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This is a cancer of the plasma cells, usually beginning in the bone marrow. These neoplastic plasma cells produce immunoglobulins and evolve from B lymphocytes.  The disease typically involves the bones and kidneys and may lead to kidney failure.  Patients may complain of back pain, weakness, and fatigue. However, rarely patients may be diagnosed during a serum protein electrophoresis. The immunoglobulins which are produced by the plasma cells may be detected in both the blood serum and urine by sophisticated electrophoresis testing.

The bone marrow aspiration and biopsy, usually performed by the pathologist, is one of the most important tests that can be performed to establish the diagnosis. If possible, the biopsy should be directed at a site of a lytic bone lesion. The pathologist can use immunohistochemistry upon the tissue sample to identify these abnormal immunoglobulins and establish the diagnosis.


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SYNONYMS Plasma cell myeloma
INCIDENCE 3.9/100,000 in USA
1% of all malignant tumors
10% of hematologic malignancies

Peak incidence in 9th decade
Rare in <35 years
No cases in children yet reported

GEOGRAPHIC DISTRIBUTION Twice as common in blacks


Generalized livedo reticularis associated with monoclonal cryoglobulinemia and multiple myeloma.

Department of Dermatology, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain.


J Cutan Pathol. 2007 Feb;34(2):198-202 Abstract quote

Cryoglobulins are detected in a wide variety of diseases, including malignancies, infections and systemic autoimmune diseases. Classically, monoclonal cryoglobulinemia is associated with hematologic malignancies, whereas mixed cryoglobulinemias are reported in association with hepatitis C virus infections or autoimmune diseases.

We present a patient with generalized livedo reticularis as the first manifestation of monoclonal cryoglobulinemia and multiple myeloma. Histopathology demonstrated that nearly all small blood vessels of the upper and deep dermis, as well as the capillaries of the fat lobule, were filled with homogeneous, eosinophilic material that corresponded to monoclonal cryoglobulin deposits within the vascular lumina.

Our case of livedo reticularis associated with monoclonal cryoglobulinemia and multiple myeloma was exceptional, because the mottled cyanotic discoloration of the skin with a reticular pattern was generalized, covering most of the skin surface.

We have not found previous report of similar cases. Therefore, we recommend that dermatologists be made aware of the significance of this diagnosis.

Sweet syndrome in multiple myeloma: a series of six cases.

Bayer-Garner IB, Cottler-Fox M, Smoller BR.

Department of Pathology, Baylor Medical College, Houston, TX, USA;Departments of Pathology and Dermatology and Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, AR, USA.

J Cutan Pathol 2003 Apr;30(4):261-4 Abstract quote

BACKGROUND: Sweet syndrome (SS), a paraneoplastic syndrome characterized by fever, neutrophilia, multiple erythematous painful plaques, and a dense dermal neutrophilic infiltration, has a known association with hematologic malignancies such as acute myelogenous leukemia. However, no clear association with multiple myeloma (MM) has been reported.

MATERIALS AND METHODS: Pathology reports of the 2357 patients with multiple myeloma at the University of Arkansas for Medical Sciences were reviewed to retrieve cases who had developed SS. Cytogenetic studies and immunoglobulin secretory status were retrieved. Five cases of SS in MM and 25 cases of SS in patients without MM underwent syndecan-1 immunohistochemistry.

OBSERVATIONS: Six cases of SS occurring in the setting of MM showed a predominance in patients secreting IgG paraprotein. Five of the six patients received granulocyte-colony stimulating factor while the sixth received granulocyte-monocyte-colony stimulating factor. Fifty percent showed a non-specific cytogenetic anomaly.

CONCLUSIONS: There is no specific cytogenetic anomaly associated with SS in the setting of MM. This paraneoplastic syndrome may be secondary to elevated levels of granulocyte colony stimulating factor (G-CSF), possibly with a component of enhanced sensitivity to endogenous G-CSF. The immunoglobulin secretory status parallels that seen in MM with cutaneous involvement, but IgG secretors may be at an increased risk of developing SS compared with their counterparts who secrete other immunoglobulins.


Thought to be derived from early hematopoietic stem cells Manifested at a mature stage of B cell development
Frequent abnormalities:

A variant Burkitt-type translocation (8;22)(q24;q11) in multiple myeloma. Report of a new case and review of the literature.

Yamamoto K, Hamaguchi H, Nagata K, Taniwaki M.

Department of Hematology, Musashino Red Cross Hospital, Tokyo, Japan.

Cancer Genet Cytogenet 1998 Jul 15;104(2):98-103 Abstract quote

We report here a new case of multiple myeloma (IgG, kappa, stage IIIA) with a variant Burkitt-type translocation (8;22)(q24;q11).

Bone marrow plasma cells were morphologically immature with fine nuclear chromatin and nucleoli. Chromosome analysis showed complex aberrations; that is, 53,XX, der(1)add(1)(p11)dup(1)(q12q32),+3,+5,t(8;22)(q24;q11),+9,add(10)( p13), +11,+15,add(19)(q13),+21. Fluorescence in situ hybridization analysis with the yeast artificial chromosome (YAC) clone I2 containing the C-MYC gene at 8q24 and the chromosome-22-specific DNA library pBS22 revealed that 12 was located on the der(8)t(8;22). A fusion signal derived from I2 and the YAC clone B99E1 containing the BCR gene at 22q11 was also observed on the der(8)t(8;22). Our results indicate that the breakpoint at 8q24 in this patient was located far downstream of the C-MYC gene. This breakpoint site is similar to Burkitt lymphoma with t(8;22)(q24;q11).

A review of eight cases in the literature and the present case of multiple myeloma with t(8;22)(q24;q11) showed that most of them were of advanced stage and had an immature phenotype. It is suggested that the C-MYC gene may be activated by t(8;22)(q24;q11) and implicated in disease progression in multiple myeloma.

Recurrent chromosomal rearrangements involving breakpoints 3p21 and 19q13 in Chinese IgD multiple myeloma detected by G-banding and multicolor spectral karyotyping: A review of IgD karyotype literature

Margaret H.L. Ng, MRCPath
Nathalie Wong, PhD
Kam-Sze Tsang, MPhil
Suk-Hang Cheng, BSc
Yuk-Fei Chung, MPhil
Kok-Wai Lo, PhD

Hum Pathol 2001;32:1016-1020 Abstract quote

Immunoglobulin D multiple myeloma (IgD MM) is a rare subtype that accounts for 1% to 3% of MM and shows higher aggressiveness with distinctive clinical and laboratory features. However, there is little information in the literature on their karyotypes, which are mainly derived from G-banding results.

Our current study on 2 Chinese IgD MM thus represents the first description of cytogenetic data on this subtype based on an integrated analysis with G-banding and multicolor spectral karyotyping (SKY).

Both of our cases showed some usual features of MM, as well as a few novel translocations including t(3;22), t(6;19), t(X;19) and the 3 whole-arm translocations namely t(1;6)(q10;p10), t(4;9)(q10;p10), and t(16;18)(q10;q10). We also identified recurrent chromosomal rearrangements involving breakpoints 3p21 and 19q13, which may suggest to be unique aberrations that may underline the pathogenesis of this distinctive biological MM subtype.

HUMAN HERPES VIRUS 8 Possible association and role in pathogenesis

The role of human herpesvirus-8 in the pathogenesis of multiple myeloma.

Sjak-Shie NN, Vescio RA, Berenson JR.

Division of Hematology and Oncology, University of California School of Medicine, Los Angeles, USA.

Hematol Oncol Clin North Am 1999 Dec;13(6):1159-67 Abstract quote

Human herpesvirus-8 has been strongly implicated in the pathogenesis of KS, BCBL, and multicentric Castleman's disease. Evidence for its role in the pathogenesis of multiple myeloma is accumulating. Human herpesvirus-8 is detectable in the nonmalignant bone marrow dendritic cells from most myeloma patients. In addition, HHV-8 is also detected in the peripheral blood of most myeloma patients. In contrast, this virus is rarely detected in close contacts of myeloma patients, healthy individuals, or patients with other malignancies. Furthermore, only about one fourth of patients with MGUS are infected with HHV-8. Sequencing of HHV-8 DNA isolated from myeloma patients shows both minor differences among patients and a conserved deletion unique to myeloma compared with HHV-8 in other malignancies. Consistent expression of both the viral homologues of IRF and IL-8R in myeloma suggests a possible role for these transforming viral genes in the pathogenesis of this disease.

Although the described association between multiple myeloma and HHV-8 implies a causal role in the pathogenesis of this disease, no cause-and-effect relationship is yet demonstrated. Evidence may be obtained directly by fulfilling Koch's postulate in an animal model and indirectly through therapeutic interventions with antiviral agents or through extensive epidemiological studies. Such epidemiological studies would be greatly facilitated by the development of antibodies directed against the HHV-8 viral proteins uniquely present in myeloma. A direct or indirect causal effect of HHV-8 has potentially enormous implications for the therapeutic benefit of antiviral agents and preventative strategies using vaccines.

There is, indeed, preliminary evidence that antiviral therapy in HIV-infected patients reduces the risk or development of KS. Clinical improvement in patients with KS treated with antiviral agents has also been reported. These observations suggest that future treatment strategies to combat multiple myeloma may include antiviral agents.

Lack of serologic association of human herpesvirus-8 (KSHV) in patients with monoclonal gammopathy of undetermined significance with and without progression to multiple myeloma.

Ablashi DV, Chatlynne L, Thomas D, Bourboulia D, Rettig MB, Vescio RA, Viza D, Gill P, Kyle RA, Berenson JR, Whitman JE.

Advanced Biotechnologies Inc, Columbia, MD 21046-2701, USA.

Blood 2000 Sep 15;96(6):2304-6 Abstract quote

Because human herpesvirus-8 (HHV-8) DNA has been found in multiple myeloma (MM) patients by polymerase chain reaction, it was suggested that HHV-8 may play a role in the transformation of monoclonal gammopathy of undetermined significance (MGUS) to MM. Therefore, 362 MGUS sera with and without progression to MM were tested for IgG antibody to HHV-8.

Only 7.8% of the MGUS sera contained HHV-8 antibody to lytic proteins, and IgG antibody to HHV-8 latent antigen was even lower than lytic antibody (2.9%). No differences were observed in the distribution of antibody to HHV-8 in sera from MGUS patients who progressed to MM.

The seroprevalences of HHV-8 in MGUS (7.8%), MM (5.4%), and healthy donors (5.9%) were similar, thus arguing for the lack of epidemiologic evidence of HHV-8 participation in the pathogenesis of MM. MGUS patients were immune competent in response to Epstein-Barr virus (EBV) infection because 97% contained antibody to EBV virus capsid antigen.

Human herpesvirus 8 open reading frame 26 and open reading frame 65 sequences from multiple myeloma patients: a shared pattern not found in Kaposi's sarcoma or primary effusion lymphoma.

Ma HJ, Sjak-Shie NN, Vescio RA, Kaminsky M, Mikail A, Pold M, Parker K, Beksac M, Belson D, Moss TJ, Wu CH, Zhou J, Zhang L, Chen G, Said JW, Berenson JR.

Division of Hematology and Oncology, Cedars-Sinai Medical Center Los Angeles, California 90048, USA.

Clin Cancer Res 2000 Nov;6(11):4226-33 Abstract quote

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus, has been implicated in the pathogenesis of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman's disease, and recently multiple myeloma (MM). DNA sequence analyses of HHV-8 suggest that multiple HHV-8 strains exist.

We extracted DNA from 24 patients with MM and 3 patients with monoclonal gammopathy of undetermined significance and compared HHV-8 open reading frames (ORFs) 26 and 65 sequences with those derived from patients with KS, PEL, and two HHV-8-positive PEL cell lines KS-1 and BC-1. ORF26 sequence data suggest that MM patients are consistently carriers of HHV-8 strain subtype C3. All MM patients also consistently revealed either a single bp deletion or substitution at position 112197 in ORF65.

This unique alteration is not present in patients with KS or PEL or in PEL cell lines. It occurs in the portion of ORF65 that is known to be responsible for a serological response to HHV-8.

Frequent demonstration of human herpesvirus 8 (HHV-8) in bone marrow biopsy samples from Turkish patients with multiple myeloma (MM).

Beksac M, Ma M, Akyerli C, DerDanielian M, Zhang L, Liu J, Arat M, Konuk N, Koc H, Ozcelik T, Vescio R, Berenson JR.

Ibni Sina Hospital, Department of Hematology, Ankara University School of Medicine, Sihhiye, Turkey.

Leukemia 2001 Aug;15(8):1268-73 Abstract quote

In order to investigate the frequency of HHV-8 in MM patients from another geographic location, we obtained fresh bone marrow (BM) biopsies from Turkish patients with MM (n = 21), monoclonal gammopathy of undetermined significance (MGUS) (n = 2), plasmacytoma (n = 1) with BM plasma cell infiltration, various hematological disorders (n = 6), and five healthy Turkish controls.

The frequency of HHV-8 was analyzed by polymerase chain reaction (PCR) in two independent laboratories in the USA and in Turkey. Using fresh BM biopsies, 17/21 MM patients were positive for HHV-8 whereas all five healthy controls, and six patients with other hematological disorders were negative. Two patients with MGUS, and one patient with a solitary plasmacytoma were also negative. The data from the two laboratories were completely concordant. Also using primer pairs for v IRF and v IL-8R confirmed the results observed with the KS330233 primers. Furthermore, sequence analysis demonstrated a C3 strain pattern in the ORF26 region which was also found in MM patients from the US.

Thus, HHV-8 is present in the majority of Turkish MM patients, and the absence of the virus in healthy controls further supports its role in the pathogenesis of MM.


Immunohistochemical expression of the p53, p21/Waf-1, Rb, p16 and Ki67 proteins in multiple myeloma.

Kanavaros P, Stefanaki K, Vlachonikolis J, Papalazarou D, Rontogianni D, Arvanitis D, Antonakopoulos G, Gorgoulis V, Bai M, Agnantis NJ.

Department of Histology, University of Thesallia, Faculty of Medicine, Papakyriazi 22, 41222, Larissa, Hellas.

Anticancer Res 2000 Nov-Dec;20(6B):4619-25 Abstract quote

The aim of this study was to investigate the immunohistochemical expression of the proteins p53, Waf-l/p21, Rb, p16 and Ki67 in 38 cases of multiple myelomas (MM) and 4 cases of solitary extramedullary plasmacytomas in relation to the tumor histological grade and stage. In bone marrow (BM) biopsies from MM, overexpression of p53 and p21 proteins, in comparison to plasma cell infiltrates in non-pathological bone marrow, was detected in 13 out of 38 and 21 out of 38 cases, respectively.

The combined immunoexpression of p53 and p21 proteins in the 38 cases of MM showed the following patterns: a) p53+/p21+ (13 cases) b) p53-/p21+ (8 cases) and c) p53-/p21- (17 cases). Rb, p16 and Ki67 proteins were detected in tumor cells in all 38 cases and their expression increased proportionally to tumor grade. The 4 cases of solitary extramedullary plasmacytomas showed the p53+/p21+ pattern in 2 cases and the p53-/p21+ pattern in 2 cases, all of them displaying Rb, p16 and Ki67 expression in tumor cells. The pattern p53+/p21+ might represent cases with wild-type p53 able to induce p21 expression. However, in previous studies p53 mutations were reported in about 3-10% of MM, and they were strongly associated with advanced disease. Thus, in some p53+/p21+ cases associated with high p53 expression and advanced disease, p53 gene cannot be excluded and up-regulation of p21 expression may be p53- independent. P53 overexpression correlated with increased tumor grade (p < 0.005), advanced histological stage (p < 0.001) and Ki67 expression in more than 10% of tumor cells (p < 0.001). Since increase in Ki67 expression also correlated with increased tumor grade (p < 0.001) and advanced histological stage (p < 0.001), these findings suggest that impairment of the p53 growth control pathway is associated with tumor progression in MM. Thus, p53 and Ki67 immunostaining in routine BM biopsies may be helpful for the detection of MM with potentially aggressive behavior.

Overexpression of p21 in MM correlated with higher Ki67 expression (p < 0.005), suggesting that the p21 function of arresting cell-cycle is impaired. Ki-67 expression in MM increased in parallel with p16 (p < 0.001) and Rb expression (p < 0.001). Rb expression could represent a growth control response which, however, might not be able to induce growth arrest in view of the parallel increase in Ki67 expression and of previous findings showing that Rb protein in MM cells is expressed mostly in its phosphorylated form.


General-Durie-Salmon Staging System

To establish the diagnosis:

>10% of bone marrow plasma cells
>3 g/dL of monoclonal serum protein
>1 g/day of kappa or lambda light chains in urine

Major Criteria
Cancer Chemother Rep 1973;4:145-158
Plasmacytoma in a tissue biopsy specimen
Bone marrow plasmacytosis >30% in bone marrow aspirate or biopsy specimen
M protein concentration:
Serum IgG >3500 mg/dL or serum IgA >2000 mg/dL or urinary Bence Jones protein (kappa or lambda) 1g/24 h or more (in the absence of amyloidosis)
Minor Criteria
Osteolytic bone lesions
Bone marrow plasmacytosis between 10-30%
M protein< than major criteria
Decline of normal serum Ig
Monoclonal proteins (Light and heavy chains) Serum and urine electrophoresis with immunofixation
Monoclonal Immunoglobulin
Percentage of cases
Light chain only
Radiographic survey

Lytic lesions in areas where the myeloma cells are proliferating-75% of cases
Proximal humeri

Generalized osteoporosis

Serum beta-2 microglobulin Elevated
Serum calcium Elevated
Serum albumin Decreased in advanced disease
Poor prognostic factor
Flow Cytometric Immunophenotypic Analysis of 306 Cases of Multiple Myeloma

Pei Lin, MD, Rebecca Owens, Guido Tricot, MD, PhD, and Carla S. Wilson, MD, PhD
Am J Clin Pathol 2004;121:482-488 Abstract quote

Bone marrow aspirates from 306 patients with multiple myeloma were analyzed by flow cytometric immunophenotyping. The plasma cells (PCs) were identified by their characteristic light scatter distribution and reactivity patterns to CD138, CD38, and CD45. Monoclonality was confirmed by immunoglobulin light chain analysis. The immunophenotypic profile of the PCs was determined with a panel of antibodies. Moderate to bright expression of CD56, CD117, CD20, CD45, and CD52 was detected in 71.7%, 17.8%, 9.3%, 8.8%, and 5.2% of cases, respectively. These antigens were expressed by a distinct subpopulation of the PCs in 6.3%, 2.2%, 3.7%, 2.9%, and 2.6% of additional cases. CD19 was negative in more than 99% of cases.

The combination of CD38 and CD138 was superior to CD38 alone for identifying CD45+ myeloma and separating CD20+ myeloma from B-cell lymphoma. PC immunophenotyping might be useful for detecting minimal residual disease in cases with aberrant antigen expression and for selection of therapeutic agents that have specific membrane targets.

A Novel Multiparametric Approach for Analysis of Cytoplasmic Immunoglobulin Light Chains by Flow Cytometry

Chung-Che Chang, M.D., Ph.D., Bernard C. Schur, M.T., Bal. Kampalath, M.D., Paul Lindholm, M.D., Carl G. Becker, M.D. and David H. Vesole, M.D., Ph.D.

Departments of Pathology (CCCBCS, BK, PL, CGB) and Medicine (DHV), Medical College of Wisconsin, Milwaukee, Wisconsin

Mod Pathol 2001;14:1015-1021 Abstract quote

We describe a novel flow cytometric approach using a two-step acquisition technique to determine the cytoplasmic immunoglobulin light chains (LC) expression.

Samples were prepared by a lysed-whole-blood technique and incubated with CD38-PE (phycoerythrin) and CD45-FITC (fluorescein isothiocyanate). The cells were fixed and acquired on an FACSCalibur flow cytometer (first acquisition). The cells were then permeabilized, incubated with either kappa-FITC or lambda-FITC and reacquired (second acquisition). Analysis of the data was performed by gating on the differing intensities of CD38 and evaluating them for the presence of a shifting FITC-positive population from the first acquisition to the second acquisition. The FITC fluorescence intensity of the second acquisition was equal to the sum of surface CD45 expression obtained during the first acquisition and the cytoplasmic LC expression obtained during the second acquisition. Thus, the shifting (increase) of FITC fluorescence intensity during the second acquisition is specifically due to the cytoplasmic expression of either the kappa or lambda LC. We studied 15 multiple myeloma (MM) patients and 10 controls (samples from patients without plasma cell dyscrasias). None of the controls showed evidence of any clonal populations. Thirteen of 15 MM patients exhibited clonal plasma cells (CD38 bright), ranging from 0.01% to 34% of total events collected. In addition, we identified another minute clonal population of lymphocytes (CD38 dim, CD45 bright, low forward and side scatter) in 12 of 13 MM patients with clonal plasma cells. This population, ranging from 0.01% to 0.6% of total events collected, had the same LC restriction as the clonal plasma cells. Patients with a ratio of minor clonal population to clonal plasma cells less than 0.07 tended to remain in partial or complete remission than those with a ratio 0.07 (4/5 versus 1/4, P < .1, 2).

We conclude that this method is highly sensitive and permits us to identify the minute clonal population of lymphocytes in MM patients. Our preliminary observations with a small cohort of patients imply that this minute clonal population may have important prognostic significance. The prognostic significance should be confirmed by further studies.


A new case of IgE myeloma.

Alexander RL Jr, Roodman ST, Petruska PJ, Tsai CC, Janney CG.

Department of Pathology, St. Louis University, MO.

Clin Chem 1992 Nov;38(11):2328-32 Abstract quote

We report a case of IgE myeloma in a 78-year-old woman who presented with bone pain in the shoulder and hip and progressive weakness.

Except for hypercalcemia, routine chemistry values were within normal limits. Hemoglobin was decreased and the leukocyte count slightly increased. Plasma cells were not observed in the peripheral blood. Serum protein electrophoresis showed a monoclonal protein in the beta-globulin fraction. Immunofixation confirmed the presence of an IgE kappa monoclonal protein. A bone marrow biopsy revealed an interstitial and nodular infiltration of abnormal plasma cells comprising 60% of nucleated cells present. Skeletal roentgenograms and bone scans of this patient showed osteolytic lesions and osteopenia of the thoracic and lumbar spine and osteolytic destruction of the right half of the sacrum. Flow-cytometric analysis of mononuclear cells isolated from peripheral blood showed that 15% of the lymphocytes bound IgE. Using cell-surface markers, we identified 45% of the IgE-positive cells as natural killer cells.Similar results have been found in other diseases marked by increased IgE.

The clinical, radiological, and laboratory findings for this patient are compared with previously reported cases of IgE and other types of myeloma.


Light chain disease Only monoclonal light chains are produced
Smoldering myeloma 2% of case
Established diagnosis of myeloma which does not progress for 5 years or more without therapeutic intervention
No evidence of underlying disease with no lytic lesions, anemia, hypercalcemia
Low proliferation rate of plasma cells
Osteosclerotic myeloma Part of the POEMS syndrome
Plasma cell leukemia

Plasma cells in blood >20% of total leukocytes or the absolute plasma cell count >2.0x10*9/L

2% of cases of plasma cell myeloma
May be primary, secondary, or evolve during the course of the disease

Median age younger with lymphadenopathy and organomegaly
Aggressive disease, poor reponse to therapy, poor survival


Plasma cell dyscrasias and the head and neck.

Batsakis JG, Medeiros JL, Luna MA, El-Naggar AK.

Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX.

Ann Diagn Pathol 2002 Apr;6(2):129-40 Abstract quote

Structures in the head and neck (bones, soft tissues, lymph nodes, mucosa) are variably affected by plasma cell dyscrasias. Involvement can be manifested by localized lesions (extramedullary plasmacytoma or solitary plasmacytoma of bone) or by more diffuse disease (multiple myeloma).

We present a contemporary review of these disorders with emphasis on patient outcomes.


Post-transplant plasma cell myeloma and polymorphic lymphoproliferative disorder with monoclonal serum protein occurring in solid organ transplant recipients.

Sun X, Peterson LC, Gong Y, Traynor AE, Nelson BP.

Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Mod Pathol. 2004 Apr;17(4):389-94. Abstract quote

Post-transplant lymphoproliferative disorders are mostly Epstein-Barr virus-related, B-cell tumors that develop as a consequence of immunosuppressive therapy in recipients of solid organ or bone marrow transplants. These disorders range from reactive, polyclonal plasmacytic hyperplasia to those that are morphologically and genotypically indistinguishable from typical non-Hodgkin's lymphomas. Plasma cell myeloma occurring after solid organ transplantation is rare.

We report three plasma cell myeloma post-transplant lymphoproliferative disorder cases and one polymorphic, monoclonal post-transplant lymphoproliferative disorder case associated with a monoclonal serum protein. All three plasma cell myeloma post-transplant lymphoproliferative disorder cases had clinical, radiologic, and pathologic features of conventional plasma cell myeloma. The one polymorphic post-transplant lymphoproliferative disorder case was associated with an IgM monoclonal serum protein and was morphologically indistinguishable from a lymphoplasmacytic lymphoma. Three of the four cases, including the one polymorphic post-transplant lymphoproliferative disorder case, were positive for Epstein-Barr virus encoded small RNA by in situ hybridization. One patient died of plasma cell myeloma post-transplant lymphoproliferative disorder. The remaining three patients are alive: two are completely free of post-transplant lymphoproliferative disorder, and one has shown partial response to therapy.

We compare the clinicopathologic features of these cases with those in the literature.

Cutaneous involvement in multiple myeloma: a clinicopathologic, immunohistochemical, and cytogenetic study of 8 cases.

Requena L, Kutzner H, Palmedo G, Calonje E, Requena C, Perez G, Pastor MA, Sangueza OP.

Department of Dermatology, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain.

Arch Dermatol 2003 Apr;139(4):475-86 Abstract quote

BACKGROUND: Specific cutaneous involvement in patients with multiple myeloma (MM) is very uncommon. It usually occurs in late stages of MM as a reflection of increased tumor cell burden. We studied 8 patients with cutaneous involvement of MM without underlying bony lesions and reviewed the literature on this rare dermatologic manifestation.

DESIGN: We were particularly interested in the clinical course of patients with MM and cutaneous metastases, including survival once metastases were detected and the possible influence of various forms of therapy. Our goal was also to identify the immunoglobulin and the light-chain type in these cases, with emphasis on any possible association between a particular immunoglobulin class and cutaneous involvement, as well as the histopathologic, immunohistochemical, and cytogenetic features of the neoplastic plasma cells involving the skin.

SETTING: University department of dermatology, university hospital, and private practice.Patients Medical records and biopsy specimens from 8 patients with MM and specific cutaneous lesions were reviewed.

RESULTS: Cutaneous lesions consisted of multiple erythematous or violaceous nodules or plaques with a wide anatomical distribution. Histopathologically, 2 different patterns were identified: nodular and diffuse interstitial. Neoplastic plasma cells showed atypical features, and in 1 case they displayed a spindle shape, giving a sarcomatoid appearance to the lesion. Immunohistochemical studies demonstrated that neoplastic plasma cells were strongly positive for CD79a, CD138, and epithelial membrane antigen, and variably positive for VS38c and CD43. In each case the immunoglobulin profile and the light-chain type expression of the neoplastic cells were the same as those identified in the serum of the patients: 5 cases were IgAlambda; 2 cases were IgGkappa; and 1 case was IgAkappa. In cases 2, 3, and 4, polymerase chain reaction investigations revealed monoclonal rearrangement for IgH genes, whereas the investigations for human herpesvirus 8 and Epstein-Barr virus yielded negative results. Fluorescent in situ hybridization investigations in these 3 cases demonstrated that the cutaneous neoplastic plasma cells showed the deletion of the rb-1 (retinoblastoma) gene. Despite aggressive chemotherapy, all 8 patients died a few months after the development of cutaneous involvement.

CONCLUSIONS: In our series, there was a perfect correlation of immunoglobulin and light-chain type between the serum electrophoresis and the cutaneous plasma cells. Patients with MM showed a short survival once cutaneous metastases appeared independently of the therapy. The deletion the rb-1 gene may provide prognostically relevant information to identify a high-risk subset of patients with MM.

The spectrum of cutaneous disease in multiple myeloma.

Bayer-Garner IB, Smoller BR.

Departments of Pathology and Dermatology, University of Arkansas for Medical Sciences.


J Am Acad Dermatol 2003 Apr;48(4):497-507 Abstract quote

BACKGROUND: Multiple myeloma (MM) is a plasma cell dyscrasia characterized by a clonal proliferation of plasma cells that produces a monoclonal protein. There are dermatologic disorders that have been associated with MM, such as amyloidosis, cryoglobulinemia, POEMS syndrome, normolipemic plane xanthoma, and plasmacytoma. The high volume of patients with MM seen at our institution presents an opportunity to define more extensively the spectrum of cutaneous diseases seen in concert with MM.

DESIGN: We reviewed 2357 pathology reports of all patients with a diagnosis of MM to find those who had undergone a skin biopsy. Files were searched for bone-marrow diagnosis, and for type and number of transplants.

RESULTS: In all, 284 patients yielded 472 skin biopsy specimens (average 1.7/patient). Skin biopsy specimen diagnoses included neoplastic lesions, (111; 73 malignant, 38 benign), graft-versus-host disease (120), drug-related lesions (46), cutaneous eruption of lymphocyte recovery (3), thrombocytopenia-related lesions (9), normolipemic plane xanthoma (1), amyloidosis (1), Sweet's syndrome (7), panniculitis (1), papulosquamous lesions (18), bullous diseases (17), vasculitis (11), infectious lesions (41), granulomatous dermatitis (6), alopecia cicatrisata (1), nonspecific lesions (77), and unrelated lesions (2).

CONCLUSIONS: Skin biopsy specimens from patients with MM less than 60 days from transplant most commonly show sequelae of the transplant such as graft-versus-host disease, Grover's disease (as a result of leukocytopenia and fever, waiting for engraftment), drug eruptions, chemotherapy effect, thrombocytopenic effect, cutaneous eruption of lymphocyte recovery, and Sweet's syndrome (possibly as a result of granulocyte-macrophage colony-stimulating factor). Biopsy specimens taken more than 60 days from transplant most commonly show graft-versus-host disease, drug eruptions, and Sweet's syndrome but also show unrelated conditions such as neoplastic lesions, nevi, papulosquamous lesions, vasculitis, infections, and nonspecific changes.

Nazarro's sign
Fine hair-like spikes on the nose, composed of immunoglobulins


Plasma cell morphology and variants Vary from normal in appearance to resembling blasts
Some have divided the cells into mature, immature, and plasmablastic
Flame cells
In cases of IgA myeloma
Red-staining cytoplasmic inclusion material
Fragments of red cytoplasm at the edges of the cell
Dutcher bodies
Intranuclear crystals
Lymphoid appearance
5% of cases
Plasma cells resemble small lymphocytes
Cytoplasmic inclusions
Often in patients with Fanconi syndrome
Other cases may resemble Buhot plasma cells in patients with mucopolysaccharidoses
Phagocytic plasma cells
Erythrophagocytosis rarely
Marked nuclear lobation
2% of myelomas
Blast configuration

Peripheral Smear and Bone Marrow examination

Rouleaux of red blood cells secondary to increase in immunoglobulins
Anemia in 60%

Distribution of plasma cells is:

9% of cases may show reticulin fibrosis

% of marrow replaced by plasma cells

Plasmablastic transformation of multiple myeloma.

Lee CK, Ma ES, Shek TW, Lam CC, Au WY, Wan TS, Chan LC.


Hum Pathol. 2003 Jul;34(7):710-4 Abstract quote

We describe morphological, immunophenotypic, and cytogenetic characterization of a case of multiple myeloma (MM) that showed plasmablastic transformation at the terminal phase with a picture resembling acute leukemia. The plasmablasts expressed monotypic cytoplasmic immunoglobulin together with myeloid and megakaryocytic markers at disease transformation.

Conventional cytogenetic study of bone marrow cells showed coexistence of hypodiploid and hyperdiploid cells, with the former being the predominant clone as evidenced by an interphase fluorescence in situ hybridization study. The clinical course in our case shows that plasmablastic transformation should be considered in the differential diagnoses of disease progression in MM.

Whether de novo plasmablastic myeloma and plasmablastic transformation can be distinguished as a progression from underlying MM merits further investigation, especially in terms of biologic features and relevance to prognosis.


Acid phosphatase Positive
Nonspecific esterase Positive
Methyl green pyronine Positive
PAS Positive for cytoplasmic and intranuclear inclusions
Lambda and kappa light chains Monoclonal light chain restriction with a light chain ratio of at least 16:1
MB2 Positive
Usually negative in MGUS
Negative for most mature B-lymphocytes markers HLA-DR, CD19, CD20, CD22, CD24, CD25

Immunophenotypic aberrations, DNA content, and cell cycle analysis of plasma cells in patients with myeloma and monoclonal gammopathies.

Lima M, Teixeira Mdos A, Fonseca S, Goncalves C, Guerra M, Queiros ML, Santos AH, Coutinho A, Pinho L, Marques L, Cunha M, Ribeiro P, Xavier L, Vieira H, Pinto P, Justica B.

Service of Clinical Hematology, Hospital Geral de Santo Antonio, Rua D Manual II, s/n, 4050 Porto, Portugal.

Blood Cells Mol Dis 2000 Dec;26(6):634-45 Abstract quote

We describe the immunophenotypic and gross DNA defects in 55 patients with myeloma and 50 patients with monoclonal gammopathy and review the literature on this subject (MedLine, 1994-2000).

Our data confirmed previous reports indicating that in myeloma nearly all marrow plasma cells are abnormal (98.7 +/- 8.1%). In monoclonal gammopathy the fraction of abnormal plasma cells was 35.0 +/- 32.8%. In both myeloma and monoclonal gammopathy, the most frequent aberrant phenotypic features consisted of absence of expression of CD19, strong expression of CD56, and decreased intensity of expression of CD38; aberrant expression of CD10, CD20, CD22, or CD28 was observed in less than one-third of myeloma cases. The vast majority of cases had two or more phenotypic aberrations.

In the DNA studies, 7% of myeloma cases were biclonal and 93% of cases were monoclonal. In those studies with only one plasma cell mitotic cycle, 37% had normal DNA content and 63% were aneuploid (hyperploid, 61%; hypoploid, 2%). The mean percentages of plasma cells in S- and G2M phases were 4.9 +/- 8.5 and 4.4 +/- 6.9%, respectively. Thirty-eight percent of cases had more than 3% of plasma cells in S phase. In monoclonal gammopathy, the DNA index of abnormal plasma cells ranged from 0.89 to 1.30 and the percentage of diploid (31%) and aneuploid (69%) cases was not different from the results found in myeloma. The differences in percentage of abnormal plasma cells in S- (7.4 +/- 8.6%) and G2M-phases (2.4 +/- 1.7%) in patients with monoclonal gammopathy were not statistically significant.

Human myeloma cells express the CD38 ligand CD31.

Vallario A, Chilosi M, Adami F, Montagna L, Deaglio S, Malavasi F, Caligaris-Cappio F.

Dipartimento di Scienze Biomediche e Oncologia Umana, Universita di Torino, Italy.

Br J Haematol. 1999 May;105(2):441-4. Abstract quote  

Multiple myeloma (MM) plasma cells (PC) are CD38+. A ligand for CD38 is the adhesion molecule CD31. By flow cytometry and immunocytochemistry we have investigated whether malignant PC co-express CD38 and CD31.

All 68 patients studied were CD38+. 14/14 monoclonal gammopathies of undetermined significance (MGUS) and 39/39 plasmacytic MM patients co-expressed CD38 and CD31 at high density. Only 1/11 plasmablastic MM and 1/4 plasma cell leukaemias (PCL) expressed CD31.

These data indicated that PC malignancies co-expressed high levels of both CD38 and its ligand CD31, with the exception of plasmablastic MM and PCL.
CD 138 (SYNDECAN-1)  
CD138 (Syndecan-1), a Plasma Cell Marker Immunohistochemical Profile in Hematopoietic and Nonhematopoietic Neoplasms

Fionnuala P. O'Connell, MD, Jack L. Pinkus, PhD, and Geraldine S. Pinkus, MD
Am J Clin Pathol 2004;121:254-263 Abstract quote

We evaluated the immunohistochemical profile and specificity of CD138 reactivity in 238 specimens from hematopoietic and nonhematopoietic neoplasms. In 91 bone marrow biopsies, CD138 reactivity was observed for nonneoplastic plasma cells, neoplastic plasma cells in multiple myeloma cases (43/43), and the plasmacytic component in lymphoplasmacytic lymphoma cases (4/4).

Stromal reactivity was noted in 7 multiple myeloma cases. Of 9 bone marrow specimens involved by metastatic carcinoma, tumor cells were CD138+ in 5 cases; stromal reactivity was noted in 7 cases.

Studies of 76 nodal and extranodal lymphomas (B-cell, 49; T-cell, 8; Hodgkin lymphoma, 19), 1 Langerhans cell histiocytosis, and 14 nonneoplastic lymph nodes revealed CD138 reactivity only for nonneoplastic plasma cells, the neoplastic cells of 2 large B-cell lymphomas (immunoblastic type, plasmacytoid features), and the clonal plasmacytic component of 3 of 3 extranodal and 1 nodal marginal zone lymphoma.

Evaluation of 56 epithelial and nonepithelial tumors revealed CD138 positivity for neoplastic cells of carcinomas of various types (30/33), frequently with associated stromal reactivity, and for neoplasms of mesenchymal, melanocytic, and other tumor types (12/23).

Within the hematopoietic system, CD138 is an excellent marker of plasmacytic differentiation. Based on its broad staining profile, CD138 reactivity for neoplastic cells is not a definitive marker for plasmacytic derivation, unless a hematolymphoid origin has been established.

Syndecan-1 (CD138) Immunoreactivity in Bone Marrow Biopsies of Multiple Myeloma: Shed Syndecan-1 Accumulates in Fibrotic Regions

Ilene B. Bayer-Garner, M.D., Ralph D. Sanderson, Ph.D., Madhav V. Dhodapkar, M.D., Rebecca B. Owens, M.T. and Carla S. Wilson, M.D., Ph.D.

Department of Pathology (IBB-GRDS, RBO, CSW) and Department of Anatomy and the Arkansas Cancer Research Center (RDS), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Laboratory of Cellular Physiology and Immunology (MVD), Rockefeller University, New York, New York

Mod Pathol 2001;14:1052-1058 Abstract quote

Syndecan-1 (CD138) mediates myeloma cell adhesion, and loss of syndecan-1 from the cell surface may contribute to myeloma proliferation and dissemination. Flow cytometry analysis of myeloma cells in bone marrow specimens shows heterogeneity in cell surface syndecan-1 expression. It is not known whether weaker expression correlates with more aggressive disease. However, recent reports suggest that variations in syndecan-1 staining intensity on myeloma cells may be an artifact of specimen handling.

In this study, we evaluate syndecan-1 expression in bone marrow biopsy sections from 28 multiple myeloma patients, to elucidate the heterogeneity of syndecan-1 expression in situ. Immunoreactivity for syndecan-1, using the antibody B-B4 (CD138), was found in more than 95% of multiple myeloma cells in 27 of 28 biopsies. However, one biopsy had more than 50% CD138-negative cells and cells with weak CD138 expression were identified in the majority of cases. Loss of syndecan-1 did not appear to relate to myeloma cell differentiation. In addition, syndecan-1 was detected on intravascular and intrasinusoidal myeloma cells suggesting that loss of syndecan-1 may not be required for extramedullary dissemination. Bone marrow biopsies from nine additional patients, with variable CD138 staining intensity on myeloma cells as determined by flow cytometry, were studied by immunohistochemistry. The heterogenous CD138 expression was confirmed in situ, with weakly positive cells concentrated in areas of reticulin fibrosis. These cells had a disrupted pattern of membrane staining in contrast to the strong linear membrane staining seen in the other multiple myeloma cells. In addition, the fibrotic stroma stained intensely for syndecan-1. Accumulation of syndecan-1 within the extracellular matrix of the marrow likely is derived by shedding of the molecule from the surface of myeloma cells.

Because syndecan-1 can act to regulate the activity of heparan-binding growth factors, these reservoirs of syndecan-1 may play a critical role in promoting myeloma pathogenesis, or in regeneration of the tumor after chemotherapy.

Expression of PAX5 in CD20-positive multiple myeloma assessed by immunohistochemistry and oligonucleotide microarray.

Lin P, Mahdavy M, Zhan F, Zhang HZ, Katz RL, Shaughnessy JD.

1Department of Pathology, University of Arkansas for Medical Science, AR, USA.

Mod Pathol. 2004 Oct;17(10):1217-22. Abstract quote  

Silencing of PAX5 gene by upregulation of B-lymphocyte-induced maturation protein-1 (PRDM1) is essential for terminal differentiation of B cells to plasma cells.

To investigate PAX5 gene expression and its protein product, B-cell-specific activator protein (BSAP), in a subgroup of multiple myeloma characterized by CD20 expression, we studied PAX5/BSAP by immunohistochemistry in 25 cases of myeloma, all expressing moderate to strong CD20 by flow cytometric analysis, and correlated the results with PAX5 and PRDM1 mRNA levels analyzed by the Affymetrix HuGeneFL GeneChip microarray in 17 cases. Using paraffin-embedded bone marrow biopsy sections, we found PAX5/BSAP was expressed in 72% (18/25) of cases overall with an intensity ranging from weak (10, 56%) to strong (8, 44%). PAX5/BSAP was negative in 10 randomly selected CD20-negative myelomas included as negative controls. PAX5 mRNA levels correlated inversely with that of PRDM1 in both CD20-positive and CD20-negative myelomas and failed to predict the expression levels of PAX5/BSAP, suggesting that detected PAX5/BSAP likely represents remnant of earlier stage of development.

We conclude that CD20-positive myelomas expressing PAX5/BSAP can present as a diagnostic pitfall mimicking B-cell neoplasms with plasmacytoid differentiation.


Immunophenotypic differentiation between neoplastic plasma cells in mature B-cell lymphoma vs plasma cell myeloma.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9072, USA.


Am J Clin Pathol. 2007 Feb;127(2):176-81. Abstract quote

Some non-Hodgkin lymphomas show marked plasmacytic differentiation. In such cases, it may be difficult to differentiate these lymphoma from plasmacytoma or myeloma, especially with limited diagnostic material. However, there may be immunophenotypic differences in the plasma cells in these disorders that distinguish them.

This study characterizes the immunophenotypes of neoplastic plasma cells in 41 cases of B-lineage non-Hodgkin lymphoma and compares them with those in plasma cell myeloma.

We found that plasma cells in lymphoma were significantly more likely to express CD19, CD45, and surface immunoglobulin and less likely to express CD56 than those in myeloma. We further show that CD 19 and CD56 expression can be used reliably to distinguish these entities. Myeloma-associated osseous lesions and solitary plasmacytoma of bone showed myeloma-like immunophenotypes. However, some extramedullary plasmacytomas showed lymphoma-like phenotypes, suggesting that, in reality, they may represent non-Hodgkin lymphomas with extensive plasmacytic differentiation.
MGUS Serum monoclonal protein IgG </=3.5 g/dL, IgA </=2 g/dL, Bence Jones Protein </= 1g/24 hours
<10% plasma cells in bone marrow
No anemia, hypercalcemia, renal failure, or osteolytic lesions
Plasmablastic Lymphoma in HIV-Positive Patients: An Aggressive Epstein-Barr Virus-Associated Extramedullary Plasmacytic Neoplasm.

Dong HY, Scadden DT, de Leval L, Tang Z, Isaacson PG, Harris NL.

From the *Department of Pathology and daggerAIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA; and double daggerDepartment of Pathology, University College of London, London, UK.

Am J Surg Pathol. 2005 Dec;29(12):1633-1641. Abstract quote  

AIDS-associated aggressive B-cell lymphomas often have plasmacytoid features. Plasma cell neoplasms in HIV patients were commonly described to have atypical morphology and an aggressive clinical course in the literature.

We reviewed 14 cases of neoplasms with marked plasmacytic differentiation in HIV-positive patients to determine their clinicopathologic features. Of these, 13 of 14 had homogeneous morphology and were generally CD45+, CD20-, PAX-5-, and CD138+. All were positive for Epstein-Barr virus-encoded RNA (EBER) but lacked EBV late membrane proteins (LMP). Human herpes virus 8 (HHV8) DNA was detected in 6 of 10 cases by nested PCR, but HHV8 latent nuclear antigen (LNA) was absent. The 13 patients ranged in age from 28 to 44 years (median, 41 years) (11 male patients; 2 female patients). All patients had extramedullary and 11 of 13 had extranodal tumor at the initial presentation; 2 had distant marrow involvement. The most commonly involved location was the oral cavity (6 of 13 cases), followed by bone and soft tissue (4 of 13), and the gastrointestinal tract (3 of 13). All 11 patients with follow-up died within 34 months (median, 7 months). The 14th patient who had a nodal disease with more undifferentiated morphology and expression of the HHV8 LNA protein was alive without disease at last follow-up (>72 months), probably representing a novel HHV8+ lymphoma.

We conclude that most plasmacytic tumors in HIV-positive individuals are extramedullary, clinically aggressive EBV+ tumors identical to plasmablastic lymphoma that does not have the clinical features of plasma cell myeloma.
Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles.

Vega F, Chang CC, Medeiros LJ, Udden MM, Cho-Vega JH, Lau CC, Finch CJ, Vilchez RA, McGregor D, Jorgensen JL.

1Department of Pathology, Baylor College of Medicine, Houston, TX, USA.
Mod Pathol. 2005 Jun;18(6):873. Abstract quote



Clinical stage is most important factor

Staging involves measurement of:
Hemoglobin level
Serum calcium
Size of monoclonal immunoglobulin spike
Bone radiographic findings
Serum creatinine levels

Poor Prognostic Factors
Plasmablastic morphology
Extensive bone marrow involvement
High plasma cell labeling proliferation index
High serum beta-2 microglobulin
Low serum albumin
Hypodiploidy and aneuploid by flow cytometry
Very low normal serum immunoglobulins

DNA Topoisomerase II in Multiple Myeloma: A Marker of Cell Proliferation and Not Drug Resistance

Carla S. Wilson, M.D., Ph.D., L. Jeffrey Medeiros, M.D., Raymond Lai, M.D., Ph.D., Anthony W. Butch, Ph.D., Althea McCourty, B.S., Kathy Kelly, Ph.D. and Russell K. Brynes, M.D.

Department of PathologyUniversity of Arkansas for Medical Sciences (CSW), Little Rock, Arkansas; Division of Pathology, The University of Texas M.D. Anderson Cancer Center (LJM, RL), Houston, Texas; Department of Pathology, UCLA Medical Center (AWB, KK), Los Angeles, California; Department of Pathology and Laboratory Medicine, University of Southern California (AM, RKB), Los Angeles, California

Mod Pathol 2001;14:886-891 Abstract quote

DNA topoisomerase II (topo II) is the target for a number of antineoplastic agents. Down-regulation of this enzyme is one form of drug resistance. Topo II is also involved in DNA replication and transcription and serves as an indicator of proliferation rate in many human malignancies.

This study examines whether topo II is one of the mechanisms of chemoresistance commonly observed in multiple myeloma (MM) or alternatively, whether topo II is associated with tumor cell proliferation.

Bone marrow (BM) biopsy sections from 72 cases of MM, stratified according to proliferative activity (bromodeoxyuridine uptake), were immunostained for topo II. Immunoreactivity with an addi- tional marker of drug resistance, glutathione-S-transferase , and the proliferation marker Ki-67 were also examined.

Topo II was expressed in 26 (36%) cases and correlated strongly with proliferative activity (P < .001). A role for drug resistance could not be supported, given this strong relationship with proliferation and the finding that glutathione-S-transferase expression in 57 (78%) cases was independent of topo II immunoreactivity. Topo II was identified in 91 to 100% of highly proliferative tumors, as evaluated by bromodeoxyuridine uptake or Ki-67 reactivity, respectively. Proliferation also correlated with the histologic grade of the MM.

Therefore, topo II immunoreactivity is primarily a marker of cell proliferation in MM and as such is likely to have prognostic significance. Highly proliferative tumors are most likely to be sensitive to chemotherapeutic protocols using anti–topo II agents.

Cyclin D1 Overexpression in Multiple Myeloma A Morphologic, Immunohistochemical, and In Situ Hybridization Study of 71 Paraffin-Embedded Bone Marrow Biopsy Specimens

Evangelia Athanasiou, MD
Vassiliki Kaloutsi, MD
Vassiliki Kotoula, MD
Prodromos Hytiroglou, MD
Ioannis Kostopoulos, MD
Costas Zervas, MD
Panagiotis Kalogiannidis, MD
Athanasios Fassas, MD
John I. Christakis, MD
Constantine S. Papadimitriou, MD

Am J Clin Pathol 2001;116:535-542 Abstract quote

Cyclin D1 expression was evaluated by immunohistochemical analysis and biotin-labeled in situ hybridization (ISH) in a series of 71 decalcified, paraffin-embedded bone marrow biopsy specimens from patients with multiple myeloma (MM).

Cyclin D1 messenger RNA (mRNA) overexpression was detected by ISH in 23 (32%) of 71 cases, whereas cyclin D1 protein was identified by immunohistochemical analysis in 17 (24%) of 71 specimens. All cases that were positive by immunohistochemical analysis also were positive by ISH. Statistically significant associations were found between cyclin D1 overexpression and grade of plasma cell differentiation and between cyclin D1 overexpression and extent of bone marrow infiltration.

Our findings demonstrate the following: (1) ISH for cyclin D1 mRNA is a sensitive method for the evaluation of cyclin D1 overexpression in paraffin-embedded bone marrow biopsy specimens with MM. (2) ISH is more sensitive than immunohistochemical analysis in the assessment of cyclin D1 expression. (3) Cyclin D1 overexpression in MM is correlated positively with higher histologic grade and stage.



International staging system for multiple myeloma.

Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, Boccadoro M, Child JA, Harousseau JL, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J.

Mayo Clinic College of Medicine and Eastern Cooperative Oncology Group, Rochester, MN, USA.

J Clin Oncol. 2005 May 20;23(15):3412-20. Epub 2005 Apr 4. Abstract quote  

PURPOSE: There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification.

PATIENTS AND METHODS: Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies.

RESULTS: Serum beta2-microglobulin (Sbeta2M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sbeta2M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sbeta2M less than 3.5 mg/L plus serum albumin > or = 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sbeta2M > or = 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and > or = 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system.

CONCLUSION) The new ISS is simple, based on easy to use variables (Sbeta2M and serum albumin), and recommended for early adoption and widespread use.
Low Tumor Mass (Stage I)

Cancer 1975;36:842-854

Volumes of tumor mass before treatment

<0.6 x 10*12 tumor cells/m2
All of the following must be present:

Hemoglobin >10.5 g/dL or hematocrit >32 volume %
Serum calcium normal
Low myeloma protein production:
IgG peak <5 g/dl
IgA peak <3 g/dl
Bence Jones protein <4 g/24 hrs

No bone lesions

Intermediate Tumor Mass
(Stage II)
0.6-1.2 x 10*12 malignant cells/m2
All patients who do not qualify for high or low tumor mass are considered to be intermediate
High Tumor Mass (Stage III)

>1.2 x 10*12 tumor cells/m2
One of the following must be present:

Hemoglobin <8.5 g/dl
Serum calcium >12 mg/dl
Very high myeloma protein production:
IgG peak >7 g/dl
IgA peak >5 g/dl
Bence Jones protein >12 g/24 hrs

>3 lytic lesions on bone survey (bone scan not acceptable)


Median survival is 3 years
10% of patients have a chronic course and survive 10 years or more, usually patients with smoldering myeloma

Death most commonly from infection and renal failure


Cell cycle regulators in multiple myeloma: prognostic implications of p53 nuclear accumulation.

Pruneri G, Carboni N, Baldini L, Intini D, Colombi M, Bertolini F, Valentini S, Maisonneuve P, Viale G, Neri A.

Division of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan, School of Medicine, Italy.


Hum Pathol 2003 Jan;34(1):41-7 Abstract quote

Multiple myeloma (MM) is characterized by a multistep process of tumorigenesis involving genes that control cell cycle progression. The prevalence and clinical implications of p53, p21, HDM-2, p27, and cyclin E immunoreactivity in MM patients, however, have not been fully elucidated.

We evaluated the immunoreactivity (IR) for p53, p21, HDM-2, p27, cyclin E, and Ki-67 in bone marrow biopsies from 48 patients. In 34 (70.8%) cases, TP53 gene mutations and HDM-2 gene amplification were analyzed by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and Southern blot densitometric analyses in the corresponding bone marrow aspirates.

Nineteen (39.6%) biopsy specimens exhibited > or =10% neoplastic cells immunoreactive for p53, 23 (47.9%) for p21, 28 (58.3%) for HDM-2, 29 (60.4%) for cyclin E, and 16 (33.3%) for Ki-67; 23 (47.9%) tumors had > or =50% neoplastic cells immunoreactive for p27. TP53 gene mutations in exons 5 through 8 were detected in 3 (8.8%) cases, whereas none exhibited HDM-2 gene amplification. In the cases bearing a wild-type TP53 gene, no association was found between p53 accumulation and HDM-2 or p21 IR.

The same cases had been previously investigated for the presence of the t(11;14) translocation and cyclin D1 IR; interestingly, a significant inverse correlation between cyclin D1 and p27 or cyclin E IR was noted. In addition to clinical stage and Bartl's histologic stage and grade, p53 accumulation was significantly associated with survival, and it maintained its prognostic significance in a multivariate analysis adjusted for age, clinical stage, and relapse.

Our data suggest that the immunohistochemical evaluation of p53 IR in bone marrow biopsies may represent an adjunct in MM patient prognostication.


CA-Journal 2001;51:273-285

Chemotherapy with alkylating agents
Possible addition of alpha-interferon

Autologous and allogeneic bone marrow transplants

Prophylactic antibiotics especially TMP-SMX

Long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma.

McCloskey EV, Dunn JA, Kanis JA, MacLennan IC, Drayson MT.

WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, Medical School, Sheffield, UK.

Br J Haematol 2001 Jun;113(4):1035-43 Abstract quote

Oral clodronate (1600 mg/d) has been shown to significantly reduce the incidence of skeletal complications in multiple myeloma. Preliminary analysis of a double-blind placebo-controlled trial of this treatment indicated that clodronate might prolong survival in patients without vertebral fractures at presentation. This issue was re-examined after further follow-up of the patients recruited into the Medical Research Council (MRC) VIth Myeloma Study.

The trial examined the effects of clodronate on the natural history of skeletal disease in multiple myeloma; 619 patients were randomized between June 1986 and May 1992 commencing 15 d after the start of ABCM [adriamycin, BCNU (carmustine), cyclophosphamide, melphalan] chemotherapy or 43 d after ABCMP (ABCM + prenisolone); 535 patients who received clodronate or placebo were included in the analysis. The presence or absence of spinal fractures was assessed centrally from spinal X-rays; long-bone fractures were assessed locally.

With a median follow-up of 8.6 years, there was no overall significant difference in survival between the two treatment groups (O/E, chi2 = 0.78, P = 0.38). Among the subgroup of 153 patients with no skeletal fractures at presentation there was a significant survival advantage (O/E, chi2 = 7.52, P = 0.006) in favour of the 73 patients receiving clodronate, with median survivals being, respectively, 59 months (95% CI 43-71 months) and 37 months (95% CI 31-52 months), and 5-year survivals being 46% and 35%.

The original analysis of this study shows that there is a benefit in taking 1600 mg clodronate daily for patients with myelomatosis to prevent the development of new skeletal disease. Bearing in mind the limitations of subgroup analysis, the present study indicates that treatment may prolong survival in patients without overt skeletal disease at diagnosis. These observations, however, require confirmation in prospective clinical trials.

Induction chemotherapy

Melphalan and prednisone

Salvage therapy with VAD (Vincristine, adriamycin, dexamethasone)

Autologous transplants
High dose therapy with autologous stem cell transplants has doubled the median survival for newly diagnosed patients
Allogeneic bone marrow transplant

<10% are candidates
High mortality 20-50% during first 100 days

Theoretical advantage that transplants do not have any contaminated myeloma cells
Median survival at 43 months collected from patients treated from 1994-1999

Maintenance therapy
Induction therapy
Thalidomide with high-dose dexamethasone pulsing may result in response rates as highas 75%
Holmium-DOTMP is a skeletal targeted radiotherapy which has been used with high-dose chemotherapy
Maintenence therapy
Myeloma vaccines
Salvage therapy
DT-PACE (dexamethasone, thalidomide-cisplatin, adriamycin, cyclophosphamide, and etoposide)
DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin)
Arsenic trioxide
Farnesyl transferase inhibitors

Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years.

Badros A, Barlogie B, Siegel E, Morris C, Desikan R, Zangari M, Fassas A, Anaissie E, Munshi N, Tricot G.

Myeloma and Transplantation Research Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Br J Haematol 2001 Sep;114(3):600-7 Abstract quote

The feasibility and efficacy of autologous stem cell transplantation (auto-SCT) in patients aged > or = 70 years was analysed.

Newly diagnosed (n = 34) and refractory multiple myeloma (n = 36) patients were studied. The median age was 72 years (range: 70-82.6). CD34+ cells were mobilized with chemotherapy and granulocyte colony-stimulating factor (G-CSF) (n = 35) or G-CSF alone (n = 35), yielding medians of 11.8 x 10(6) versus 8 x 10(6) cells/kg respectively (P = 0.007). Because of excessive mortality (16%) in the first 25 patients who received melphalan 200 mg/m2 (MEL-200), the dose was subsequently decreased to 140 mg/m2 (MEL-140). Median times to absolute neutrophil count (ANC) > 0.5 x 10(9)/l and to platelets > 20 x 10(9)/l were 11 and 13 d respectively. Thirty-one patients (44%) received tandem auto-SCT. Complete remission (CR) was 20% after the first SCT and 27% after tandem SCT. Median CR duration was 1.5 years and was significantly longer for patients with < or = 12 months of prior chemotherapy (2.6 versus 1.0 years, P = 0.0008). The 3-year event-free survival (EFS) and overall survival (OS) (+ standard error, SE) were projected at 20% + 9% and 31% + 10% respectively. Tandem SCTs positively affected EFS (4.0 versus 0.7 years; P = 0.003) and OS (4.0 versus 1.4 years; P = 0.02) compared with single auto-SCT.

In conclusion, MEL-140 is less toxic and appears equally as efficacious as MEL-200 in elderly patients. The benefits of tandem SCT in this patient population need further evaluation in a randomized trial.

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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Bence Jones Protein-Monoclonal light chains found in the urine of some patients without a detectable monoclonal protein in the serum.

Clockwork Chromatin-Distinct pattern of chromatin or nuclear DNA clumping within the nucleus, found in plasma cells.

Heavy Chain Disease

Light Chain Restriction-Hallmark of a neoplastic clonal proliferation of plasma cells.  Immunoglobulins are composed of a heavy chain and two light chains.  The light chains can be kappa or lambda but usually never both.  The normal individual has a mixture of plasma cells with either kappa or lambda light chains.  A clonal proliferation will have plasma cells overwhelmingly composed of one light chain type and one heavy chain type. Most cases are kappa light chain.

Monoclonal Gammopathy of Undetermined Significance (MGUS)


POEMS Syndrome


Waldenstrom Macroglobulinemia (Lymphoplasmacytoid Lymphoma)

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