As previously stated, sPCL is the terminal stage of a preexisting multiple myeloma. Patients affected by sPCL usually show renal failure, even though renal dysfunction is more commonly seen in people affected by pPCL.

Blood and bone marrow findings

Circulating tumor cells may be detected with a specific leuko-erythroblastic blood picture in up to 67% of the patients. In many cases, the tumor cells look like normal plasma cells, but often they appear as lymphoplasmacytoid or immature plasma cells. Often, it is difficult to classify circulating plasma cells by using only light microscopy. For this reason, PCL may be hard to distinguish from other disorders with similar clinical pictures, like hairy cell leukemia, marginal zone lymphoma with circulating lymphocytes, or chronic lymphocytic leukemia. A correct diagnosis is only possible by using immune-phenotypic analysis in addition to light microscopy.

The typical signs of pPCL include the presence of less often positive HLA-DR, CD56, CD71, and CD117. These are usually associated with a lower expression of receptors like CD19, CD20, CD23, CD27, and CD45. The high incidence of the t(11;14) translocation in pPCL can be related to the increased expression of CD20 and CD23, as well as the decreased expression of CD56. A progressive decrease in the expression of the receptor CD38 can be observed, starting from levels in normal plasma cells to MGUS plasma cells, further to multiple myeloma plasma cells and finally to PCL plasma cells. This might indicate a progressive process of cell differentiation which characterizes the PCL pathophysiology. Some studies have revealed no expression of the receptor CD56, or a higher expression of other receptors like CD28 which appears more frequently in sPCL [11].

• Splenomegaly

  Primary Plasma cell leukaemia is more characterised by an extra medullar involvement such as hepatomegaly, splenomegaly, lymphadenopathy, lepto-meningeal infiltration or extramedullary plasmocytomas. The prognosis of pPCL is very poor. [ncbi.nlm.nih.gov]

  Bence Jones proteinuria, abnormal serum globulins, hepatomegaly, and splenomegaly are usual in plasma cell leukemia. [medical-dictionary.thefreedictionary.com]

  Extramedullary involvements, such as hepatomegaly, splenomegaly, lymphadenopathy, leptomeningeal infiltration, or extramedullary plasmocytomas, are more frequent in PCL. [panafrican-med-journal.com]

• Anemia

  Blood cell count showed anemia and thrombocytopenia and a hyperleukocytosis composed of deeply basophilic cells with a polylobulated nucleus resembling flower cells. [ncbi.nlm.nih.gov]

• Sepsis

  In the course of a second mobilization, 2 months after, the patient died from sepsis. We considered it important to report this case, in order to keep in mind the possibility of SR in patients with malignant gammopathy. [ncbi.nlm.nih.gov]

  The patient was unable to receive further therapy for plasma-cell leukemia because of the development of severe sepsis with multiorgan failure. [nejm.org]

  […] agranulocytosis, burns, chronic granulomatous disease, collagen vascular disease, exanthematous lesions, hypersensitivity reactions, non-malignant liver disease, nonmyelomatous malignancy, sarcoidosis, syphilis, subacute bacterial infection, streptococcal sepsis [medical-dictionary.thefreedictionary.com]

  He was then transferred to hospice care and succumbed to his underlying disease and sepsis. The patient died at day 75 post-transplant, 25 days after his diagnosis of leukemia cutis. [cureus.com]

  Nevertheless, the patient died of sepsis. Therapy with proteasome inhibitors and stem cell transplantation may also provide increased survival and improve the prognosis of patients with primary plasma cell leukemia. [omicsonline.org]

• Hepatomegaly

  Primary Plasma cell leukaemia is more characterised by an extra medullar involvement such as hepatomegaly, splenomegaly, lymphadenopathy, lepto-meningeal infiltration or extramedullary plasmocytomas. The prognosis of pPCL is very poor. [ncbi.nlm.nih.gov]

  The frequency of osteolytic lesions and splenomegaly among our PPCL cases were comparable to previous reports, but the incidence of hepatomegaly (75%) was higher and lymphadenopathy was absent in our cohort. [doi.org]

• Hepatosplenomegaly

  Our first case had hepatosplenomegaly and lymphadenopathy with few lytic bone lesions whereas the second case had hepatosplenomegaly with irregular lytic bone lesions in the skull. [jpgmonline.com]

  The major clinical manifestations of malaise, hepatosplenomegaly, anemia, and leukocytosis are related to abnormal, excessive, unrestrained overgrowth of granulocytes in the bone marrow. [medical-dictionary.thefreedictionary.com]

  Ultrasound revealed hepatosplenomegaly with moderate ascitis. [ijpmonline.org]

  CT scans of the abdomen and chest were notable for hepatosplenomegaly (fig. 1 a) and a left chest wall mass with destruction of the underlying rib (fig. 1 b). [karger.com]

  Hepatosplenomegaly (3/8) and isolated hepatomegaly (3/8) were both present in 37.5% of patients. Hence, enlarged liver (6/8) was noted in 75% of the patients. By imaging, 62% were confirmed to have lytic bone lesions. [doi.org]

• Suggestibility

  Five newly acquired SNVs, including truncating mutations of RB1 and ZKSCAN3, were observed only in the final sPCL sample suggesting leukemic transformation events. [ncbi.nlm.nih.gov]

• Renal Insufficiency

  PCL patients presented with a low peripheral blood plasmacytosis, extensive involvement of visceral organs and poor residual bone marrow function, without severe renal insufficiency. [ncbi.nlm.nih.gov]

  Only one patient presented with renal insufficiency and myeloma defining hypercalcemia (Sr.Ca >11 mg/dL). [doi.org]

  insufficiency and organomegaly.2,3 Two types of PCL are seen: secretory and non-secretory. [jpma.org.pk]

  insufficiency Amyloidosis ( MGUS comprises those cases exhibiting both lower levels of M protein and marrow involvement and lacking complications) Variants: Non-secretory myeloma ( Same as above but absence of M protein by immunofixation electrophoresis [surgpathcriteria.stanford.edu]

• Kidney Failure

  Similar to B cell leukemias, but unlike multiple myeloma, pPCL patients exhibit relative high frequencies of splenomegaly, lymphadenopathy, hepatomegaly, kidney failure, bone marrow failure (i.e. thrombocytopenia, anemia, and/or, rarely, leukopenia), [en.wikipedia.org]

Other common signs found in patients affected by plasma cell myeloma include:

• Bone pan
• Anemia
• Renal dysfunction
• Hypercalcemia
• Lytic bone lesion
• Leukocytosis
• Thrombocytopenia
• Hepatosplenomegaly

These are usually coupled with frequent infections and elevated levels of LDH, β-2-microglobulin, and a significant extramedullary involvement observed in affected patients [12].

• Decreased Platelet Count

  platelet count, and anemia due to decreased erythrocyte count. [medical-dictionary.thefreedictionary.com]

• Bone Marrow with Tumor Cells

  The tumor cells rely on the microenvironment in the bone marrow in regard to survival, growth and protection. [symptoma.com]

• Leukocytosis

  In addition, PPCL is associated with significant leukocytosis, markedly elevated lactate dehydrogenase levels, high beta-2-microglobulin (B2M) levels, and a higher incidence of tumor lysis syndrome [ 3 ]. [doi.org]

  The major clinical manifestations of malaise, hepatosplenomegaly, anemia, and leukocytosis are related to abnormal, excessive, unrestrained overgrowth of granulocytes in the bone marrow. [medical-dictionary.thefreedictionary.com]

  Prior to surgery, the blood count showed mild leukocytosis (13.6 × 10 9 /L), with predominance of neutrophils. [omicsonline.org]

  Hemogram revealed anemia (hemoglobin [Hb] 6.8 g/dl), thrombocytopenia (75,000/cumm), and leukocytosis with total leukocyte count (TLC) of 19,370/cumm. [ijpmonline.org]

  The clinical presentation typically involves symptoms attributed to end organ damage seen in MM (hypercalcemia, renal failure, anemia, and lytic bone lesions) or to leukemia (leukocytosis, thrombocytopenia and organomegaly). [karger.com]

Conventional chemotherapy

Chemotherapy appears to have a limited effectiveness in treating PCL. However, survival rates are improved when a multiagent conventional chemotherapy is applied (such as vincristine, adriamycin, and dexamethasone (VAD)-based regimens) rather than the approaches based on the use of an alkylating agent plus a corticosteroid. In any case, survival associated with conventional chemotherapy with the use of no novel agent is generally very poor, extending no further than 7 months on average.

Novel agents

Survival has significantly benefited from the introduction of immunomodulatory drugs and proteasome inhibitors, especially when treatment is based on bortezomib and/or thalidomide. However, the efficacy of these drugs is still under debate among experts.

• Bortezomib

Bortezomib reduces the tumor load and reverses complications like renal failure and hypercalcemia. Furthermore, it allows to achieve a better prognosis when dangerous chromosomal aberrancies like del(13q) or t(4;14) appear. Bortezomib mitigates the adverse outcome associated with some of them. Clinical data suggest that bortezomib, alone or combined with another agent, is effective especially in cases of newly diagnosed pPCL.

• Thalidomide

This agent is more effective to treat multiple myeloma rather than pPCL, and in any case its overall efficiency, especially as single-agent, remains limited. Furthermore, the use of this drug is even less attractive due to its decreased activity in extramedullary multiple myeloma.

• Lenalidomide

Lenalidomide carries the advantage of being less toxic and more potent than thalidomide. Its use has turned out to be very effective when combined with dexamethasone in newly diagnosed pPCL and this, together with other qualities, makes it very promising to treat relapsed/refractory diseases, especially when combined with bortezomib.

• Combinations of novel agents

For its promising results, the combination of novel agents is considered to be the standard rule in the treatment of PCL in the future. However, other possible and equally promising approaches have to be remembered, like autologous and allogeneic stem cell transplant, both well known to considerably enhancing survival rates.

Unfortunately, the prognosis of PCL is still very poor due to the absence of effective therapies and the aggressive nature of this disorder. On average, survival is estimated to be around 7 months when patients are treated with conventional chemotherapy. Prognosis may be improved by stem cell transplantation, but even in this case survival does not extend beyond 3 years. sPCL is associated with a particularly poor prognosis, survival averaging no longer than two months.

The precise etiology of PCL is still largely unknown. However, it is believed that the disorder must be caused by a series of genetic changes occurring during the development of plasma cells which subsequently lead to a state of uncontrolled cell growth and proliferation. Other important risk factors which seem to play an important role into the development of PCL include age and exposure to industrial and environmental factors, as found also in other forms of multiple myeloma. The risk factors underlying PCL can be summed up as follows:

• Age: Myeloma mostly occurs in people over 60 years of age, with a diagnosis made around 70. Just around 2% of the cases are reported in people younger than 40. 
• Race: Myeloma appears more frequently in blacks than in whites, with a frequency that is usually twice as much. The reason for this tendency remains unknown.
• Exposure to radiations and chemicals: Myeloma is particular frequent in people who have been exposed to radiations or chemicals such as asbestos, benzene, pesticides, and other chemicals generally employed in the rubber industry.
• Personal history: Multiple myeloma is particularly frequent in people affected by solitary plasmacytoma of the bone.
• Monoclonal gammopathy of unknown significance (MGUS): People who show only a small amount of monoclonal protein (M protein) in the blood plasma have a 1% chance of developing myeloma (or another blood-related disorder called Waldenstrom macroglobulinemia) every year.
• Gender: Myeloma appears to be a slightly more frequent in men than women.

As previously stated, PCL represents 2-4% of all cases of diagnosed plasma cell myeloma, more common than originally described. The disorder tends to appear late in life, with an average age of appearance around 70 years. Almost two-thirds of the patients are older than 60 years at the time of the diagnosis [3]. Furthermore, the disorder is more frequent in blacks than whites, with a frequency that is generally twice as much.

The tumor cells rely on the microenvironment in the bone marrow in regard to survival, growth and protection. After initial accumulation in the bone marrow, the tumor cells proceed to re-circulate into the blood, followed by the formation of extramedullary disease. This dissemination of the tumor cells shows correlations to alterations in expression of adhesion molecules and chemokine receptors, the inhibited apoptosis and the escape from immune surveillance. Moreover, a series of other molecular aberrations may enhance the tumor growth. These genetic events accumulate until they lead to the acquisition of the aggressive phenotype of the clonal plasma cells. Interestingly, the gene expression of pPCL appears to have a distinctive profile among the other myeloma samples [6]. Some cases of PCL report a preexisting monoclonal gammopathy of undetermined significance [7]. However, at the moment it is not known to what extent this protracted premalignant phase usually precedes pPCL or if this mainly arises as a de novo condition.

Initial immortalizing events

The early oncogenic event leading to the plasma cell clone immortalization is primary IgH translocation and hyperdiploidy. However, these are not sufficient for the development of the disorder. In fact, hyperdiploidy has been observed just in 0%-8.8% of the cases of pPCL and in around 50% of the cases of diagnosed multiple myeloma. On the contrary, it is possible to observe a significant increase in the incidence of hypodiploidy and IgH translocation, something that underlines the association of the 14q32 translocation with nondyperdiploidy as seen in cases of multiple myeloma. sPCL follows a similar pattern of development, with the only exception represented by the slightly higher prevalence of hyperdiploidy (around 17%) compared to the one found in pPCL [8]. The significance of this pattern is still under debate among experts, but it is possible that this emphasizes a lower dependence of the nonhyperdiploid tumors to the bone marrow microenvironment compared to the one found in hyperdiploid cases. The IgH translocation t(11;14) in pPCL is the most recurrent, with a frequency ranging from 25% to 65%. Most frequent and associated with a poor prognosis is also the t(4;14) translocation. In both cases, the prognosis observed is poorer in pPCL than in multiple myeloma [9].

Secondary epigenetic events

In general, the prevalence of chromosomal abnormalities like del(17p) or del(13q) seen in both pPCL and sPCL is significantly higher than in multiple myeloma. Many of these chromosomal abnormalities result in mutations in coding sequences, but sometimes they might lead to epigenetic mutations like the increased rate of methylation of CpG nucleotides in gene promoter, which have showed to play a pivotal role in the pathogenesis of PCL [10].

Adhesion molecules and chemokine receptors

It has to be noted that tumor cells in PCL cases show a reduced gene expression of important adhesion molecules like NCAM (neural cell adhesion molecule/CD56) and LFA-1 (leukocyte function-associated antigen-1). These mutations are thought to contribute to the reduced binding of the tumor cells to the stromal cells into the bone marrow and in general the extramedullary accumulation of tumor cells characterizing PCL. The loss of CD56 also results in an increase in the production of the matrix metalloproteinase-9, which play a pivotal role in the degradation of extracellular matrixes. This finally leads to the destruction of the basal membrane and extracellular matrix, typical events in the pathophysiology of PCL. The impaired adhesion, together with a decreased motility and invasion, are also associated with the loss of very late antigen-5 (VLA-5, LFA-3) and some tetraspanin proteins like CD9 and CD82. In addition, chemokine receptors like CXCR4 show a marked down-regulation. An impaired retention of PCL may be the consequence.

Immune evasion

Impaired T cell and NK cell-mediated immune responses in PCL may arise due to´chromosomal abnormalities. An example for such an abnormality is the reduced expression of the antigen-presenting HLA class I molecules which, together with the loss of adhesion molecules like LFA-1, might also favor the capacity of tumor cells in PCL to elude immune surveillance.

Being a congenital disorder, no particular measure can be suggested to prevent PCL.

Plasma cell leukemia (PCL) is a lymphoproliferative disorder [1] which consists in a rare cancer that involves a subtype of white blood cells called plasma cells [2]. This disorder is considered one of the most aggressive forms of human neoplasm representing 2% to 4% [3] [4] of all plasma cell disorders. Plasma cells compose more than 20% of the cells contained in the peripheral blood, with an absolute plasma cell count over 2 x 109/l.

The presentation is defined as primary if the disorder evolves "de novo" and secondary if it develops from a preexisting form of multiple myeloma as its terminal and final stage. Similarly, PCL can be primary (pPCL) if no previous history of plasma cell myeloma can be found and secondary (sPCL) if it arises from a well known diagnosis of a primary form of plasma cell myeloma. According to clinical data, around 60-70% of all cases are primary forms of plasma cell myeloma, while the remaining 30% represent secondary ones [5] . Recent reports indicate that the average time needed to transform a form of plasma cell myeloma into sPCL is around 21 months [5]. Clinical signs include aggressive symptoms such as extramedullary diseases and bone marrow failure generally associated with distinct immunophenotypic markers like the lack of CD56 and the presence of CD20. Patients affected by PCL usually present a very poor prognosis, with an average survival of no more than a few months.

Treatment of PCL is mostly palliative, as just a small minority of patients experiences a durable remission. The impact of new agents like bortezomib and lenalidomide, usually administered with concomitant autologous and allogeneic stem cell transplantation, is still largely uncertain, even though recent data seem to suggest that these approaches might improve the currently poor prognosis. Diagnosis criteria include the presence of circulating clonal plasma cell count over 2000/µl, if total white blood cell count is over >10,000/µl, or the presence of more than 20% circulating plasma cells.

Plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma which is mainly characterized by the presence of circulating plasma cells. It can be classified into two major forms: primary PCL (pPCL), associated with no previous disorder, and secondary PCL (sPCL), which usually appears after relapsed/refractory myeloma.

The clinical course of PCL is marked by an aggressive presentation associated with a short remission and survival duration. The diagnosis is based on the measurement of plasma cells found in the peripheral blood. Conventional chemotherapy based on the use of important agents such as bortezomib remains the mainstay in the treatment of PCL, together with other possible approaches such as autologous and allogeneic stem cell transplant. Novel agents are still being developed, but their use as therapeutic tools, especially in combination, is very promising.

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