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Testicular Lymphangiectasis in Noonan’s Syndrome
00~'.2-534 7/84/1314·-0759$02.00/0 THE JOURNAL OF UROLOGY
Copyright© 1984 by The VVilliarns & Yf! ilkins Co.
TESTICULAR LYMPHANGIECTASIS IN NOONAN'S SYNDROME MANUEL NISTAL,* RICARDO PANIAGUA
AND
MARIA PILAR BRAVO
From the Department of Pathology, La Paz Hospital and the Department of Morphology, School of Medicine, Autonomous University of Madrid, Madrid, Spain
ABSTRACT
We decribe a boy with testicular lymphangiectasis and Noonan's syndrome. Both testes showed seminiferous tubules with a reduced tubular diameter, containing few spermatogonia. The testicular interstitium exhibited a number of large, dilated lymphatic vessels forming irregular channels among the seminiferous tubules and surrounding them. Since there was no accompanying pathological condition to indicate an obstruction to the lymphatic flow at the level of the spermatic cord or in the regional lymph nodes, the abnormal development of testicular lymphatic vessels suggests a congenital malformation. Congenital lymphangiectasis has been reported as either affecting single organs, such as the lung1 • 2 or, less frequently, as a generalized systemic disease. 2 Previously, we described testicular lymphangiectasis in a boy with bilateral inguinal cryptorchidism that was not associated with another pathological condition. 3 We report another case of testicular lymphangiedasis in a boy with Noonan's syndrome.
because of the presence of dilated lymphatic vessels as well as by the increase of loose connective tissue (fig. 1). On electron microscopy the lymphatic vessels showed a thin endothelium, with a thickness <0.2 µm. in some portions. Microvilli usually were absent at the luminal face, which had an irregular contour. Micropinocytotic vesicles were present in variable proportions. Cytoplasmic microfilaments were numerous. The interstitial surface of endothelial cells projected cytoplasmic processes into the interstitial connective tissue. The endothelial cells were provided with incomplete basal lamina and anchoring filaments from the adjacent connective tissue. Adjacent endothelial cells were connected by interlocking cytoplasmic processes occasionally joined by desmosomes. Frequently, the endothelial cells were separated by gaps measuring up to 5 µ.m. Subjacent to the endothelium were ground substance, collagen fibers and fibroblasts (fig. 2).
CASE REPORT
A showed many of the characteristic stigmas of Noonan's syndrome, such as hypertelorism, inner epicanthal folds, ptosis palpebral, webbing of the neck, low posterior hair line, low set posteriorly rotated ears, high arched palate, shieldshaped chest, cubitus valgus, dental malocclusion, pulmonary stenosis and bilateral cryptorchidism. Testicular biopsy samples were obtained during orchiopexy for evaluation of fertility. For light microscopy samples were fixed in buffered 10 per cent formalin for 48 hours and embedded in paraffin. Sections of 6 µm. thickness were stained with hematoxylin and eosin, periodic Schiff and Masson trichrome, For electron microscopy testicular samples were fixed in the Karnovsky fixative for 4 hours post-fixed in 1 per cent phosphate buffered osmium tetroxide for 2 hours, dehydrated in ethanol and embedded in Epon-812. Sections of l µm. thickness were stained with toluidine blue. The ultrathin sections were doublestained with uranyl acetate and lead citrate, and subsequently were studied in a Philips-300 electron rr""'°'""(•rn-,,, Exploration during oxchiopexy showed both testes and the related structures. The testis and ,.,,...,ri,,nmm were normal. in size. of the on the testis also was normal. The sperrnatic cord did not show any apparent alterations and structures compressing the spermatic cord were not seen. Both testes showed a similar histological pattern. The seminiferous tubules had a reduced mean tubular diameter (35 and contained immature Sertoli cells and scarce spermatogonia (tubular fertility index 15 per cent). The basement membrane was not thickened but the number ofperitubular myofibroblasts was increased. The testicular interstitium exhibited a number of large, dilated lymphatic vessels forming irregular channels among the seminiferous tubules, and surrounding the arteries and veins. Dilated lymphatic vessels also were seen in the tunica vasculosa of the testis. The interstitium was enlarged Accepted for publication November 7, 1983. Supported in part by a grant from the Fondo de Investigaciones Sanitarias de la Seguridad Social, Madrid, Spain. *Requests for reprints: Departmento de Morfologia, Facultad de Medicina, Universidad Aut6noma, C/ Arzobispo Morcillo 4, Madrid34, Spain.
DISCUSSION
The presence of testicular lymphangiectasis in a boy with Noonan's syndrome might be related to the characteristic stigmas of this syndrome, inasmuch as congenital lymphatic vessel dysplasia has been reported previously in male patients with Noonan's syndrome, 4 - 6 and could be related to the hypogonadism with or without cryptorchidism, which usually is present in this syndrome. 7 · 8 Nevertheless, in cases of Noonan's syndrome lymphatic vessel dysplasia affects the pelvis and legs but not the visceral organs, such as the lungs, kidneys and so forth. 4 - 6 On the other we studied testicular biopsies of 8 infants and children with syndrome and found 1 case with testicular lymphangiectasis, Thus, testicular phangiectasis does not seem to be a characteristic of Noonan's The other reported patient with testicular lymphangiectasis had cryptorchidism, as in the present case. 3 However, undescended testes have been studied widely and there have been no references on testicular lymphangiectasis. 9 • 10 Therefore, this association should also be fmtuitous. However, the possibility that the abnormal location and related disturbances of undescended testes might facilitate the development of testicular lymphangiectasis should be considered. In our case generalized lymphangiectasis was not found with testicular lymphangiectasis and there was no accompanying pathological condition to indicate an obstruction to the lymphatic flow at the level of the spermatic cord or in the regional lymph nodes. This allowed us to consider testicular lymphangiectasis as a separate entity. The distribution of lymphatic vessels in the normal human testis differs from that found in most mammals. Whereas lymphatic vessels are a common feature of intertubular spaces
759
760
NISTAL, PANIAGUA AND BRAVO
in ruminants, mice, rats, guinea pigs and other mammals,1 1 lymphatic vessels are restricted to the septula testis in humans.12 Despite their normal ultrastructural features, the dilated lymphatic vessels in testes with lymphangiectasis are distributed extensively, reaching the intertubular spaces. This enlargement of lymphatic vessels may interfere mechanically with tubular development. The mean tubular diameter and the tubular fertility index are reduced markedly, which may be attributed, in part, to the congenital affectation of cryptorchid testes9• 10 but also to the mechanical obstruction caused by the lymphatic vessels, making the prognosis even worse in regard to fertility.
FIG. 1. Numerous, interconnected, dilated lymphatic vessels among seminiferous tubules with reduced tubular diameter and low spermatogonium number. H & E, reduced from Xl25.
REFERENCES 1. Noonan, J. A., Walters, L. R. and Reeves, J. T.: Congenital pulmonary lymphangiectasis. Amer. J. Dis. Child., 120: 314, 1970. 2. France, N. E. and Brown, R. J. K.: Congenital pulmonary lymphangiectasis. Report of 11 examples with special reference to cardiovascular findings. Arch. Dis. Child., 46: 528, 1971. 3. Nistal, M. and Paniagua, R.: Congenital testicular lymphangiectasis. Virch. Arch. f. Path. Anat., 377: 79, 1977. 4. Miller, N. and Motulsky, A. C.: Noonan syndrome in an adult
FIG. 2. A, testicular interstitium shows part of lymphatic vessel with discontinuous endothelium (E) displaying gaps (asterisk) between endothelial cells. L, lumen of lymphatic vessel. C, collagen fibers. F, fibroblast. ST, seminiferous tubule. Reduced from X 5,000. B, 2 adjacent endothelial cells (E) of lymphatic vessel are joined by desmosomes (arrow) and basal cytoplasmic projections (open arrow). Basal lamina (arrowheads) is discontinuous. C, collagen fibers. F, fibroblast. L, lumen of lymphatic vessel. Reduced from Xl5,000.
761 pi·,es,,ffti:r,g ,vith chronic lyrnphedema. Arr.a.er. J. Med, 65: 379, Juncker, P., Hoeffel, J. C., Remy, J. and Etzel, J. C.: Dysplasie du systeme lymphatique clans le syndrome de Noonan. Ann. Rad., 22: 53, 1979. Hoeffel, J.C., Juncke:r, P. and Remy, J.: Lymphatic vessels dysplasia in Noonan's syndrome. Amer. J. Roentgen., 134: 399, 1980. Redman, J. F.: Noonan's syndrome and cryptorchidism. J. UroL, 109: 909, 1973. Okuyama, A., Nishimoto, N., Yoshioka, T., Namiki, M., Itatani, H., Takaha, IVL, Mizutani, S., Aono, T., Matsumoto, K. and Sonoda, T.: Gonadal findings in crypto:rchid boys with Noonan's 1
5. 6. 7.
8.
Scorer, and w,,rrrn,,i'.c,n Histological studies of the undescended testis. In: c.,u,u~:e,uc,~, Deformities of the Testis and Epididymis. New York: Appleton-Century-Crofts, chapt. 5, p. 58, 1971. 10. Nistal, M., Paniagua, R. and Diez-Pardo, J. A.: Histo!ogic classification of the undescended testes. Hum. Path., 11: 666, 1981. 11. Wrobel, K H., Sinowatz, F. and Mademann, R.: Intertubular topography in the bovine testis. Cell Tissue Res., 217: 289, 1981. 12. Holstein, A. F., Orlandini, G. E. and Moller, R.: Distribution and fine structure of the lymphatic system in the human testis. Cell Tissue Res., 200: 15, 1979.
Copyright© 1984 by The VVilliarns & Yf! ilkins Co.
TESTICULAR LYMPHANGIECTASIS IN NOONAN'S SYNDROME MANUEL NISTAL,* RICARDO PANIAGUA
AND
MARIA PILAR BRAVO
From the Department of Pathology, La Paz Hospital and the Department of Morphology, School of Medicine, Autonomous University of Madrid, Madrid, Spain
ABSTRACT
We decribe a boy with testicular lymphangiectasis and Noonan's syndrome. Both testes showed seminiferous tubules with a reduced tubular diameter, containing few spermatogonia. The testicular interstitium exhibited a number of large, dilated lymphatic vessels forming irregular channels among the seminiferous tubules and surrounding them. Since there was no accompanying pathological condition to indicate an obstruction to the lymphatic flow at the level of the spermatic cord or in the regional lymph nodes, the abnormal development of testicular lymphatic vessels suggests a congenital malformation. Congenital lymphangiectasis has been reported as either affecting single organs, such as the lung1 • 2 or, less frequently, as a generalized systemic disease. 2 Previously, we described testicular lymphangiectasis in a boy with bilateral inguinal cryptorchidism that was not associated with another pathological condition. 3 We report another case of testicular lymphangiedasis in a boy with Noonan's syndrome.
because of the presence of dilated lymphatic vessels as well as by the increase of loose connective tissue (fig. 1). On electron microscopy the lymphatic vessels showed a thin endothelium, with a thickness <0.2 µm. in some portions. Microvilli usually were absent at the luminal face, which had an irregular contour. Micropinocytotic vesicles were present in variable proportions. Cytoplasmic microfilaments were numerous. The interstitial surface of endothelial cells projected cytoplasmic processes into the interstitial connective tissue. The endothelial cells were provided with incomplete basal lamina and anchoring filaments from the adjacent connective tissue. Adjacent endothelial cells were connected by interlocking cytoplasmic processes occasionally joined by desmosomes. Frequently, the endothelial cells were separated by gaps measuring up to 5 µ.m. Subjacent to the endothelium were ground substance, collagen fibers and fibroblasts (fig. 2).
CASE REPORT
A showed many of the characteristic stigmas of Noonan's syndrome, such as hypertelorism, inner epicanthal folds, ptosis palpebral, webbing of the neck, low posterior hair line, low set posteriorly rotated ears, high arched palate, shieldshaped chest, cubitus valgus, dental malocclusion, pulmonary stenosis and bilateral cryptorchidism. Testicular biopsy samples were obtained during orchiopexy for evaluation of fertility. For light microscopy samples were fixed in buffered 10 per cent formalin for 48 hours and embedded in paraffin. Sections of 6 µm. thickness were stained with hematoxylin and eosin, periodic Schiff and Masson trichrome, For electron microscopy testicular samples were fixed in the Karnovsky fixative for 4 hours post-fixed in 1 per cent phosphate buffered osmium tetroxide for 2 hours, dehydrated in ethanol and embedded in Epon-812. Sections of l µm. thickness were stained with toluidine blue. The ultrathin sections were doublestained with uranyl acetate and lead citrate, and subsequently were studied in a Philips-300 electron rr""'°'""(•rn-,,, Exploration during oxchiopexy showed both testes and the related structures. The testis and ,.,,...,ri,,nmm were normal. in size. of the on the testis also was normal. The sperrnatic cord did not show any apparent alterations and structures compressing the spermatic cord were not seen. Both testes showed a similar histological pattern. The seminiferous tubules had a reduced mean tubular diameter (35 and contained immature Sertoli cells and scarce spermatogonia (tubular fertility index 15 per cent). The basement membrane was not thickened but the number ofperitubular myofibroblasts was increased. The testicular interstitium exhibited a number of large, dilated lymphatic vessels forming irregular channels among the seminiferous tubules, and surrounding the arteries and veins. Dilated lymphatic vessels also were seen in the tunica vasculosa of the testis. The interstitium was enlarged Accepted for publication November 7, 1983. Supported in part by a grant from the Fondo de Investigaciones Sanitarias de la Seguridad Social, Madrid, Spain. *Requests for reprints: Departmento de Morfologia, Facultad de Medicina, Universidad Aut6noma, C/ Arzobispo Morcillo 4, Madrid34, Spain.
DISCUSSION
The presence of testicular lymphangiectasis in a boy with Noonan's syndrome might be related to the characteristic stigmas of this syndrome, inasmuch as congenital lymphatic vessel dysplasia has been reported previously in male patients with Noonan's syndrome, 4 - 6 and could be related to the hypogonadism with or without cryptorchidism, which usually is present in this syndrome. 7 · 8 Nevertheless, in cases of Noonan's syndrome lymphatic vessel dysplasia affects the pelvis and legs but not the visceral organs, such as the lungs, kidneys and so forth. 4 - 6 On the other we studied testicular biopsies of 8 infants and children with syndrome and found 1 case with testicular lymphangiectasis, Thus, testicular phangiectasis does not seem to be a characteristic of Noonan's The other reported patient with testicular lymphangiectasis had cryptorchidism, as in the present case. 3 However, undescended testes have been studied widely and there have been no references on testicular lymphangiectasis. 9 • 10 Therefore, this association should also be fmtuitous. However, the possibility that the abnormal location and related disturbances of undescended testes might facilitate the development of testicular lymphangiectasis should be considered. In our case generalized lymphangiectasis was not found with testicular lymphangiectasis and there was no accompanying pathological condition to indicate an obstruction to the lymphatic flow at the level of the spermatic cord or in the regional lymph nodes. This allowed us to consider testicular lymphangiectasis as a separate entity. The distribution of lymphatic vessels in the normal human testis differs from that found in most mammals. Whereas lymphatic vessels are a common feature of intertubular spaces
759
760
NISTAL, PANIAGUA AND BRAVO
in ruminants, mice, rats, guinea pigs and other mammals,1 1 lymphatic vessels are restricted to the septula testis in humans.12 Despite their normal ultrastructural features, the dilated lymphatic vessels in testes with lymphangiectasis are distributed extensively, reaching the intertubular spaces. This enlargement of lymphatic vessels may interfere mechanically with tubular development. The mean tubular diameter and the tubular fertility index are reduced markedly, which may be attributed, in part, to the congenital affectation of cryptorchid testes9• 10 but also to the mechanical obstruction caused by the lymphatic vessels, making the prognosis even worse in regard to fertility.
FIG. 1. Numerous, interconnected, dilated lymphatic vessels among seminiferous tubules with reduced tubular diameter and low spermatogonium number. H & E, reduced from Xl25.
REFERENCES 1. Noonan, J. A., Walters, L. R. and Reeves, J. T.: Congenital pulmonary lymphangiectasis. Amer. J. Dis. Child., 120: 314, 1970. 2. France, N. E. and Brown, R. J. K.: Congenital pulmonary lymphangiectasis. Report of 11 examples with special reference to cardiovascular findings. Arch. Dis. Child., 46: 528, 1971. 3. Nistal, M. and Paniagua, R.: Congenital testicular lymphangiectasis. Virch. Arch. f. Path. Anat., 377: 79, 1977. 4. Miller, N. and Motulsky, A. C.: Noonan syndrome in an adult
FIG. 2. A, testicular interstitium shows part of lymphatic vessel with discontinuous endothelium (E) displaying gaps (asterisk) between endothelial cells. L, lumen of lymphatic vessel. C, collagen fibers. F, fibroblast. ST, seminiferous tubule. Reduced from X 5,000. B, 2 adjacent endothelial cells (E) of lymphatic vessel are joined by desmosomes (arrow) and basal cytoplasmic projections (open arrow). Basal lamina (arrowheads) is discontinuous. C, collagen fibers. F, fibroblast. L, lumen of lymphatic vessel. Reduced from Xl5,000.
761 pi·,es,,ffti:r,g ,vith chronic lyrnphedema. Arr.a.er. J. Med, 65: 379, Juncker, P., Hoeffel, J. C., Remy, J. and Etzel, J. C.: Dysplasie du systeme lymphatique clans le syndrome de Noonan. Ann. Rad., 22: 53, 1979. Hoeffel, J.C., Juncke:r, P. and Remy, J.: Lymphatic vessels dysplasia in Noonan's syndrome. Amer. J. Roentgen., 134: 399, 1980. Redman, J. F.: Noonan's syndrome and cryptorchidism. J. UroL, 109: 909, 1973. Okuyama, A., Nishimoto, N., Yoshioka, T., Namiki, M., Itatani, H., Takaha, IVL, Mizutani, S., Aono, T., Matsumoto, K. and Sonoda, T.: Gonadal findings in crypto:rchid boys with Noonan's 1
5. 6. 7.
8.
Scorer, and w,,rrrn,,i'.c,n Histological studies of the undescended testis. In: c.,u,u~:e,uc,~, Deformities of the Testis and Epididymis. New York: Appleton-Century-Crofts, chapt. 5, p. 58, 1971. 10. Nistal, M., Paniagua, R. and Diez-Pardo, J. A.: Histo!ogic classification of the undescended testes. Hum. Path., 11: 666, 1981. 11. Wrobel, K H., Sinowatz, F. and Mademann, R.: Intertubular topography in the bovine testis. Cell Tissue Res., 217: 289, 1981. 12. Holstein, A. F., Orlandini, G. E. and Moller, R.: Distribution and fine structure of the lymphatic system in the human testis. Cell Tissue Res., 200: 15, 1979.