Multiple myeloma is a plasma cell tumor that homes to and expands in the bone marrow and that, despite the new available drugs, remains incurable. Extramedullary plasmacytoma is a not frequent manifestation during the natural history of multiple myeloma and is frequently associated with plasma cell bone marrow infiltration. The most common locations for an EMP include the gastrointestinal tract, pleura, testis, skin, peritoneum, liver, endocrine glands, and lymph nodes. Primary involvement of the gallbladder fossa is exceedingly rare. In this report, we describe a patient with multiple myeloma who achieved a clinical and serological remission after autologous transplant but progressed rapidly at extramedullary site mimicking a second cancer (i.e., pancreatic or biliary cancer). In this case, the extramedullary localization was refractory to standard therapy, differently from bone marrow localization, but responded to lymphoma-like therapy. In this patient (i) the particular site of developing plasmacytoma is the gallbladder fossa, (ii) the timing of onset of this neoplasm is immediately after autologous transplant, and (iii) its disjunction from primary myeloma is that it appears in clinical and serological remission phase which may be confounding during the diagnostic approach simulating a different tumor (solid tumor).
Extramedullary plasmacytomas (EMP) represent a rare manifestation in the course of multiple myeloma (MM) [
Moreover, extramedullary progression of MM has consistently been associated with a poorer disease prognosis [
It has also been reported that extramedullary progression or relapse is often associated with the “escape” phenomenon of the monoclonal component [
A 62-year-old man had come to our observation in December 2013 because of the onset of a monoclonal component (MC) of about 51 gr/L typing as IgG-k at immunofixation in absence of anamnestic evidence of hematologic and extrahematologic diseases. Blood tests were normal: Hb 131 g/L, platelets 176000/
(a) May-Grunwald-Giemsa stain of bone marrow aspirate at diagnosis showing infiltrate of atypical plasma cells and (b) May-Grunwald-Giemsa stain after ASCT at VGPR showing reduction of the infiltration.
In November 2014, after the first consolidation cycle, patient developed fever, mild abdominal pain, and jaundice. The new evaluation of myeloma showed persistence of response with MC of 3 gr/L, Hb 12 g/L, platelets 195000/
MR cholangiopancreatography showed a tumor mass localized at the hepatic hilum without cleavage plane with the head of the pancreas and blood vessels of about 8.35 × 8.7 × 8.9 cm (Figures
MR cholangiopancreatography before VBD therapy. (a) and (b) show a tumor mass localized at the hepatic hilum without cleavage plane with the head of the pancreas and blood vessels of about 8.35 × 8.7 × 8.9 cm. ((c) and (d)) Hematoxylin and eosin stain. Original magnification ×100 and ×200. The myeloma cell size and nucleus are polymorphic. Many cells have large eccentric nuclei, prominent nucleoli, and abundant basophilic cytoplasm (i.e., nuclear and cytoplasmic maturation asynchrony). (e) The neoplastic cells are positive for CD138. (f) The ki67 labeling index exceeds 50%.
During the diagnostic period, since the patient had discontinued the specific therapy for myeloma for about one month, it has highlighted also a serological progression of disease with increase of the MC to 24 g/L, decrease of Hb (100 g/L) and albumin (17 g/L), alteration of k/
Final diagnosis was “multiple myeloma progression with associated extramedullary plasmocytoma” and the patient underwent new therapy with bendamustine, prednisone, and lenalidomide (BPR) in December 2014.
The evaluation after eight cycles of BPR (August/September 2015) showed a new serological response of the disease (CM: 13 g/L, Hb 119 g/L, albumin 34 g/L, normal free light chain ratio, and clonal bone marrow plasma cells 3%) but progression of extramedullary disease because of the increase of the dimension of the primary plasmocytoma (Figures
MR cholangiopancreatography after VBD therapy. Panels (a) and (b) show progression of extramedullary disease in the primary site (increase of dimension) and panels (c) and (d) show the appearance of new lesions in the liver.
Patient underwent salvage therapy with D-PACE (dexamethasone, cis-platinum, adriamycin, cyclophosphamide, and etoposide) and after two cycles of therapy (February 2016) obtained a good serological disease response and regression of extramedullary plasmacytoma. From March 2016 patient underwent continuous treatment with pomalidomide and dexamethasone.
The clonal evolution theory has been refined to include the concepts of cancer stem cell and intermediate subclones with cancer stemness properties, the importance of genomic instability, the role of epigenetics, and the impact of cancer microenvironment on clonal selection [
Moreover, growing evidence supports a pivotal role of the microenvironment in guiding clonal evolution and heterogeneity in MM [
Our case is indicative of the selection of almost two different clones in this patient with different biological and clinical behaviour. The different response to therapy of medullary and extramedullary disease indicate that, immediately after ASCT, under the pressure of therapy, an aggressive and refractory clone has been selected. This clone, resistant to new drugs, rapidly spread at extramedullary sites and progressed under proteasome inhibitors and immunomodulatory therapy. Only an aggressive treatment induced a response of both clones with remission of bone marrow disease and extramedullary spread.
The knowledge that intraclonal heterogeneity is an important feature of MM biology has changed our way of addressing cancer, now considered as a composite mixture of clones and not as a linear evolving disease. In this variable therapeutic landscape, it is of primary importance for clinicians and researchers to consider the impact that evolutionary biology and intraclonal heterogeneity have on the treatment of myeloma and the emergence of resistance clones. Only by doing so will we be able to effectively use all of the new tools we have at our disposal to cure myeloma and to use treatment in the most effective way possible. All this evidence provides a strong biologic rationale for using combinatory chemotherapy in an attempt to eradicate all clones and avoid selection of aggressive ones.
The authors declare that they have no competing interests.
Roberto Ria prepared the draft and Daniela Sciancalepore, Sergio Musci, Maria Rosaria Fracella, Grazia D’Alesio, Azzurra Sportelli, Giuseppe Ingravallo, Angelo Vacca, and Roberto Ria contributed to the care of patient and all reviewed and contributed to the final manuscript.
This work was supported by the Italian Association for Cancer Research (AIRC, Milan), Investigator Grant 2013 (no. 14095) and the 5 per thousand Molecular Clinical Oncology Special Program (Grant no. 9965 to Angelo Vacca), and Grants from MIUR PRIN 2009WCNS5C_004 (to Roberto Ria) and 2010NECHBX (to Angelo Vacca).