Moderators: Dr. K. Krishnan Unni and Dr. Franco Bertoni
Case 3 -
Bone, ilium, right, biopsy: Malignant lymphoma, Hodgkin lymphoma, nodular sclerosis
Yasuaki Nakashima, M.D.
Laboratory of Anatomic Pathology, Kyoto University Hospital
Sakyo-ku, Kyoto 606-8507, JAPAN
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Twenty-four year old female.
The patient noted pain in the right flank to right hip, and consulted a local practitioner. On
laboratory tests, however, there were no abnormal findings. Six months later, an elevated erythrocyte
sedimentation rate was detected. Because of radiating pain from her right hip, through the right lower
extremity, to the right toe, she consulted an orthopedic surgeon and an osteolytic lesion in the right
ilium was identified. She also demonstrated a fever of 38 centigrade. Five months later, about one
year after the onset of her initial symptom of pain in the right flank, she underwent biopsy of the
lesion in the right ilium.
An osteolytic and destructive lesion was identified in the right ilium, with permeation into the
adjacent bone medulla, accompanied by extraosseous extension in the soft tissue. In MRI, the lesion
showed low intensity in T1-weighted images and high intensity in T2-weighted images.
The biopsy specimen was composed of several fragments, histologically showing variegated
histologic features, including fibroblastic proliferation, mature lymphocytic mononuclear cells, many
eosinophils and plasma cells, and histiocytic cells, In the granulation-like polymorphous background.
There were haphazardly scattered large atypical cells with amphophilic dark-stained cytoplasm. In the
large nucleus with an irregularly thickend nuclear membrane and coarsely aggregated chromatin, a single
large nucleolus was prominent. Most of these atypical large cells demonstrated immunohistochemical
profiles of CD15+, CD30+, CD3-, CD20-, CD1a-, S-100 protein-, CAM5.2-, and EBER-.
Case 3 - Slide 1
Bone, ilium, right, biopsy: Malignant lymphoma, Hodgkin lymphoma, nodular sclerosis.
Treatment and Course
On CT scan, swelling of the mediastinal and paraaortic lymph nodes was identified. In addition
to positive findings in the ilium and lymph nodes, involvement of multiple bones and the spleen was
suspected on FDG-PET. The patient was diagnosed as having stage IVB, and underwent chemotherapy with the
ABVD regimen accompanied by 36 Gy radiation for the right ilium. Thirteen months after the initial
diagnosis, the patient is well without residual lymph node swelling, and there are no positive findings
Malignant lymphoma may involve the skeletal system either as a primary tumor or, far more
commonly, as a manifestation of generalized disease, and the exact incidence of skeletal lymphoma is
difficult to determine. If we adopt the definition of primary lymphoma of bone as biopsy-confirmed
skeletal lesion associated without evidence of disease elsewhere even within 6 months after the
diagnosis, cases of primary lymphoma exclusively affecting the bone are extremely rare, and, from a
practical perspective, almost all cases of malignant lymphoma of the bone represent a secondary skeletal
involvement of systemic disease.
Lymphoma of bone, mainly of the large B-cell type, constituting approximately 7% of all skeletal
sarcomas and about 5% of extranodal lymphomas, usually occurs in adults over the age of 30 years, and
rarely affects children with an incidence equal to about 10% of that of Ewing sarcoma. There is a slight
or modest predilection for males. The femur, pelvic bones, and spine are common sites of involvement,
and the metaphysis or diaphysis of the long bone is frequently affected.
Pain and/or swelling may be initial symptoms, and systemic or B symptoms including fever and
night sweats are rare. Patients with involvement of the spine may demonstrate neurologic symptoms due to
compression of spinal cord.
Roentgenological change of the affected bone with combined sclerotic and lytic features is
generally extensive. Patchy cortical destruction is frequent, and periosteal reaction is not common.
Occasionally, findings on plain roentgenograms can be subtle or even negative and, if combined with
positivity on isotope bone scan, suggest malignant lymphoma of bone. MRI may be useful for showing a
permeative and destructive process difficult to identify on simple X-rays.
Hematological investigation, including flow cytometry and cytogenetic studies, and
immunohistochemistry are mandatory for the diagnosis of malignant lymphoma. From a practical perspective
of routine general surgical pathology, in performing immunostaining as the initial approach to a
suspected case, a battery of immunostaining including CD3, CD5, CD10, CD15, CD20 (L26), and CD30 (Ki-67,
BerH2), may be recommended. Immunostaining for CD1a, CD43, CD45RO, CD56, CD68 (KP-1, PG-M1), CD79a,
CD138, bcl-2, and cyclin D1, may be employed in some difficult cases as auxiliary procedures or for
further investigations. Myeloperoxidase reaction may also be used for differential diagnosis for myeloid
sarcoma. Immunostaining for CD45 (LCA) is frequently nonspecific and may be of less importance.
On gross inspection, the tumor is pale to pinkish gray, with a granular and fish flesh-like
appearance. Some lesions show osteosclerotic change, and identification of the lesion may be difficult.
Extraosseous extension to the soft tissues and invasion into the surrounding muscles are frequent.
Histologic appearances and morphologic spectrum of malignant lymphoma of the bone are
fundamentally similar to those of nodal lymphomas or lymphomas in other extranodal locations, and diffuse
large B-cell lymphomas are most common, and generally CD3-, CD5-, CD20+, and CD79a+ on immunostaining.
Malignant cells infiltrate between bony trabeculae sometimes with reactive sclerotic bony change, and
permeate within the fatty marrow. Crush artifact may be prominent in lymphoid cells, frequently causing
difficulties in the identification of cytological characteristics. In addition to cases showing typical
diffuse infiltration of large lymphoid cells, mixed proliferation of mature small lymphocytic cells,
medium-sized cells, and large cells are frequent, producing a variegated polymorphous appearance. In
some cases, fibrotic change is prominent and neoplastic lymphoid cells show spindle cell-like elongation,
with even storiform arrangement, simulating sarcomatoid proliferation or granulation-like histologic
Skeletal involvement of a low-grade or follicular lymphoma is extremely rare, and usually shows
CD5-, CD10+, and bcl-2+ on immunohistochemistry.
Anaplastic large cell lymphoma, null cell type or T-cell type, infrequently affects the skeleton,
usually shows immunostaining of CD15-, CD30+, EMA+, ALK+ and granzyme B+, and the main differential
consideration is Hodgkin lymphoma.
Burkitt lymphoma, typically affects the jawbone, can also involves the long bones and pelvic
bones, generally with EBER+ for EB virus.
Lymphoblastic lymphoma of precursor B-cell type may produce a solitary skeletal involvement,
histologically simulating Ewing sarcoma, with Immunohistochemical profiles of TdT+, CD43+, CD79a+, CD99+
and sometime CD20+.
Hodgkin lymphoma can present with bone lesions in about 12% to 19% of the patients, mainly as a
late manifestation of the disease, with multiple involvement in approximately 60 % of the cases, and not
infrequently without symptoms. Vertebrae are the most common site, and involvement of the pelvis, rib,
sternum, and femur can also be seen. Lymph node involvement, mediastinal and/or paraaortic, is almost
always detected. Exceptionally, however, bone involvement is the initial presentation of Hodgkin
lymphoma. Radiographically, osteolytic or mixed lytic and sclerotic appearance can be seen, and
sclerotic change may prominent especially in spinal lesions. In approximately 50% of the cases, however,
roentgenological findings may be unremarkable.
Histologically, according to the latest WHO classification of lymphoid neoplasia, Hodgkin
lymphomas are divided into nodular lymphocyte predominant Hodgkin lymphoma characterized by L&H cells
(lymphocyte and/or histiocytic Reed-Sternberg cell variants) or popcorn cells, and classical Hodgkin
lymphoma in which identification of typical Hodgkin and Reed-Sternberg cells (HRS cells) is the
histological requisite for diagnosis. Hodgkin lymphoma of the bone can show the same histological
features and variations as seen in classical Hodgkin lymphomas in the lymph nodes and extraskeletal soft
tissue, with predominance of nodular sclerosis classical Hodgkin lymphoma and mixed cellularity classical
Hodgkin lymphoma. Mixed cellular arrangement composed of mature lymphocytes, polymorphonuclear cells
mainly of eosinophils, plasma cells, histiocytic cells, and other mesenchymal cell, in the
granulation-like fibrosing background, is a common feature, and identification of classic HRS cells with
large nucleus and big nucleoli may sometimes be difficult. Immunohistochemically, large cells are
usually CD15+, CD30+, EMA-, and ALK-, and infiltration of reactive CD3+ T-lymphocyte may be prominent.
Differential consideration for malignant lymphoma may usually concentrate on neoplastic and
nonneoplastic lesions composed of small round cell proliferation.
Clinical and roentgenological features of osteomyelitis can simulate those of malignant
lymphoma, and histologic arrangement of mixed cellular infiltration of lymphoma may also be mistaken for
chronic osteomyelitis. Even in small foci, however, lymphoma shows relatively monotonous or homogenous
proliferation of atypical lymphoid cells, and complete effacement of the histology by granulation tissue
is unusual in malignant lymphoma. Immunohistochemically, proliferation of CD3+ cells can occur even in
reactive situations, and may be nonspecific. Prominent and monotonous proliferation of CD20+ or CD79+
lymphoid cells, however, suggests large B-cell lymphoma.
Ewing sarcoma generally affects children, histologically showing a large lobular arrangement,
separated by fibrous septa, with frequent central necrosis, whereas the mixed and polymorphic appearances
frequently seen in malignant lymphomas are not found. Nuclear features are predominantly regular with a
fine chromatin pattern, and differ from those see in malignant lymphomas frequently accompanied by
somewhat polymorphic nuclear features with indentation, lobulation, or convolution, and showing prominent
nucleoli. Scant cytoplasm with an indistinct cell border offers a good contrast to well defined,
relatively abundant eosinophilic or amphophilic cytoplasm of malignant lymphomas. Negative
Immunostaining for TdT and CD79a of Ewing sarcoma can be useful for differentiation from lymphoblastic
lymphoma of precursor B-cell type with CD99+ in immunostaining.
Acute leukemia, especially in children, frequently produce roentgenologically visible
involvement, while the systemic and widespread nature of the lesions may cause slight problems in
differentiating the disease from primary malignant lymphoma of bone.
Myeloid sarcoma (granulocytic sarcoma) may present with acute myeloid leukemia or a
myeloproliferative disorder, simultaneously or after the foregoing hematological findings, and can also
occur de novo as an isolated lesion without leukemia or as the initial manifestation of myeloid disease.
In addition to lymph node and skin, the subperiosteal bone structure is mainly affected, and the skull,
paranasal sinuses, sternum, ribs, vertebrae, and pelvis are the most common sites of involvement.
Histologic differentiation between malignant lymphoma and granulocytic sarcoma, especially the lytic type
primarily composed of myeloblasts, or the immature type with myeloblasts, promyelocytes and eosinophilic
myelocytes, may be difficult or even impossible simply in H&E stained sections. In
immunohistochemistry, granulocytic sarcoma is generally CD3-, CD20-, and frequently CD43+, and positivity
for lysozyme and myeloperoxidase may be the most important clue for the diagnosis.
Plasma cell myeloma and plasmacytoma may show the same skeletal distribution of predominant
involvement as seen in malignant lymphoma, namely, vertebrae, ribs, skull, pelvis, femur, clavicle and
scapula, in order of frequency. Detection of monoclonal protein in serum and urine can establish the
diagnosis of plasmacytic neoplasm. Radiologically, purely lytic change frequently showinga punched-out
pattern, is usual, and sclerotic features sometimes found in malignant lymphoma are rare in plasma cell
tumors, except in cases showing POEMS (Crow-Fukase) syndrome. Radioisotope scan is frequently negative
and is useful for differentiation from malignant lymphoma usually visualized positively in scintigram.
Eccentrically located nucleus with coarsely clumped chromatin in the amphophilic cytoplasm with
perinuclear Hof produce typical cytological features of plasma cells, and binucleation is relatively
common. Amyloid deposition in bone is generally considered a manifestation of plasma cell neoplasm.
Immunohistochemically, tumor cells are usually CD20-, CD56+, CD79a+, CD138+, showing monoclonality for a
kappa or lambda light chain of immunoglobulin.
Anaplastic large cell lymphoma can histologically mimic metastatic undifferentiated carcinoma,
especially large cell carcinoma. Cellular nest formation surrounded by desmoplastic dense fibrous septa
highly suggests a metastatic carcinoma. Fibrosis in lymphoma is more diffuse and fine than that seen in
fibrosing stroma with metastatic carcinoma. In addition to lymphoid markers, immunohistochemical stains
for epithelial markers, including CAM5.2, AE1/3, CK group, etc., may be useful for differentiating
between carcinoma and lymphoma, and for detecting the primary site of metastatic tumor, some
immunohistochemical markers including CD10 for renal cell carcinoma, TTF1 for lung and thyroid cancers,
PSA for prostate cancer, Hep-Par1 for hepatocellular carcinoma, CD56 for small cell (neuroendocrine cell)
carcinoma of the lung or other organs, and progesterone and estrogen receptors for breast carcinoma, may
sometimes be helpful.
Langerhans cell histiocytosis commonly occurs in childhood, and can simulate the roentgenologic
and histologic findings of Hodgkin lymphoma, producing a polymorphous histologic appearance composed of
lymphocytes, plasma cells, neutrophils, and histiocytic cells including multinucleated giant cells, with
frequent infiltration of eosinophils in granulation-like stroma. Histologically, patchy arrangement by
relatively haphazard distribution of the dense aggregations of histiocytic cells in low power
magnification is an important clue for the diagnosis. Langerhans cells have a characteristic oval
nucleus with indentation and lobulation and frequent coffee bean-like feature due to the longitudinal
nuclear groove in the abundant eosinophilic cytoplasm, showing CD1a (O10)+, S-100 protein+, and
frequently CD68 (KP-1, PG-M1)+ immunostaining.
Almost all malignant lymphomas of bone may be considered part of the systemic involvement of nodal
disease, and chemotherapy with or without radiation is usually the treatment of choice. Both the stage
and histologic cell type are the most important prognostic factors. In the most common type of skeletal
malignant lymphoma of large B-cell type, the 5-year survival rate ranged from approximately 22% to 48%
in several reported series. Tumors of centrocytic cleaved cell type may show a better prognosis, while
the prognosis of anaplastic large cell lymphoma with CD30+, EMA+, and granzyme B+, ALK+ in
immunoreactivity is generally poor. As a complication of treatment for malignant lymphoma of bone,
osteonecrosis of the femoral head or humeral head can occur.
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