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Establishing the Diagnosis of Lymphoma: From Initial Biopsy to Clinical Staging

Establishing the Diagnosis of Lymphoma: From Initial Biopsy to Clinical Staging

ABSTRACT: Successful therapy for most of the non-Hodgkin’s lymphomas requires an accurate pathologic diagnosis. Routine morphologic examination of excisional biopsies from nodal or extranodal sites provides the cornerstone for establishing a definitive diagnosis. The list of ancillary studies, however, used to complement these routine approaches is increasing both in number and complexity. Proper use of these diagnostic tools can be of great help in arriving at the correct diagnosis in difficult cases. Fine-needle aspiration and needle-core biopsies have a role in lymphoma staging and in the assessment of recurrent disease, but are limited as primary diagnostic tests. This review will focus on the standard approaches used to establish a diagnosis of malignant lymphoma, and the clinical utility of immunophenotypic, molecular genetic, and cytogenetic studies in providing useful data for diagnosis. The standard practice of synthesizing all of the data from multiparameter analysis to arrive at a diagnosis in difficult cases will be emphasized. [ONCOLOGY 12(Suppl 8):11-16, 1998]


During the past decade, a significant amount of clarity has been
brought to our understanding of the pathogenesis of non-Hodgkin’s
lymphoma. Many of the insights gleaned from our knowledge of the
molecular mechanisms that underlie lymphomagenesis have translated
into improved classification schemes. The Working Formulation is a
clinically driven scheme that has long since outlived its
usefulness.[1] It has largely been replaced by the Revised European
and American Lymphoma classification, now known as the REAL proposal.[2]

This scheme recognizes “real” disease entities that have a
clinical, morphologic, immunophenotypic, cytogenetic, and molecular
genetic correlate. Within each lymphoma category, a spectrum of
clinical behavior may be seen, and this diversity is important to our
understanding of non-Hodgkin’s lymphoma.[3]

Pathologists welcome this classification, as it focuses on the
biology of these disorders rather than lumping diseases together
based on a common clinical outcome. The information imparted by an
accurate diagnosis, together with the relevant clinical data, can now
be used to make definitive treatment decisions.

Classification Techniques

The newly developed and more sophisticated techniques for analysis of
lymphoma cells have provided us with the tools necessary for precise
classification of non-Hodgkin’s lymphoma. Nonetheless, routine
histologic studies remain the gold standard for diagnosis. This
review will focus on the approaches used both for diagnosis and
staging and will attempt to provide some guidelines as to how and
when these tests should be employed.

Excisional Biopsy

A well-processed hematoxylin and eosin (H&E) stained section of
an excised lymph node is the mainstay of pathologic diagnosis.[4]
Most often, the diagnosis of difficult lesions relies heavily on a
careful assessment of the underlying architecture. Lymphoma diagnoses
are much less about cytologic detail and far more about altered
architecture. For example, follicular small-cleaved cell lymphoma
(FSC) is characterized by an abundance of neoplastic lymphoid
follicles containing monomorphous small-cleaved lymphocytes. The
individual cells themselves, however, are otherwise typical
smallcleaved lymphocytes seen in the benign follicles of reactive
lymph nodes.

The loss of normal nodal architecture that accompanies an infiltrate
is of paramount importance in making a diagnosis. An incisional lymph
node provides only a glimpse of the architecture, making
interpretation difficult. Our surgical colleagues must be instructed
to biopsy the most clinically significant site, and whenever
possible, to remove an intact lymph node for pathological processing.
The tissue should be delivered fresh to pathology at an appropriate
time of the day in order to maximize the material for lymphoma
protocol studies.

Many hematopathologists prefer to triage the material using imprint
preparations, whereby a fresh cut surface of the node is touched onto
glass slides for Romanowsky staining. Experienced pathologists are
able to make a good approximation of the disease process based on the
touch prep morphology, thus resulting in the efficient ordering of
additional tests.

When the size of the tissue is limiting, the first priority must be
to process the material routinely for fixation and H&E sections.
Properly fixed specimens can be used for regular histologic
examination, paraffin section immunoperoxidase staining, and
depending on the fixative, for gene rearrangement studies by
polymerase chain reaction (PCR).[5] Although B5 is the optimal
fixative for routine lymphoid histology and is preferred for
immunoperoxidase studies, it precludes PCR studies in most
laboratories. Formalin fixation is preferred when the biopsy is small
because all of the above studies, including PCR, can be performed.

Diagnosing Disease at Extranodal Sites—Approximately 30%
to 35% of cases of non-Hodgkin’s lymphoma in adults present
primarily at extranodal sites. Much less is known about the molecular
mechanisms involved in these disorders in comparison to node-based
disease. Therefore, it is important to remember to process extranodal
biopsy material for lymphoma protocol studies whenever there is a
suspicion of a hematolymphoid neoplasm.

Molecular genetic and cytogenetic data from gastric and pulmonary
resection specimens have enormous potential to provide insights into
the pathogenesis of mucosal-associated lymphoid tissue (MALT)
lymphomas but, unfortunately, lymphoma protocol is frequently
overlooked in this setting.[7,8] Nonetheless, examination of a
well-processed H&E section from an excisional biopsy by an
experienced hematopathologist will be sufficient to establish a
diagnosis in the majority of cases.

Needle-Core Biopsy

Needle-core biopsies have a role in lymphoma pathology, although it
remains limited.[9] The use of 14 to 22 gauge needles under
ultrasound or radiological guidance to establish a diagnosis of non-Hodgkin’s
lymphoma is problematic because of technical difficulties with
biopsy crush artifact, inadequate sampling, and the usual vagaries of
lymphoma pathology. Although this technique has advantages over
fine-needle aspiration (FNA), it should be used judiciously as a
diagnostic tool for patients with suspected non-Hodgkin’s
lymphoma. Needle-core biopsies do allow a minimal assessment of
architecture in addition to immunostaining procedures, but
interpretation can be problematic in cases of T-cell rich B-cell
lymphoma, angioimmunoblastic-type peripheral T-cell lymphoma, or MALT
lymphoma where much of the lymphoid infiltrate is reactive.

A careful review of most excisional lymph node biopsies demonstrates
marked cytologic and architectural variation throughout the section,
underscoring the complexity of non-Hodgkin’s lymphoma diagnoses
in what would otherwise be considered routine circumstances.
Needle-core biopsies are unable to detect this variability, leading
to the possibility of incorrect diagnoses in many cases. Although
recent studies have recommended increased use of these techniques,
patient selection and failure to provide convincing evidence that the
“right treatment” decision was made in the majority of
cases hamper their interpretation.[10,11] Also, many of these studies
included patients with an established diagnosis of either
non-Hodgkin’s lymphoma or Hodgkin’s disease—an
approach that differs significantly from a diagnostic procedure.[9]

In managing ill patients or those with significant comorbid disease
who are unable to tolerate an invasive surgical procedure,
needle-core biopsies offer a better alternative to FNA for the
diagnosis of intra-abdominal or thoracic disease. Ideally, two or
three cores should be obtained with one core routinely processed for
histology and the remainder used for lineage and clonality studies.
In this setting, cautious interpretation of the biopsy by an
experienced hematopathologist and integration of the results of the
ancillary studies should allow a reasonable treatment decision to be
made in most cases.


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