Case 6 -
Plasmacytoma of Liver
Charles D. Sturgis
Evanston Northwestern Healthcare
Northwestern University Feinberg School of Medicine
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The patient was a 56 year-old male with a history of
acute myelogenous leukemia (M0) diagnosed at an outside institution. He was status post autologous stem
cell transplant (8 months remote). He presented with abdominal pain and was diagnosed with a liver mass
by CT. Digital photomicrographs were taken from microscopic slides prepared following image-guided
biopsy of the liver mass.
Plasmacytoma of Liver
Four digital images were provided for review. Image
one (20X Diff Quik) demonstrates a cohesive and crowded group of high nuclear/cytoplasmic ratio cells
with erythrocytes in the background. Nucleoli are discernible within some cells even at this
intermediate power. No admixed liver cells are seen. The cells are small in size with most nuclei being
no larger than 1.5X the size of the red blood cells; however, a few cells with nuclei more than 3X the
size of erythrocytes are noted. In image two (40X Papanicolaou) another three dimensional aggregate of
haphazardly arranged cells is seen. In this group the nuclei are hyperchromatic, and nuclear smearing
artifact is present. Variability in nuclear size is again noted. The vast majority of the cellular
elements present in the slides from this case had the appearance of crowded groups such as those depicted
in the first two images. The digital image numbered as three (60X Diff Quik) was taken from a feathered
edge of one of the direct smears. This region of this slide showed intact individual lesional cells
rather than cohesive groups. Some of the cells were devoid of cytoplasm while others showed moderately
abundant basophilic cytoplasm with eccentric round nuclei containing large single nucleoli. Erythrocytes
and segmented neutrophils noted among the lesional cells provide an internal control for size
comparison. In the high power oil immersion image number four (100X Diff Quik) a single intact lesional
cell is noted. This cell contains an eccentrically located nucleus that is slightly larger than two red
cells. (The red cells in the background are seen in rouleaux formation as a "stack of coins"). The
lesional cell cytoplasm is deeply basophilic with a suggestion of perinuclear clearing / halo. An
indistinct but large nucleolus is noted. Based on the cytologic impression at the bedside an additional
needle pass was requested for immunophenotypic analysis by flow cytometry.
Flow Cytometric and Electrophoresis Follow-up:
Approximately 30% of the
nucleated cells in the cell suspension utilized for immunophenotypic analysis by flow cytometry were
noted to be positive for the plasma cell antigens CD38 and CD138, helping to confirm the morphologic
impression of a plasmacytoma. In addition, a monoclonal serum IgG paraprotein was documented by
The clinical setting and disease presentation in this case of
hepatic plasmacytoma are unique. Although hepatic involvement by neoplastic plasma cells in cases of
advanced systemic plasma cell dyscrasia is not altogether uncommon, primary hepatic forms of
extramedullary plasmacytoma are reportable as individual cases. Publications addressing the incidence
and pattern of liver involvement in hematologic malignancies have shown that between 30 and 50% of
patients with multiple myeloma develop diffuse liver infiltration by clonal plasma cells.
This infiltration is typically seen in a sinusoidal distribution.  The diagnosis of plasma
cell myeloma is based on combined pathologic, radiologic, and clinical features and is characterized by
elevated serum monoclonal protein, bone marrow plasmacytosis exceeding 30% of cells, skeletal destruction
with lytic lesions, hypercalcemia, and anemia.  In the United States, myeloma is the most
common lymphoid malignancy in blacks and the second most common lymphoid malignancy in whites,
representing 15% of all lymphomas and leukemias combined.  Plasma cell myeloma is a disease
of older adults, typically presenting in the decade spanning 65 to 75 years of age and occurring equally
in women and men. By contrast, extraosseous (extramedullary) plasmacytomas are rare lesions,
constituting only 5% of plasma cell neoplasms and having a slight male predominance. By definition,
pathologic and radiographic examinations of the bones and bone marrow should show no evidence of plasma
cell disease in patients diagnosed with localized extramedullary plasmacytoma. If plasma cell
infiltrates are found outside of a solitary plasmacytoma in patients thought originally to have only
localized disease, then the diagnosis of a myeloma precursor or evolving/smoldering myeloma should be
considered. A minority of patients (20%) with solitary plasmacytoma may demonstrate a monoclonal
gammopathy.  The majority of solitary extramedullary plasmacytomas (approximately 80%) occur
in the upper respiratory tract including the larynx, pharynx, and sinuses; however, primary plasmacytomas
have been reported in many other body sites including but not necessarily limited to lung, pleura,
thyroid, lymph node, breast, skin, soft tissue, and orbit.
Cases of primary hepatic
plasmacytoma and of plasma cell myeloma presenting as liver masses have been reported in the medical
literature from North America, Japan, Italy, India, France, and Turkey.
presentations such as Pancoast's syndrome and non-obstructive jaundice have been attributed to plasma
Of relevance to cytopathologists is the fact that rare cases of plasma cell
neoplasms have also been reported presenting in the form of malignant effusions from the abdomen and
pproximately 15% of patients with solitary extraosseous plasmacytomas progress
on to develop myeloma. 
Let us turn to the classical cytomorphology of extramedullary plasmacytoma. Smears made
from needle aspiration biopsies of these lesions are reported to be of variable but usually high overall
cellularity. Possible explanations for lesser overall cellularity include sampling technique and tumor
associated amyloid protein deposition entrapping the lesional cells within the tumor. Hepatic amyloid
deposition itself can be mass forming and associated with subacute or fulminant hepatic failure in
patients with systemic plasma cell dyscrasias.
In aspiration slides, amyloid protein
appears as a waxy amorphous extracellular material with a cyanophilic to eosinophilic appearance on
Papanicolaou stains. It can be confirmed by demonstrating apple-green birefringence with polarized light
on Congo Red staining. Lesional plasma cells can display varying degrees of differentiation both between
cases and within a single case. Mature-appearing neoplastic plasma cells can be so bland as to not be
separable from benign/reactive cells by morphologic studies, showing an eccentric nucleus, abundant
deeply basophilic cytoplasm on Diff Quik, Giemsa, and Wright stains, and prominent paranuclear halos.
These better differentiated lesional cells typically display a "clock face" chromatin without nucleoli.
Plasmablasts (immature cell forms) are more difficult to categorize. These cells have higher
nuclear/cytoplasmic ratios, more finely dispersed chromatin, and nucleoli. Pleomorphic/anaplastic cell
forms may be monstrous with segmented nuclei, macronucleoli, and far less obvious to absent
Morphologists should note that in rare reported instances, "Auer rod-like"
cytoplasmic structures have been noted in myeloma cells.  These structures could be cause
for confusion in a patient with prior / concomitant history of acute myelogenous leukemia, as in the case
presented above. More typical cytoplasmic inclusions are intracytoplasmic immunoglobulin aggregates
(Russell bodies) and intranuclear inclusions (Dutcher bodies). The intranuclear bodies are classically
reported only in malignant plasma cells, while cytoplasmic bodies are described in both benign and
malignant plasma cell proliferations. Plasmacytoma/myeloma cells with multiple, pale blue, grape-like,
cytoplasmic inclusions are known as Mott or Morula cells.
Immunophenotypic studies performed by immunocytochemistry, immunohistochemistry and/or
flow cytometry may be necessary to demonstrate clonality in a plasma cell proliferation and/or to prove
that cells are of a plasma cell lineage. Malignant plasma cells typically express monotypic cytoplasmic
immunoglobulin and lack surface immunoglobulin. The cytoplasmic immunoglobulin is usually IgG,
occasionally IgA, and rarely other types. Most plasmacytoma cells lack the pan-B antigens
CD19 and CD20, and most express the plasma cell antigens CD38 and CD138 as well as the Ig-associated
antigen CD79a. Monotypic immunoglobulin light chain expression by immunochemistry can be useful in
confirming clonality when the differential diagnosis includes mass forming chronic inflammatory processes
containing plasma cells. Complex karyotypes characterized by multiple chromosomal gains and losses are
the most frequently demonstrated cytogenetic findings in plasma cell tumors. 
The patient presented in the history above had been previously diagnosed with acute
myelogenous leukemia. Plasmacytoma/myeloma has been reported to arise in association with other
hematologic malignancies including but not necessarily limited to refractory anemia with excess blasts in
transformation, acute undifferentiated myelogenous leukemia, acute myelomonocytic leukemia, acute
promyelocytic leukemia, chronic myelomonocytic leukemia, and Hodgkin's disease.
non-neoplastic plasmacytosis has been reported in association with AML FAB M4 and M4eo and is seen in
association with increase IL-6 production by the AML blasts.  In addition, plasmacytoma has
been reported in association with hepatitis C infection and HIV infection.
Plasmacellular lymphoproliferative disorders are known to arise following both solid organ and bone
marrow transplantation. The classical setting for these diseases is one in which a solid organ is
received and is then followed by immunosuppressive therapy to prevent graft rejection.  In
both autologous and allogeneic bone marrow transplantation, ablative chemotherapy is received prior to
infusion of the recuperative stem cells or donor marrow cells. Lymphoproliferative disorders arising
after marrow ablative therapies and the immunosuppression associated with solid organ transplantation are
most often B-cell neoplasms associated with Epstein-Barr virus. Patients with hematologic and solid
tumors that are treated with autologous stem cell transplantation are treated with hopes of long
survivorship; however, secondary hematologic malignancies are known to occur, and hepatic extramedullary
plasmacytomas have been diagnosed in posttransplantation settings.
It should also be
pointed out that invasive fungal infections can arise in these immunocompromised
individuals.  Fungal infections can in certain cases cause mass effect and mimic neoplasms.
In this final paragraph, we will turn to the "plasmacytoid" tumor cell differential
diagnosis. In case #2, an occult hepatic malignancy with metastatic disease to bone was presented. In
the current case (#6), a hematologic malignancy that is most often primary to bone is discussed as a
primary neoplasm in the liver (hepatic extramedullary plasmacytoma). As seen in the lower power images
that started this unknown presentation, cohesive, three dimensional aggregates of crowded lesional cells
represented the majority of the cellularity in this case. The individual cells were plasmacytoid.
Plasmacytoid cells have been described in myriad solid tumors, and some hematolymphoid cells other than
true plasma cells are often described as plasmacytoid. A non-exhaustive but appropriately lengthy list
of neoplasms that are reported to be comprised in part or in total of plasmacytoid cells includes
neuroendocrine carcinomas such as islet cell tumors and carcinoids, medullary and insular types of
thyroid carcinomas, plasmacytoid urothelial carcinomas, pheochromocytomas and paragangliomas, some
rhabdomyosarcomas, epithelioid hemangioendotheliomas, melanomas, epithelioid gastrointestinal stromal
tumors, myoepitheliomas, osteoblastomas, and plasmacytoid dendritic cell leukemias and
In addition, some mass forming reactive mesenchymal proliferations such as
nodular fasciitis have been reported to display plasmacytoid cells in needle aspiration
cytology.  It must also be remembered that patients with plasmacytoma and plasma cell
myeloma may present with mass lesions in locations where other plasmacytoid neoplasms can
This is exemplified by a reported case of synchronous plasmacytoid breast
carcinoma and plasmacytoma in an elderly female.  Careful attention to cytologic details and
correlations with clinical and radiologic settings are of paramount importance in correctly interpreting
plasmacytoid tumors. In many instances, immunocytochemical and/or flow cytometric studies may be
necessary to pinpoint the best single diagnosis. Whether dealing with bone metastasis from primary
hepatocellular carcinoma (case #2) simulating myeloma or with plasmacytoma in the hepatic parenchyma,
it's best to keep an open mind and let the cells do the talking. 
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