Paraganglion cells mimicking metastatic clear cell carcinoma JUDIT M A K I N E N & JUHA N I C K E L S Department of Pathology, University of Helsinki, Finland Accepted for publication 14 May 1979 MAKINEN J. & NICKELS J. (1979) Histopathology h 459-465 Paraganglion cells mimicking metastatic clear cell carcinoma Four patients are presented in whom normal paraganglion cells simulated metastases of clear cell carcinomas of the urogenital tract. The cells, located within and near the lumbar sympathetic ganglia, were initially interpreted by the pathologist as metastatic, but a later examination showed them to be normal paraganglion cells. One ganglion was also examined electron microscopically. Normal ganglion cells were seen, as were cells with intracytoplasmic osmophilic neurosecretory granules, confirming their paraganglionic origin. Awareness of the appearance of paraganglion cells in some instances is essential to avoid their misinterpretation as metastases of clear cell carcinomas. Keywords : paraganglion cells, secondary clear cell carcinoma, electron microscopy
Introduction The extra-adrenal paraganglionic system is a complex of cell groups originating from the neural crest. These cells are functionally related to the ganglia of the autonomic nervous system, being located mainly near the chain of the sympathetic ganglia of the paravertebral, thoracolumbar region (Glenner & Grimley’1974). Light microscopically the paraganglion cells may closely resemble the clear cells frequently seen in some carcinomas. Thus, these cells may lead to a false diagnosis of metastasis within the sympathetic ganglia or in the fat tissue surrounding the sympathetic chain. The purpose of the present paper is to call attention to the existence of paraganglion cells causing diagnostic pitfalls in connection with clear cell carcinomas.
Case reports CASE I
A 65-year-old female was admitted to hospital due to an episode of macroscopic Address for correspondence: J.Makinen MD, Department of Pathology, University of Helsinki, Haartmaninkatu 3, SF-00290 Helsinki 29, Finland. 0309-0167/79/11oo-o~5~ 6oz.oo
0 1979 Blackwell Scientific Publications
459
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J.Miikinen and J . Nickels
haematuria which took place 7 months before admission. Urography was performed because of a tumour, palpated in the right kidney area. An expansion of the lower pole of the right kidney was found which angiographically strongly suggested malignancy. Cavography revealed no infiltration. Surgery showed a macroscopically malignant tumour, 1 0 x 10 cm, which distorted the pelvis of the right kidney. Histological examination showed a clear cell carcinoma (Figure I ) .
Figure I . Case I . Adenocarcinoma of the kidney composed of moderately differentiated clear cells. Van Gieson. x 380.
At the same operation some renal hilar lymph nodes as well as a short part of the sympathetic chain were removed for histological examination. There were no macroscopic metastases and the patient was recorded as T,N,M, in the TNM classification. A small group of clear cells was found in one of the sympathetic ganglia and first interpreted as metastatic tumour cells. On later examination, however, these were reassessed as paraganglion cells (Figure 2). The ganglion containing the clear cells was also examined electron microscopically. The material was fixed in formalin, embedded in paraffin, deparaffinized with xylol, passed through a descending alcohol series, postfixed in osmium tetroxidc, and embedded in Epon. Electron microscopically the light microscopic clear cells contained numerous electron dense granules, 0. I 0 . 3 pm and typical of paraganglion
Figure 2. Case I . A sympathetic ganglion removed during the opcration for renal carcinoma. Note paraganglion cells within the ganglion. Van Gieson. x 380. Figure 3. Case I . Electron micrograph from the paraganglionic area seen in Figure 2 . One paraganglion cell (P) with electron-dense granules can be seen. Part of a ganglion cell (G) with three lipofuscin granules (arrows) is also visible. S = supporting cell. x 3040.
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cells (Figure 3). These chief cells had protoplasmic processes which also contained electron-opaque granules and they were surrounded by supporting cells. Ganglion cells with intracytoplasmic lipofuscin granules but no neurosecretory bodies were seen around the paraganglion cells. CASE 2
A 6o-year-old, previously healthy, man who was admitted to hospital because of haematuria of 2 months’ duration. Urography showed a suspected tumour in the region of the right kidney. Angiography revealed a large tumour at the upper pole. Roentgenologically suspect metastases were seen in the lower lobe of the right lung. An extrafascial nephrectomy was performed and the kidney, as well as a short part of macroscopically normal sympathetic chain, were sent for histological examination. The tumour, 10 x 10 cm, was cystic and showed large haemorrhagic areas, but did not infiltrate the capsule of the kidney or the renal vein. The patient was classified as T3NoMo. Microscopically, the tumour was mainly composed of large clear cells, with some areas of smaller cells of granular appearance. A small group of clear cells within a sympathetic ganglion was diagnosed as metastatic. On later investigation these were reinterpreted as paraganglionic cells. CASE
3
A 24-year-old male had had trauma to the right testicle 2 months before hospitalization. The swelling was interpreted as a haematoma and, at the first visit, no therapy was given. As the painful swelling did not disappear the patient was admitted to hospital where a tumour 8 cm in diameter was palpated within the right testicle. Lymphography detected no metastases. A radical orchidcctomy and funiculectomy were performed. The patient was classified as T,N,Mo. Macroscopically, the testicle was almost totally replaced by tumour. Microscopically the diagnosis of immature teratoma (WHO classification) with clear cell areas was made (British Testicular Tumour Panel classification : malignant teratoma intermediate group with differentiated components, MTIA) (Figure 4). One week later dissection of the retroperitoneal lymph nodes was performed on both sides up to the level of the kidneys. Microscopically there was no detectable tumour tissue within the lymph nodes, but there were small groups of clear cells near the sympathetic chain in the fatty tissue. These cells were at first, interpreted as metastatic, but on a later investigation they were reclassified as paraganglionic cells (Figure 5). Blood level of alpha-fetoprotein was 90 ng/ml preoperatively with a rapid decrease to o ng/ml after surgery. CASE
4
A 22-year-old, previously healthy man had a painless nodule in his left testicle for
one month before admission to hospital, approximately 3 cm in diameter and it was
Figure 4. Case 3 . Malignant teratorna of the right testis with clear cell areas. Van Gieson. x 380. Figure 5. Case 3 . The evacuated retropei itoneal material showing sympathetic ganglion and paraganglion areas. Van Gieson. x 57.
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suspected of being a malignant tumour. A radical orchidectomy was performed. On operation a white, friable, partly necrotic tumour was seen within the left testicle. Microscopically the tumour was shown to be a combination of embryonal carcinoma and teratoma (teratocarcinoma : WHO classification) with some certain areas of clear cells (malignant teratoma intermediate group with organoid components, MTIA : British Testicular Tumour Panel classification). No metastases were seen in the lymph nodes of the left iliac region. A small group of large, clear cells was noted within one ganglion of the sympathetic chain and, at first examination, misinterpreted as metastatic tumour. These later proved to be paraganglion cells.
Discussion The distribution of paraganglion cells is more extensive in the foetus and newborn infant than in adults (Glenner & Grimely 1974), but recent investigations have shown that such cells also persist in adults as widespread macroscopic bodies and microscopic cell groups in various areas (Leestma & Price 1974, Kuo, Anderson & Rosai 1974, Fuselier 1974, Freedman & Goldman 1975, Hervonen et al. 1976).The present cases also suggest that these cells are seen more frequently in the surroundings of the thoracolumbar sympathetic chain than might be expected. Attention needs to be drawn to this phenomenon since the existence of these cells may lead to a misdiagnosis of clear cell carcinomas, as in the four cases presented here. Special stains give little information at light microscopic level. The reticulin fibre network is characteristic, but the density may vary between tumours and tumour sites. Intracellular glycogen is absent and cells do not react with periodic acid-Schiff stain. The cells are characterized by the absence of much. The cytoplasmic granules sre best preserved by fixation in glutaraldehyde and may stain with Grimclius silver reaction. Electron microscopy seems to be useful in confirming the origin of these cells. Autoradiography and cell fractionation experiments have shown that the intracytoplasmic, osmiophilic granules contain catecholamines (Grimley & Glenner I 967) corresponding to the granules of the adrenal medulla (Elfvin 1968, Mascorro & Yates 1970). These granules are common to paraganglion cells and their protoplasmic processes but not to sympathetic neurons (Mascorro & Yates 1970).The ganglion cells of adult mammals also contain lipofuscin and pigmented granules which are, however, larger than these specific, neurosecretory granules (Elfvin 1968), and can thus be differentiated electron microscopically from each other. References COLLINS D.H. & PWGHR.C.B. (1964) Classification and frequency of testicular tumours. British Journal of Urology 36, Suppl., 1 - 1 I ELNINL.-G. (1968) A new granule-containing nerve cell in the inferior mesenteric ganglion of the rabbit. Journal of Ultrastructural Research 2 2 , 37-44
Paraganglion cells and clear cell carcinomas
465
FREEDMAN R.S. & GOLDMAN R.L. (1975) Normal paraganglion in the human prostate. Journal of Urology 113, 874-875 FUSELIER H. (1975) Paraganglioma of the bladder. Report of a case. Journal of Uroiogy 113,42-44 GLENNER G.G. & GRIMLEY P.M. (1974) Tumours of the Extra-adrenal Paraganglion System (Inch ding Chernoreceptors), Second series, Fascicle 9. Armed Forces Institute of Pathology, Washington DC GRIMLEY P.M. & GLENNER G.G. (1967)Histology and ultrastructure of carotid body paragangliomas. Comparison with the normal gland. Cancer 2 0 , 1473-1488 HERVONEN A., VAALASTI A., PARTANEN M., KANERVA L. & VAALASTI T. (1976) The paraganglia, a persisting endocrine system in man. American Journal of Anatomy 146, 207-210 Kuo T., ANDERSON C.B. & RCSAIJ. (1974) Normal paraganglia in the human gall bladder. Archives of ParhokY 97,4&47 LEESTMA J.E. & PRICEE.B. (1971)Paraganglioma of the urinary bladder. Cancer 28, 1063-1068 MASCORRO J.A. & YATESR.D. (1979) Sympathetic paraganglia. Texas Reports on Biology and Medicine 28, 363-372
Introduction The extra-adrenal paraganglionic system is a complex of cell groups originating from the neural crest. These cells are functionally related to the ganglia of the autonomic nervous system, being located mainly near the chain of the sympathetic ganglia of the paravertebral, thoracolumbar region (Glenner & Grimley’1974). Light microscopically the paraganglion cells may closely resemble the clear cells frequently seen in some carcinomas. Thus, these cells may lead to a false diagnosis of metastasis within the sympathetic ganglia or in the fat tissue surrounding the sympathetic chain. The purpose of the present paper is to call attention to the existence of paraganglion cells causing diagnostic pitfalls in connection with clear cell carcinomas.
Case reports CASE I
A 65-year-old female was admitted to hospital due to an episode of macroscopic Address for correspondence: J.Makinen MD, Department of Pathology, University of Helsinki, Haartmaninkatu 3, SF-00290 Helsinki 29, Finland. 0309-0167/79/11oo-o~5~ 6oz.oo
0 1979 Blackwell Scientific Publications
459
460
J.Miikinen and J . Nickels
haematuria which took place 7 months before admission. Urography was performed because of a tumour, palpated in the right kidney area. An expansion of the lower pole of the right kidney was found which angiographically strongly suggested malignancy. Cavography revealed no infiltration. Surgery showed a macroscopically malignant tumour, 1 0 x 10 cm, which distorted the pelvis of the right kidney. Histological examination showed a clear cell carcinoma (Figure I ) .
Figure I . Case I . Adenocarcinoma of the kidney composed of moderately differentiated clear cells. Van Gieson. x 380.
At the same operation some renal hilar lymph nodes as well as a short part of the sympathetic chain were removed for histological examination. There were no macroscopic metastases and the patient was recorded as T,N,M, in the TNM classification. A small group of clear cells was found in one of the sympathetic ganglia and first interpreted as metastatic tumour cells. On later examination, however, these were reassessed as paraganglion cells (Figure 2). The ganglion containing the clear cells was also examined electron microscopically. The material was fixed in formalin, embedded in paraffin, deparaffinized with xylol, passed through a descending alcohol series, postfixed in osmium tetroxidc, and embedded in Epon. Electron microscopically the light microscopic clear cells contained numerous electron dense granules, 0. I 0 . 3 pm and typical of paraganglion
Figure 2. Case I . A sympathetic ganglion removed during the opcration for renal carcinoma. Note paraganglion cells within the ganglion. Van Gieson. x 380. Figure 3. Case I . Electron micrograph from the paraganglionic area seen in Figure 2 . One paraganglion cell (P) with electron-dense granules can be seen. Part of a ganglion cell (G) with three lipofuscin granules (arrows) is also visible. S = supporting cell. x 3040.
462
J . Makinen and J .Nickels
cells (Figure 3). These chief cells had protoplasmic processes which also contained electron-opaque granules and they were surrounded by supporting cells. Ganglion cells with intracytoplasmic lipofuscin granules but no neurosecretory bodies were seen around the paraganglion cells. CASE 2
A 6o-year-old, previously healthy, man who was admitted to hospital because of haematuria of 2 months’ duration. Urography showed a suspected tumour in the region of the right kidney. Angiography revealed a large tumour at the upper pole. Roentgenologically suspect metastases were seen in the lower lobe of the right lung. An extrafascial nephrectomy was performed and the kidney, as well as a short part of macroscopically normal sympathetic chain, were sent for histological examination. The tumour, 10 x 10 cm, was cystic and showed large haemorrhagic areas, but did not infiltrate the capsule of the kidney or the renal vein. The patient was classified as T3NoMo. Microscopically, the tumour was mainly composed of large clear cells, with some areas of smaller cells of granular appearance. A small group of clear cells within a sympathetic ganglion was diagnosed as metastatic. On later investigation these were reinterpreted as paraganglionic cells. CASE
3
A 24-year-old male had had trauma to the right testicle 2 months before hospitalization. The swelling was interpreted as a haematoma and, at the first visit, no therapy was given. As the painful swelling did not disappear the patient was admitted to hospital where a tumour 8 cm in diameter was palpated within the right testicle. Lymphography detected no metastases. A radical orchidcctomy and funiculectomy were performed. The patient was classified as T,N,Mo. Macroscopically, the testicle was almost totally replaced by tumour. Microscopically the diagnosis of immature teratoma (WHO classification) with clear cell areas was made (British Testicular Tumour Panel classification : malignant teratoma intermediate group with differentiated components, MTIA) (Figure 4). One week later dissection of the retroperitoneal lymph nodes was performed on both sides up to the level of the kidneys. Microscopically there was no detectable tumour tissue within the lymph nodes, but there were small groups of clear cells near the sympathetic chain in the fatty tissue. These cells were at first, interpreted as metastatic, but on a later investigation they were reclassified as paraganglionic cells (Figure 5). Blood level of alpha-fetoprotein was 90 ng/ml preoperatively with a rapid decrease to o ng/ml after surgery. CASE
4
A 22-year-old, previously healthy man had a painless nodule in his left testicle for
one month before admission to hospital, approximately 3 cm in diameter and it was
Figure 4. Case 3 . Malignant teratorna of the right testis with clear cell areas. Van Gieson. x 380. Figure 5. Case 3 . The evacuated retropei itoneal material showing sympathetic ganglion and paraganglion areas. Van Gieson. x 57.
464
J . Makinen and J . Nickels
suspected of being a malignant tumour. A radical orchidectomy was performed. On operation a white, friable, partly necrotic tumour was seen within the left testicle. Microscopically the tumour was shown to be a combination of embryonal carcinoma and teratoma (teratocarcinoma : WHO classification) with some certain areas of clear cells (malignant teratoma intermediate group with organoid components, MTIA : British Testicular Tumour Panel classification). No metastases were seen in the lymph nodes of the left iliac region. A small group of large, clear cells was noted within one ganglion of the sympathetic chain and, at first examination, misinterpreted as metastatic tumour. These later proved to be paraganglion cells.
Discussion The distribution of paraganglion cells is more extensive in the foetus and newborn infant than in adults (Glenner & Grimely 1974), but recent investigations have shown that such cells also persist in adults as widespread macroscopic bodies and microscopic cell groups in various areas (Leestma & Price 1974, Kuo, Anderson & Rosai 1974, Fuselier 1974, Freedman & Goldman 1975, Hervonen et al. 1976).The present cases also suggest that these cells are seen more frequently in the surroundings of the thoracolumbar sympathetic chain than might be expected. Attention needs to be drawn to this phenomenon since the existence of these cells may lead to a misdiagnosis of clear cell carcinomas, as in the four cases presented here. Special stains give little information at light microscopic level. The reticulin fibre network is characteristic, but the density may vary between tumours and tumour sites. Intracellular glycogen is absent and cells do not react with periodic acid-Schiff stain. The cells are characterized by the absence of much. The cytoplasmic granules sre best preserved by fixation in glutaraldehyde and may stain with Grimclius silver reaction. Electron microscopy seems to be useful in confirming the origin of these cells. Autoradiography and cell fractionation experiments have shown that the intracytoplasmic, osmiophilic granules contain catecholamines (Grimley & Glenner I 967) corresponding to the granules of the adrenal medulla (Elfvin 1968, Mascorro & Yates 1970). These granules are common to paraganglion cells and their protoplasmic processes but not to sympathetic neurons (Mascorro & Yates 1970).The ganglion cells of adult mammals also contain lipofuscin and pigmented granules which are, however, larger than these specific, neurosecretory granules (Elfvin 1968), and can thus be differentiated electron microscopically from each other. References COLLINS D.H. & PWGHR.C.B. (1964) Classification and frequency of testicular tumours. British Journal of Urology 36, Suppl., 1 - 1 I ELNINL.-G. (1968) A new granule-containing nerve cell in the inferior mesenteric ganglion of the rabbit. Journal of Ultrastructural Research 2 2 , 37-44
Paraganglion cells and clear cell carcinomas
465
FREEDMAN R.S. & GOLDMAN R.L. (1975) Normal paraganglion in the human prostate. Journal of Urology 113, 874-875 FUSELIER H. (1975) Paraganglioma of the bladder. Report of a case. Journal of Uroiogy 113,42-44 GLENNER G.G. & GRIMLEY P.M. (1974) Tumours of the Extra-adrenal Paraganglion System (Inch ding Chernoreceptors), Second series, Fascicle 9. Armed Forces Institute of Pathology, Washington DC GRIMLEY P.M. & GLENNER G.G. (1967)Histology and ultrastructure of carotid body paragangliomas. Comparison with the normal gland. Cancer 2 0 , 1473-1488 HERVONEN A., VAALASTI A., PARTANEN M., KANERVA L. & VAALASTI T. (1976) The paraganglia, a persisting endocrine system in man. American Journal of Anatomy 146, 207-210 Kuo T., ANDERSON C.B. & RCSAIJ. (1974) Normal paraganglia in the human gall bladder. Archives of ParhokY 97,4&47 LEESTMA J.E. & PRICEE.B. (1971)Paraganglioma of the urinary bladder. Cancer 28, 1063-1068 MASCORRO J.A. & YATESR.D. (1979) Sympathetic paraganglia. Texas Reports on Biology and Medicine 28, 363-372
