Hematologic Malignancies

By admin On Apr 17, 2023

Ovid: Oncology and Basic Science

Editors: Tornetta, Paul; Einhorn, Thomas A.; Damron, Timothy A.

Title: Oncology and Basic Science, 7th Edition

> Table of Contents > Section II – Specific Bone Neoplasms and Simulators > 9 – Hematologic Malignancies

Hematologic Malignancies

Valerae O. Lewis

Hematologic malignancies such as lymphoma and myeloma
can manifest in bone, and these osseous manifestations can often be the
first presentation of the systemic disease. After metastatic disease,
myeloma and lymphoma are the second and third major categories in the
differential diagnosis of an aggressive bone lesion in an adult. To
avoid unnecessary surgery and to create a definitive treatment plan, it
is important to become familiar with the presentation and the work-up
of these lesions. Often the orthopaedic surgeon is the first to
diagnose these diseases; however, surgical intervention may not be
required. In addition, because the principles for treatment of
hematologic malignancies differ so greatly from sarcomas, the diagnosis
must be established before initiation of treatment.

Lymphoma

The vast majority of cases of lymphoma involving bone
are non-Hodgkin’s lymphoma (NHL). Non-Hodgkin’s lymphoma is not a
single disease, but a group of closely related B- and T-cell cancers of
the lymphatic system. B-cell lymphomas represent 85% of NHL cases.
Non-Hodgkin’s lymphoma can start in the lymph nodes or lymphatic tissue
such as the spleen, stomach, or skin, and because lymphocytes circulate
throughout the lymphatic vessels and bloodstream, abnormal lymphocytes
can reach any organ. Thus, lymphoma can manifest in any organ. In fact,
along with lung carcinoma, lymphoma is one of the most common
malignancies that may manifest as soft tissue metastases.

Epidemiology

Incidence of NHL is increasing.
- Worldwide incidence has risen steeply from the 1970s to the 2000s.
- From a relatively rare disease to the fifth most common cancer in the United States
Purported reasons for rise
- Increasing exposure to chemicals
- Increasing incidence of viral infections
- Increasing incidence of organ transplantation
- Increasing number of blood transfusions

Classification

Revised European-American Classification of Lymphoid Neoplasms (REAL) (Table 9-1)
- Most common types: diffuse large B-cell lymphoma (45%) and follicular (25%) lymphomas
Clinical classification
- Low grade (indolent), intermediate, or aggressive (high grade)
- Based on the natural history of the disease
Modified Ann Arbor Staging System (Table 9-2)
- Describes extent of disease
  - International Prognostic Index (IPI: an excellent prognostic tool)
    
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    - Clinical stage (I/II versus III/IV)
    - Number of extranodal sites (0 or 1 versus >1)
    - Lactic dehydrogenase (LDH) (normal versus >1)
    - Age at diagnosis
    - Performance status (Eastern Cooperative Oncology Group [ECOG])
  - The IPI can identify prognostic groups,
    and for patients with IPI >2 peripheral stem cell or bone marrow
    transplantation should be considered.

Table 9-1 Real (Revised European-American Classification of Lymphoid Neoplasms) Classification of Non-Hodgkin’s Lymphoma

B-cell Lymphoma	T-cell Lymphoma
Precursor B-cell lymphomas	Precursor T-cell lymphomas
B-lymphoblast	T-lymphoblast
Mature B-cell lymphomasFollicular Marginal zone nodal Extranodal marginal zone (MALT) Splenic marginal zone Lymphoplasmacytic Mantle cell Diffuse large B-cell Primary mediastinal large B-cell Burkitt-like Burkitt’s	Mature T-cell lymphomas Mycosis fungoides/Sezary syndrome Peripheral T-cell Anaplastic large T/null cell Adult T-cell leukemia/lymphoma

Table 9-2 Modified Ann Arbor Staging System

Stage	Characteristics
I	Single lymph node region (I) or Single extralymphatic site (IE)
II	Two or more lymph node regions on the same side of the diaphragm (II) May include localized involvement of extralymphatic site (IIE)
III	Two or more lymph node regions on both sides of the diaphragm (III) May include localized involvement of extralymphatic site (IIIE) or spleen (IIIS) or both (IIISE)
IV	Diffuse or disseminated involvement of extralymphatic organ, with or without associated lymph node involvement

Diagnosis

Clinical Findings

Painless swelling of lymph nodes
Chills
Fever
Night sweats
Malaise
Unexplained weight loss

Staging Studies

Biopsy of lesion/lymph nodes
Computed tomography (CT) scan
Positron emission tomography (PET) scan
Bone marrow biopsy

Treatment

Depends on stage of disease
Multimodality
Combination of chemotherapy and radiation
- CHOP with rituximab
  - CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone
  - Rituximab: works by targeting the CD20 antigen on normal and malignant B cells
Peripheral stem cell transplantation
Bone marrow transplantation

Primary Lymphoma of Bone

Primary lymphoma of bone (PLB) is a distinct clinical
entity. Although it was first identified by Oberlin in 1928, it was not
until 1939, when Parker and Jackson reported on their series of
“reticulum cell sarcoma,” that lymphoma of bone was classified distinct
from systemic lymphoma.

Definition: malignant lymphoid infiltrate within bone with or without cortical invasion or soft tissue extension but without concurrent involvement of regional lymph nodes or distant viscera
Synonyms
- Reticulum cell sarcoma (misnomer; not a sarcoma)
- Malignant lymphoma of bone
- Primary skeletal lymphoma
- Osteolymphoma

Epidemiology

0.2% of all bone tumors and 5% of all extranodal lymphomas
Large B-cell lymphoma represents 90% of the cases of PLB.

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Age: broad range
Male:female 1.8:1
Location
- Femur
- Ilium
- Ribs

Diagnosis

Clinical Findings

Localized bone pain
Mass
Pathologic fracture in 20% to 30%
Generally not systemically ill

Radiologic Findings (Fig. 9-1)

Plain Radiographs

Diaphyseal
Permeative/mottled
Poorly marginated
Associated soft tissue mass

Figure 9-1
Anteroposterior radiograph of the proximal femur and MRI (axial T1 with
contrast) of a 20-year-old man with primary lymphoma of bone. Note
permeative changes in the diaphysis of the femur on the radiograph and
large enhancing soft tissue mass demonstrated on the MRI.

Magnetic Resonance Imaging (MRI)

Large soft tissue mass
Enhances with gadolinium

Histologic Findings

Sheet-like proliferation of round blue cells without significant matrix (Fig. 9-2)
Pleomorphic
Nuclear heterogeneity
Special stains
- Reticulum stains
- Leukocyte common antigen (LCA)
  - CD45
- B-cell marker
  - CD19, CD20

Treatment

Multidisciplinary: combination of
systemic chemotherapy and local radiation is thought to be the most
effective treatment in decreasing the local recurrence and systemic
relapse
- Chemotherapy: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)
- Rituximab (monoclonal antibody to CD20)
Radiation: to the local site
Surgery: limited to diagnostic biopsy and to prevent impending pathologic fractures or to repair actual pathologic fractures

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Figure 9-2 Diffuse large B-cell lymphoma of bone: (A) 20× magnification, (B) 40× magnification.

Prognosis

60% to 80% 5-year survival rate
Worsens with age

Multiple Myeloma

Multiple myeloma is a plasma cell dyscrasia, but it is
not the only such entity. Other plasma cell dyscrasias sometimes
encountered in orthopaedic oncology include monoclonal gammopathy of
uncertain significance (MGUS) and solitary plasmacytoma. Both MGUS and
plasmacytoma may progress, and often do, to the disseminated form,
multiple myeloma.

Definition: disseminated malignancy of monoclonal plasma cells
- Monoclonal proteins
  - IgG: 60%
  - IgA: 20%
  - IgD: 2%
  - IgE: 0.1%
  - Light-chain kappa or lambda: 18%
  - Biclonal: <1%
  - Nonsecretory: <5%

Pathophysiology

Increased expression by osteoblasts of the receptor activator of nuclear factor KB (NF–KB) ligand (RANKL) and a reduction in the level of its decoy receptor osteoprotegerin
The increase in the ratio of RANKL to osteoprotegerin results in activation of osteoclasts and bone resorption.

Epidemiology

1% of all malignancies
14,400 new cases/year
Male:female 1.8:1
Age: 50s to 70s
- Median 65 years
Race propensity
- African Americans > Caucasians (2:1)
Risk factors: obesity, genetics (HLA), immunological challenges

Diagnosis

Clinical Findings

Pain
Pathologic fracture
Bone marrow failure
- Anemia: fatigue and weakness
- Thrombocytopenia: bruising, bleeding
- Neutropenia: recurrent infections (gram-negative infections)
Renal insufficiency (50%): multifactorial
- Bence Jones protein precipitation
- Interstitial nephritis
- Hypercalciuria
Hypercalcemia (25%)
- Manifestations
  - Nausea
  - Muscle weakness
  - Confusion
  - Polyuria
  - Constipation
- Treatment
  - Bisphosphonates
    - Pamidronate (Aredia) 90 mg IV
    - Zolendronate (Zometa) 4 mg IV
  - Hydration: normal saline + Lasix
    - The combination of the hypercalcemia and
      renal insufficiency leads to the need to hydrate the patient well
      before surgical intervention.
- Diagnostic criteria
  - 10% plasma cells in the bone marrow
  - Monoclonal protein in the serum (serum protein electrophoresis) or urine (urine protein electrophoresis)
  - Evidence of end-organ failure (CRAB)
    - Hypercalcemia
    - Renal insufficiency
    - Anemia
    - Bone lesions

Diagnostic Work-Up

Serum protein electrophoresis
- Monoclonal gammopathy does not automatically signify multiple myeloma.
- MGUS
  - IgG peak slightly elevated
    - IgG ≤3.5 g/dL, IgA ≤2 g/dL, urine light chain ≤1 g/dL
  - Normal radiographs
  - < 10% plasmacytosis
  - No symptoms
Urine protein electrophoresis
- Monoclonal gamma globulin spike
- Quantitative Ig levels
Serum chemistries
- Complete blood count (may show anemia)
- Electrolytes
  - Blood urea nitrogen (BUN), creatinine, calcium (may show azotemia, hypercalcemia)
- β₂-microglobulin
Bone marrow aspiration
- Plasmacytosis >10%
Bone survey
- Bone scan can underestimate extent of disease.
  - 80% of lesions are “cold.”
- Spine MRI
  - Vertebral lesions difficult to visualize on plain film
Biopsy: need for biopsy can be alleviated
in the face of multiple osseous lesions on bone survey and a positive
serum/urine protein electrophoresis.

Radiologic Findings

Punched-out lytic lesions (Fig. 9-3): single or multiple

Histologic Findings

Uniform plasma cells (Fig. 9-4)
Large round nuclei
- Clockface
- Eccentric
Distinct cell borders
Abundant cytoplasm, perinuclear clearing

Figure 9-3 Lateral radiograph of skull displaying “salt-and-pepper” punched-out lesions of multiple myeloma.

Treatment

Local Treatment

Radiation (very sensitive)
- Surgical adjuvant (postoperative): 30 Gy
- Radiation alone
  - Moderate, symptomatic lesions without impending or actual fracture
  - <50% cortex, <2.5 cm
Surgery
- Large lesions
  - Impending pathological fracture
  - Actual pathological fracture
- Protect the whole bone
  - Intramedullary rod fixation
Perioperative management
- Highly vascular
- Preoperative embolization of lesion important to consider
- Type and cross-match
  - Even for closed nailing
Acute renal failure
- Hydrate the patient well!

Systemic Treatment

Chemotherapy and corticosteroids: If
patient is eligible for stem cell transplantation, alkylating agents
for induction chemotherapy should be avoided.
- Pulsed steroids alone
- Melphalan + prednisone (MP)
- Vincristine + doxorubicin (Adriamycin) + dexamethasone (VAD)
- Thalidomide and dexamethasone: anti-angiogenic
- Bortezomib (Velcade, PS-341): proteasome inhibitor

Stem cell transplantation

Autologous stem cell transplantation

Can prolong disease-free survival and overall survival

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Figure 9-4
Representative pathology sections from a multiple myeloma specimen.
Note eccentric nuclei, abundant cytoplasm, and distinct cell borders. (A) Tissue section (20×). (B) Cytology on touch prep (80×).

Can be done in tandem
Can be used as salvage therapy
Induction chemotherapy before stem cell harvest reduces the tumor burden.

Allogenic stem cell transplantation
- Transplant not contaminated with tumor cells
- Only 5% to 10% of patients are candidates.
- High mortality rate

Prognosis

Median survival 3 years
Overall survival depends on stage.
International Staging System (Table 9-3): based on serum β₂-microglobulin and albumin levels

Solitary Plasmacytoma of Bone

Pathophysiology

Rare presentation of a plasma cell dyscrasia
- 3% of patients with myeloma
- Early manifestation of multiple myeloma: 70% progress to multiple myeloma

Epidemiology

Male:female 3:1
Age of presentation younger than multiple myeloma
Most common locations
- Long bones
- Pelvis
- Spine

Diagnosis

Solitary bone lesion
Skeletal survey: normal
MRI skull/spine/pelvis: normal
Bone marrow: normal plasma cell count
No anemia, hypercalcemia, or renal disease
Normal serum/urine protein electrophoresis or serum protein electrophoresis that becomes normal after treatment of the lesion

Treatment

Radiation only (45 Gy)
- Exquisitely sensitive
- Rapid response

Table 9-3 International Staging System for Multiple Myeloma with Corresponding Median Survival

Stage	Serum Albumin and Serum β₂-Microglobulin	Median Survival (months)
I	Serum albumin ≥3.5 g/dL and serum β₂-microglobulin <3.5 µg/mL	62
II	Neither stage I nor III	44
III	Serum β₂-microglobulin ≥5.5 µg/mL	29

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Prognosis

Relatively good
20% remain free of disease >10 years.
Better than multiple myeloma