Histology, diagnostics and disease staging

Histology of tumor tissue

The neoplastic Hodgkin lymphoma cells – the Hodgkin cells, the Reed-Sternberg cells and their variants – are characterized by a typical morphology (appearance). The Hodgkin lymphoma infiltrate contains only a few of these cells (approx. 1%), but a large amount of non-malignant cells, such as T- and B lymphocytes, macrophages (scavenger cells) and eosinophil granulocytes (defense cells).

By means of a histopathological tissue examination, Hodgkin lymphoma can be diagnosed and classified. According to the WHO classification, there are two types of Hodgkin lymphoma:

which is considered as an independent entity.
Classic Hodgkin lymphoma is divided into four histologic subtypes. These are:

• Nodular sclerosis Hodgkin lymphoma

• Mixed cellularity Hodgkin lymphoma
  

• Lymphocyte-rich classic Hodgkin lymphoma

• Lymphocyte-depleted classic Hodgkin lymphoma

Nowadays, the histologic subtypes of Hodgkin lymphoma do not influence the choice of treatment.
However, it should be mentioned that nodular lymphocyte-predominant Hodgkin lymphoma at stage I A (no other risk factors; only one lymph node region is affected; see below) has a very favorable course compared to other types at stage I, so that its treatment is more gentle than for the other types.

Diagnostics

Anamnesis

In general, the anamnesis is a patient’s personal medical history. When the medical history is taken, the treating physician questions the patient on his present illnesses, complaints and disorders, their start and development. The patient is also asked to provide details on his current living conditions (e.g. smoker/non-smoker, malignant diseases of family members etc.) as well as on previous diseases in order to detect potential risk factors. If a malignant lymphoma is suspected, special attention should also be paid to the presence or absence of B symptoms.

Physical examination and analysis of laboratory parameters

If a malignant lymphoma is suspected, the physical examination should not only include a measurement of blood pressure and pulse, auscultation of the lung etc., but the patient should also be carefully palpated for swollen lymph nodes. A very careful manual examination of the liver and the spleen is also of great importance because these organs are frequently enlarged (hepatosplenomegaly) if they are affected by the lymphoma. In order to determine the stage of disease (staging), an analysis of the laboratory parameters of the blood is just as essential.

Lymph node biopsy and histology

The withdrawal of body tissue from a living organism is called biopsy. To confirm the diagnosis of a malignant lymphoma, a biopsy of an whole lymph node is indispensable. This lymph node should be easily accessible and as large as possible. In most cases, the biopsy can be performed under local anesthesia, but if the mediastinum or the abdomen are involved, a general anesthesia is necessary.

The lymph node is histologically examined after its removal. This includes a staining of the cells and a microscopic analysis. This process allows the pathologist to identify the characteristic signs of the potential disease. In case of classic Hodgkin lymphoma, this would be the typical Hodgkin cells and Reed-Sternberg cells.

If possible, the diagnosis should be verified by a pathologist who is highly experienced in the field of lymphoma diagnostics (review pathologist), which is the common standard within the GHSG trials.

Computed tomography (CT)

A CT is an X ray based imaging technique through which the human body is scanned layer by layer. A computer uses these single scans to reconstruct a full image that shows the soft-tissue structures of the body and that reveals small differences in tissue density caused by tumors or other tissue changes. The scans are performed in an fast rotating tube with beams of rays which have nearly the diameter of a pencil. CT imaging has become a frequently used technique in X ray diagnostics and has meanwhile replaced many invasive methods.

Sonography (ultrasonic diagnostics))

This imaging technique uses ultrasound (1-10 MHz) according to the principles of echography to picture inner organs and is a standard procedure in lymphoma diagnostics. The intra-abdominal organs as well as the soft tissue of the neck can easily be examined with ultrasound. Especially if liver and spleen are involved, sonography can provide additional information to the CT findings. In contrast to CT scans, ultrasound imaging does not expose the patient to radiation.

Chest X-ray (two planes)

An X ray image of the chest is particularly helpful to examine the heart and the lungs. Such a image shows extensive tumor involvement of the lungs, effusions or large mediastinal tumor masses. For a more detailed recording of the tumor spread in the chest, a CT scan is required. However, a chest X ray is an obligatory diagnostic measure because by means of this imaging technique it can be determined whether a large mediastinal mass – an important risk factor – is present.

Bone marrow puncture / biopsy

By using a special type of needle, the marrow of a flat bone (e.g. the breastbone or the iliac crest) is punctured to extract bone marrow material, the examination of which may reveal if the bone marrow is infiltrated by a lymphoma or another malignant disease. This procedure is also used for intraossal (into the bone) injections or transfusions.

Scintigraphy of the skeleton

The scintigraphy is a nuclear-medical technique that uses a tagged radioactive substance as a so-called ‘tracer’. The tracer is administered by intravenous injection. The choice of the correct tracer depends on the organ that is to be examined. After the tracer has accumulated in the target organ, it can be detected through its radioactive marking by a special camera that produces an image of the accumulation. The more a tissue is supplied with blood (this is e.g. the case when an infection or a tumor is present), the more tracer substance accumulates at the respective location and the stronger is the signal detected by the camera. In lymphoma diagnostics, a skeleton or bone marrow scintigraphy is used for detecting or ruling out a bone involvement.

Positron emission tomography (PET)

The impact of PET in lymphoma diagnostics is currently subject to investigation in the GHSG’s ongoing HD15 trial. PET is, like CT or NMR, a cross-sectional imaging technique, but in contrast to these, it does not visualize single organs but the metabolism of different body tissues.

In tumor diagnostics, a special type of sugar tagged with a slightly radioactive fluorine is used as a tracer. It is injected into a vein and metabolized almost like normal sugar. Because of its radioactive labelling, it is possible to visualize the metabolization of the tracer by means of a special PET camera. Cells with a high metabolization rate, like tumor cells or infected tissue, need a high amount of sugar, so that the PET camera detects a strong signal in the respective areas.

Thereby, it is possible to distinguish between normal and malignant tissue. Depending on the treatment concept, PET examinations are used for initial staging, during chemotherapy (treatment monitoring), after end of chemotherapy (treatment control) or in case of a suspected relapse. Clinical trials have proven the prognostic value of PET imaging in treatment monitoring and treatment control. The currently ongoing GHSG trials are investigating the possibility to intensify or reduce therapy according to the PET monitoring results with the aim to individualize treatment.