Physician/Scientist

Pathology

The Niemann-Pick Disease Cell

The histologic hallmark of NPD is the pathological "foam cell" or "Niemann-Pick cell." This histiocyte is found in clinically involved tissues and organs, primarily in those of the monocyte-macrophage system. These cells should not be confused with "Gaucher cells," the histiocytic storage cells found in Gaucher disease. The two cell types can be readily distinguished by their histologic and histochemical characteristics, as described below. It should be noted that the presence of NPD foam cells is not pathognomonic for NPD, since histologically similar cells are found in patients with Wolman disease, cholesterol ester storage disease, and lipoprotein lipase deficiency and in some patients with GM1 gangliosidosis, type 2.

The NPD foam cell is ~25 to 75 mm in diameter (smaller than the average Gaucher cell) and usually has one nucleus, and the cytoplasm is generally filled with lipid droplets or particles. These droplets are usually uniform in size and give the cell its characteristic foamy appearance. This appearance has been referred to as "mulberry-like" or "honey comb-like." Under polarized light, many of the droplets are birefringent, and under UV light they may appear greenish-yellow to brownish-yellow. In frozen sections, the droplets stain positive for lipid with Sudan black B and oil red O. The Schultz reaction for cholesterol is positive in most NPD cells, a reaction that is negative in Gaucher cells. In contrast, NPD cells stain poorly with PAS stain, a reaction that is positive in Gaucher cells. In bone marrow, the intracellular material may appear bluish, giving rise to the descriptive term "sea-blue histiocytes." Excellent reviews are available describing the histologchemistry and histochemistry of the NPD cell. Ultrastructurally, the NPD foam cell contains numerous, granular lipid inclusions in the cytoplasm that are about 0.5 to 50 mm. The inclusions may appear lamellar, having an average periodicity of about 50 ‰. They are smaller than the inclusions in Tay-Sachs disease, although there is considerable variation in their appearance. Older patients generally have the most pronounced inclusions, while in younger and mildly involved patients, the inclusion bodies are more amorphous. In contrast to Gaucher cells, in which the inclusion bodies stain strongly for acid phosphatase, the NPD cell inclusions usually stain weakly for this lysosomal marker. The inclusion bodies are often associated with ceroid granules at their surfaces.

NPD cells originate from lipid-accumulating bone marrow progenitor cells. Thus, in the NPD patient it is rare to find any tissues without at least some foam cells. Organs of the monocyte-macrophage system, such as the lymph nodes and spleen, are often completely infiltrated with these cells at the end stages of the disease. Rarely, parenchymal cells may have a foam-cell appearance.

It is important to note that the foam cells found in NPD resemble those found in the sea blue histiocyte syndrome. These latter cells are macrophages that contain varying numbers of cytoplasmic granules, which impart a distinct blue color on Wright's-Giemsa stain. The first reports of patients with widespread accumulation of these cells were in 1970, and since then many similar patients have been described. Although the underlying defect in the sea blue histiocyte syndrome remains unknown, some patients thought to have this syndrome based on their histopathology have, in fact, been shown to have NPD. Thus, it is important to note that the diagnosis of NPD cannot be made based on histologic evidence alone. Enzymatic and/or DNA studies must be used to confirm the histologic findings.

Organ System Involvement

Central Nervous System
At autopsy, the brains of Type A NPD patients appear firm and leathery. The overall weight of the brain tends to be less than normal. Although the cerebellum is generally more severely affected than the cerebrum, characteristic lesions may be found in both. Histologically, the ganglion cells are swollen and pale, and the cytoplasm is often filled with large vacuoles. There is frequent swelling of the dendrites, disappearance of normal fibrillae, and a severe deficiency of myelin. Foam cells and/or lipid-laden glial cells are prominent in the brain and in the connective tissue surrounding the cerebral vessels. Similar changes occur in the spinal cord, the autonomic nuclei, and the sympathetic nerve cells in the adrenal medulla; however, the distribution of these lesions may be quite variable.

Peripheral neuropathy also has been noted in Type A NPD, although not as frequently or as extensively as the central nervous system involvement. Nerve conduction velocities may be severely diminished, and nerve biopsies may reveal isolated fibers with demyelination and numerous dense bodies in the Schwann cells. Often, electron microscopy of nerves reveals two categories of inclusion bodies. One contains the lysosomal inclusions typical of NPD, and the second is composed mostly of myelin. Both the myelin debris and NPD inclusions have been found in axoplasm, probably originating from Schwann cell cytoplasm through axolemma lesions.

Spleen
The spleen is the most extensively involved visceral organ in both Types A and B NPD. The splenomegaly may be as much as 10 times normal size, and may be readily detected as early as the first month of life in Type A patients. In Type B NPD, the onset and severity of splenomegaly may be quite variable. At autopsy, the organ is usually firm and pale. Malpighian bodies may be seen as numerous small reddish-yellow spots. Histologically, the architecture is dramatically abnormal because of the extensive infiltration of foam cells. These cells are arranged mainly between the sinuses, but involvement of the white pulp also may be found, particularly around the arteries. In the most severe cases, the red pulp may be almost completely replaced by NPD cells. NPD cells also may appear within the numerous malpighian bodies. The formation of accessory spleens in Type B patients has been described.

Lymph Nodes
The degree of lymph node involvement is variable. As the disease progresses, the lymph nodes may become extensively involved, often enlarging to three to five times their normal size. Lymphadenopathy is most marked in the mesentery, the hilus of the spleen, liver, and lungs. In addition, the head of the pancreas, the thymus, and the tonsils also may be enlarged. Enlargement of peripheral nodes is not often detected. On gross examination, the nodes may appear grayish-yellow, because of infiltration of lipid-laden NPD cells in the parechyma. As with the NPD cells of the spleen, the lymph node NPD cells may show signs of erythrocyte phagocytosis.

Bone Marrow
Since the bone marrow is the major source of cells for repository for cells of the monocyte-macrophage system, this organ is one of the most extensively involved in Types A and B NPD. The marrow of affected individuals generally appears hyperplastic, and on histologic examination is usually infiltrated with NPD cells. In the most severely affected Type A patients, NPD cells may compose up to 3 percent of the nucleated cells of the bone marrow. In general, the NPD cells in the bone marrow are larger than those found in other organs, and a higher percentage of multinucleated cells are observed. In contrast to the NPD cells in the spleen and lymph nodes, phagocytosis of erythrocytes is rarely seen, and the formation of other blood components in the marrow is normal in most NPD patients.

Lungs
The lungs are usually affected in both Types A and B NPD, although the extent of involvement may vary considerably. In the classic studies of Crocker and Farber, the weights of the lungs from Type A NPD patients were found to be generally increased when compared to age-matched normal controls, the maximum being about 2.4-fold. In Type B NPD patients, the lung pathology is more prominent, and foam cells may be present throughout the entire organ, including in the lymphatic vessels and pulmonary arteries. Significant foam-cell infiltration of the pulmonary alveoli also may be observed.

Liver
The liver of Type A NPD patients may be enlarged from 1.5- to twofold. On gross analysis, the livers of NPD patients are firmer than normal and grayish-yellow; however, histologic abnormalities may take up to 6 months to appear. The onset of hepatomegaly and histologic abnormalities may be quite variable in Type B NPD. On histologic examination, large Kupffer cells and vacuolated parenchymal cells are generally visible, the former presumably becoming NPD cells during the end stages of the disease. The distribution of these cells may be quite spotty, leading to a variable disruption of the liver architecture. However, the early formation of NPD cells clearly favors the sinuses, and then later involves the portal areas.

Kidneys
The kidneys are only moderately involved in Types A and B NPD. In fact, Crocker and Farber found that the kidneys from most Type A NPD patients at autopsy were slightly smaller than normal. On gross examination, the kidneys may have a fatty, light-yellow cortex. However, histologic findings have been variable. In Pick's 1927 study, about 50 percent of the kidneys from Type A NPD patients had visible foam cells, which originated from the tubular epithelium and glomerular endothelial cells. They may frequently be found within the glomerular capillaries and the lumen of the renal arteries. Other pathological changes in the kidneys of NPD patients have been variably noted, though kidney dysfunction has not been observed.

Eyes
Lipid-laden retinal ganglion cells, as well as vacuolated cells in the inner and outer nuclear layers and in the choroid, have been noted. Lamellar deposits in the corneal and lens epithelium also may be found. Eye changes have been noted as early as the twenty-third week of gestation in a Type A NPD fetus.

Other Organs
In general, most organs of the monocyte-macrophage system contain cells with the characteristic lipid-laden appearance. In addition, large yellow adrenal glands have been noted in a number of cases; however, adrenal insufficiency has not been found. Other endocrine organs, including the gonads, thyroid, and pituitary, also may show histologic changes, but no functional abnormalities. Similar findings have been reported for the pancreas and salivary gland. In addition, the thymus of NPD patients is often strikingly yellow and massively infiltrated with foam cells. NPD cells are frequently found within the bowel wall, and vacuolated epithelial cells have been observed in the stomach and colon. NPD cells also may be found between the endothelial and smooth muscle cells of the heart, and involvement of the epicardium has been noted.