Renal Cell Carcinoma Associated with Mycosis Fungoides: A Paraneoplastic Syndrome

Patients with mycosis fungoides have an increased risk for additional malignancies, particularly hematologic malignancies. Of the malignancies that have been associated with mycosis fungoides, renal cell carcinoma and other solid tumor malignancies have not been studied extensively. In this case series, we describe three mycosis fungoides patients who were diagnosed with clear cell renal cell carcinoma and discuss the potential pathophysiology underlying this association.


Introduction
Patients with mycosis fungoides (MF) have an increased risk for additional malignancies, particularly hematologic malignancies [1][2][3]. MF patients are also at an increased risk for solid tumor malignancies, but this association is less frequent and not well-characterized [2]. In 2019, Goyal et al. detailed a link between MF and solid tumor malignancies such as RCC. e study found elevated standardized incidence ratios (SIRs) for kidney and renal pelvis cancer in patients with MF [2]. SIR for kidney and renal pelvis cancer within a year of diagnosis of MF was 12.05. In our study of 672 patients with cutaneous T-cell lymphoma (CTCL) in 2008, 112 patients (17%) had at least one additional malignancy. Overall, patients with CTCL had a 1.79-fold risk for developing an additional malignancy [4]. In this case series, we describe three MF patients who were diagnosed with clear cell RCC and discuss the potential pathophysiology underlying this association.  e patient first noticed a lesion on his right thigh approximately 10 years prior. He was diagnosed as having "dry skin" and treated with an unknown ointment with no improvement.

Case Presentation
e lesion continued to expand, becoming raised and indurated. In June 1996, a skin biopsy was performed by the patient's local dermatologist, which was consistent with MF. On presentation at MDACC, full-body skin exam revealed an 18 cm × 13 cm dusky red plaque on the right upper thigh with a net-like pattern. e plaque was rebiopsied at MDACC, which confirmed MF. e patient's MF lesion was treated with tazarotene 0.05% gel and mometasone 0.1% cream with minimal improvement. In February 1998, the patient was hospitalized for atrial fibrillation. During hospitalization, he was found to have a 3.3 cm × 2.5 cm solid mass on the left lower pole of the kidney. A biopsy of the mass revealed clear cell RCC. e patient denied any urinary symptoms. A left partial nephrectomy was performed. Within months of removal of the renal mass, the patient began to notice significant flattening and decreased hyperpigmentation of his MF lesion without changes to his treatment regimen (Figure 2). His skin lesion has since remained stable.

Discussion
Decreased cellular immunity and immune surveillance in MF patients may be a driving factor for secondary malignancies [2]. While the occurrence of RCC in our patients may have been incidental, the expanded number of CD4+ lymphocytes present in existing MF may have triggered the development of RCC. Using both in vitro and in vivo studies of mice RCC tissue, Wang et al. found that RCC cells have a better ability to recruit CD4+ lymphocytes than normal renal cells [5]. e recruited CD4+ lymphocytes stimulate RCC cell proliferation, promoting RCC [5].
e senior authors of this manuscript report that, in their clinical experience, nearly all MF patients have a tendency to relapse despite adequate treatment, and periodic flares are expected throughout their lifetime. In our patients, the absence of MF flares in over 16 years following removal of their RCC increases suspicion of a paraneoplastic syndrome. Paraneoplastic syndrome refers to specific clinical manifestations that are triggered by an altered immune system in response to a malignancy; the symptoms may not be directly attributable to invasion of the primary tumor, metastasis, or direct compression [6]. e stimulation of lymphocytes in response to RCC may have triggered the development of MF, and subsequent removal of the RCC resulted in return to normal lymphocyte levels, halting progression of MF.
While RCC was found after the diagnosis of MF in each of these patients, it remains unknown how long the RCC was present. Due to the lack of widely accepted guidelines regarding screening for renal cancer, more stringent screening guidelines may be required. Routine screening for underlying solid organ malignancies in patients with MF may be

Conclusion
Patients with MF are at higher risk for second malignancies [4]. Of the malignancies that have been associated with MF, renal cell carcinoma (RCC) and other solid tumor malignancies have not been studied extensively [2]. e presence of a second malignancy, such as RCC, in MF patients may be a result of a paraneoplastic syndrome. Further research is needed to characterize the association between MF and RCC.

Data Availability
No data were used to support this study. Case Reports in Nephrology 3