Immature Plasma Cell Myeloma Mimics Metastatic Renal Cell Carcinoma on 18F-PSMA-1007 PET/CT Due to Endothelial PSMA-Expression

We present a 71-year-old female patient who underwent 18F-PSMA-1007 PET/CT for suspected metastatic renal cell carcinoma (RCC), as RCC also shows high PSMA-expression in tumor neovascularization. 18F-PSMA-1007 PET/CT showed a high PSMA-avidity in the renal tumor, enlarged intra-abdominal and mediastinal lymph nodes. Moreover, PSMA-positive pleural, pulmonal and osseous lesions were found. However, histopathology revealed an immature plasma cell myeloma with an endothelial PSMA-expression of the neovasculature. This case illustrates the increased PSMA-avidity in multiple myeloma and highlights PSMA as a potential theragnostic target in multiple myeloma. For clinical routine, lymphatic diseases such as extramedullary myeloma should be considered as differential diagnosis in PSMA-avid renal masses on PET/CT.

A 71-year-old woman presented to the uro-oncological department with a newly diagnosed, left-sided renal tumor for further clinical workup and the subsequent initiation of therapy. Contrast-enhanced computed tomography (CT), initially performed at the pelvis and the lower limbs to rule out arterial occlusion, revealed an incidental finding of an extensive, inhomogeneous, marginal contrast-enhancing renal tumor of the left kidney. In addition, there were surrounding, pathologically enlarged abdominal lymph nodes ( Figure 1A). The primary differential diagnosis consisted of renal cell carcinoma (RCC) with nodal abdominal spread. As the initial results highlighted the added clinical value of prostate-specific-antigen (PSMA)-targeted positron emission tomography (PET) imaging in metastatic RCC due to the PSMA-expression of tumor neovascularization [1][2][3][4][5], this patient underwent 18 F-PSMA-1007 PET/CT for whole body staging before any further tumor-specific therapies. Here, the left renal lesion showed a markedly increased PSMAexpression (maximal standardized uptake value (SUV max ) 30.0; tumor-to-background ratio (TBR), SUV max /SUV mean-liver 3,1; Figure 1B). markedly increased PSMA-expression (maximal standardized uptake value (SUVmax) 30.0; tumor-to-background ratio ((TBR), SUVmax/SUVmean-liver 3,1; Figure 1B). The pre-known enlarged lymph nodes also showed a high PSMA-avidity on PET (SUVmax 17.0). In addition, mediastinal lymph nodes, multilocular pulmonary, pleural, and osseous lesions presented with PSMA-avidity, partially even with extra-osseous soft tissue extension and mixed sclerotic/lytic correlate on CT. Beyond this, a left para-ovarian soft tissue bulk with highly increased PSMA-expression was found ( Figure 1C,D). A MIP projection demonstrates the whole tumor burden ( Figure 1E). For further evaluation, histological specimens of the left renal tumor were obtained using ultrasound-guided biopsy.
The microscopic examination of the biopsy revealed dense aggregates of mature and immature plasma cells in hematoxylin and eosin (H&E)-stained tissue specimens ( Figure  1F) with positivity for CD38 and CD138 and strong nuclear staining for multiple myeloma oncogene 1 (MUM1) ( Figure 1G). Staining for pan-cytokeratin (KL1 staining) was negative, ruling out a plasmacytoid urothelial carcinoma of the renal pelvis ( Figure 1H). The lesion was negative for CD20, cytokeratin-7 (CK7), paired box gene 8 (Pax8), and GATA3. Limitations in biopsy quantity and quality prevented the immuno-histochemical analysis of kappa and lambda light chains; however, based on histomorphology and the typical expression profile the diagnosis was confirmed as an immature plasma cell myeloma independently by two experienced pathologists. Immunohistochemical staining for PSMA showed a strong expression in tumor-associated microvasculature ( Figure 1I).
To date, increased PSMA-avidity in multiple myeloma has been described only sporadically in the literature [6][7][8] Of note, in a single case, PSMA expression was additionally shown to decrease after systemic therapy, highlighting PSMA-expression as a potential theranostic target for multiple myeloma, e.g., during radioligand therapy using 177 Lu-or 225 Ac-labeled PSMA-ligands [9]. To date, however, there is no literature describing PSMA-avid masses suggestive of renal RCC, which was then confirmed to be highly PSMA-avid multiple myeloma. For clinical routine, this case underlines that lymphatic diseases such as extramedullary myeloma should be considered as differential diagnosis in PSMA-avid renal masses on PET/CT despite their rare occurrence, as manifestations of multiple myeloma may also show a highly endothelial PSMAexpression.  The pre-known enlarged lymph nodes also showed a high PSMA-avidity on PET (SUV max 17.0). In addition, mediastinal lymph nodes, multilocular pulmonary, pleural, and osseous lesions presented with PSMA-avidity, partially even with extra-osseous soft tissue extension and mixed sclerotic/lytic correlate on CT. Beyond this, a left para-ovarian soft tissue bulk with highly increased PSMA-expression was found ( Figure 1C,D). A MIP projection demonstrates the whole tumor burden ( Figure 1E). For further evaluation, histological specimens of the left renal tumor were obtained using ultrasound-guided biopsy.
The microscopic examination of the biopsy revealed dense aggregates of mature and immature plasma cells in hematoxylin and eosin (H&E)-stained tissue specimens ( Figure 1F) with positivity for CD38 and CD138 and strong nuclear staining for multiple myeloma oncogene 1 (MUM1) ( Figure 1G). Staining for pan-cytokeratin (KL1 staining) was negative, ruling out a plasmacytoid urothelial carcinoma of the renal pelvis ( Figure 1H). The lesion was negative for CD20, cytokeratin-7 (CK7), paired box gene 8 (Pax8), and GATA3. Limitations in biopsy quantity and quality prevented the immuno-histochemical analysis of kappa and lambda light chains; however, based on histomorphology and the typical expression profile the diagnosis was confirmed as an immature plasma cell myeloma independently by two experienced pathologists. Immunohistochemical staining for PSMA showed a strong expression in tumor-associated microvasculature ( Figure 1I).
To date, increased PSMA-avidity in multiple myeloma has been described only sporadically in the literature [6][7][8] Of note, in a single case, PSMA expression was additionally shown to decrease after systemic therapy, highlighting PSMA-expression as a potential theranostic target for multiple myeloma, e.g., during radioligand therapy using 177 Luor 225 Ac-labeled PSMA-ligands [9]. To date, however, there is no literature describing PSMA-avid masses suggestive of renal RCC, which was then confirmed to be highly PSMA-avid multiple myeloma. For clinical routine, this case underlines that lymphatic diseases such as extramedullary myeloma should be considered as differential diagnosis in PSMA-avid renal masses on PET/CT despite their rare occurrence, as manifestations of multiple myeloma may also show a highly endothelial PSMA-expression.

Institutional Review Board Statement:
The ethics committee waives additional approval for case reports from clinical routine.

Consent for Publication:
The patient gave written consent prior to the PET/CT exam.

Data Availability Statement:
The data presented in this study are available on reasonable request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.