-old woman comes to the clinic due to a lesion on the left side of her chest. The lesion first appeared several months ago and is slowly enlarging and occasionally oozing blood. The patient underwent a living-donor kidney transplant 5 years ago for end-stage renal disease due to IgA nephropathy. She also has hypothyroidism due to Hashimoto thyroiditis. Medications include tacrolimus, mycophenolate, low-dose prednisone, and levothyroxine. Vital signs are normal. On physical examination, a 1 × 2 cm crusted lesion is noted over the midsternal area. Biopsy of the lesion is performed; histopathology findings are shown in the exhibit.
Which of the following most likely contributed to the development of this patient's skin lesion?

Question

A 42-year-old woman comes to the clinic due to a lesion on the left side of her chest.  The lesion first appeared several months ago and is slowly enlarging and occasionally oozing blood.  The patient underwent a living-donor kidney transplant 5 years ago for end-stage renal disease due to IgA nephropathy.  She also has hypothyroidism due to Hashimoto thyroiditis.  Medications include tacrolimus, mycophenolate, low-dose prednisone, and levothyroxine.  Vital signs are normal.  On physical examination, a 1 × 2 cm crusted lesion is noted over the midsternal area.  Biopsy of the lesion is performed; histopathology findings are shown in the exhibit.  
Which of the following most likely contributed to the development of this patient's skin lesion?

Quizplus · Accepted Answer

Microscopy of this patient's enlarging, crusted skin lesion reveals invasive nests of atypical cells surrounding keratin pearls, which is consistent with cutaneous squamous cell carcinoma (SCC). Although risk of cutaneous SCC is increased by solar damage, chronic inflammation, and ionizing radiation, the primary driver of malignancy in this patient is likely the use of immunosuppressive medications (eg, tacrolimus, mycophenolate, prednisone). The innate and adaptive immune responses play a crucial role in the control of neoplasms, as follows: Natural killer cells, a component of the innate immune system, destroy host cells with surface markers signaling damage or distress and cells deficient in self markers such as class I major histocompatibility complexes (MHC). Cytotoxic T-cells identify tumor neoantigens on the surface of cancer cells and destroy the cell with cytotoxic granules. Helper T-cells identify tumor neoantigens on the surface of antigen-presenting cells and secrete effector cytokines (eg, interferon gamma, tumor necrosis factor alpha) that promote anti-tumor immune activity. Patients who are immunosuppressed from medications or infections (eg, HIV) are at increased risk for malignancy due to reduced immunosurveillance by natural killer cells and the cell-mediated immune response. Reduced immunosurveillance allows malignant cells to avoid immunologic identification with fewer evasive adaptations; it also allows oncogenic viruses to replicate in an unchecked fashion, which can trigger malignancy. (Choice B) Peripheral T-cell tolerance (anergy) occurs when a T-cell binds to its complementary antigen on surface MHC molecules but does not undergo costimulation. Cancer cells often overexpress molecules (eg, CTLA-4) that bind up surface proteins (CD80/86) required for T-cell costimulation, which increases (not decreases) peripheral T-cell tolerance. (Choice C) Telomeres are repetitive DNA sequences at the end of chromosomes that shorten progressively with cellular division, leading to chromosomal instability. Most tumors increase (not decrease) the activity of telomerase, an enzyme that adds nucleotides to the telomere in order to counteract shortening. (Choice D) Tumors produce cytokines that impede the differentiation of monocytes to macrophages in the tumor microenvironment, which helps prevent phagocytosis and destruction of tumor cells. (Choice E) Tumor cells typically decrease (not increase) expression of class I MHC in order to reduce display of neoantigens on their surface; this limits the ability of cytotoxic T-cells to identify tumor antigens on the cell surface. Educational objective: Natural killer cells and the cell mediated immune response play a major role in cancer cell detection and destruction. Therefore, patients who are immunocompromised from medication or infection are at much higher risk for cancer. __________ References: Cutaneous squamous cell carcinoma (cSCC) and immunosurveillance-the impact of immunosuppression on frequency of cSCC. (http://www.ncbi.nlm.nih.gov/pubmed/31833604)

A 42-Year-Old Woman Comes to the Clinic Due to a Lesion