832
0 1992 The Japanese Society of
Pathology
An Autopsy Case of lnvasive Pituitary Adenoma (Prolactinoma) with Rapid Fatal Clinical Course Due to Streptococcal Meningitis
Noboru Onodal, Yutaka Kamezu2, Shigeharu Takagi2, Yukito Shinohara2, and R. Yoshiyuki Osamural
A 44-year-old male suffered epistaxis and headache of sudden onset and was diagnosed as having suppurative meningitis due to streptococci. Four days after the onset of symptoms, he died despite treatment with antibiotics. Destruction and ballooning of the sella turcica was revealed by a plain head X-ray examination during the clinical course. At autopsy, a massive tumorous lesion extended from the ballooned sella turcica to the paranasal cavities, nasopharynx and facial bone, and this had resulted in suppurative meningitis. The tumor was also disseminated to the basal skull. The tumor cells possessed prominent nuclear atypia and were immunohistochemically positive for prolactin. This was diagnosed as a case of pituitary adenoma with markedly invasive pathological findings and a rapid and fatal clinical course. Acta Pathol Jpn
42 : 832-836,1992. Key words : Pituitary carcinoma,
Pituitary adenoma, Prolactin, Meningitis, lmmunohistochemistry
Primary malignant pituitary tumors are rare. The distinction between invasive pituitary adenoma and pituitary carcinoma is sometimes difficult if the patient has no extracranial metastases. In this report, we describe a case of pituitary tumor with intracranial dissemination and marked extra-sellar invasion, which showed a rapid and fatal clinical course due to streptococcal meningitis. The literature on similar cases is also reviewed.
Received January 29, 1992. Accepted for publication June 1, 1992. Departments of 'Pathology and *Internal Medicine V, Tokai University School of Medicine, Isehara. Mailing address : Noboru Onoda M.D., Department of Pathology, Tokai University School of Medicine, Boseidai, Isehara, Kanagawa 259-1 1, Japan.
CASEREPORT A 44-year-old male video cameraman, who had been working without difficulty, developed sudden epistaxis and headache. Two days later, high fever appeared, followed by clouding of consciousness. He was then referred to the emergency department of Tokai University Hospital. Physical examination revealed signs of meningeal irritation and intracranial hypertension. Numerous neutrophils were present in the cerebrospinal fluid, and group A streptococci were cultured from it. He was therefore diagnosed as having intracranial hypertension due to acute streptococcal meningitis. However, four days after onset, he died of cerebral herniation despite treatment with antibiotics and mannitol. Destruction and ballooning of the sella turcica were evident at the time of admission (Fig. I), but no histological, hormonal or immunological studies were performed because of the rapid clinical course.
AUTOPSY FINDINGS Autopsy was performed 17 h after death. The patient was 1 6 7 c m in height and weighed 81 kg. There were no apparent signs of Cushing's syndrome or gynecomastia. The edematous brain weighed 1,100 g and showed bilateral tonsillar herniation. Diffuse suppurative inflammation was seen in the subarachnoidal space of the cerebrum. Group A streptococci were also detected in postmortem cultures of cerebrospinal fluid. A 3 x 3 x 2 - c m firm, gray tumor was seen in the ballooned hypophyseal fossa. The tumor had grown downward, destroying the thin-walled fossa, and filling the maxillary sinuses and upper pharynx (Figs. 2, 3a). Small implanted tumor nodules were also seen on the basal skull. The extracranial organs were free of distant
Acta Pathologica Japonica 42 (11): 1992
833
Figure 1. Marked ballooning of the sella turcica associated with destruction of the floor is seen in a plain X-ray film (a). A round suprasellar tumor is revealed by computed tomography (b, arrows).
Intra-(thin arrows) and extrasellar solid tumors, including dissemination to the skull base, are evident (thick arrows).
Figure 2. Sagittal section of the pituitary tumor.
metastasis. Histologically, the main tumor was solid, vascular and composed of neoplastic cells possessing hyperchromatic round nuclei and eosinophilic cytoplasm (Fig. 3b). Pleomorphic and multinucleated cells were noted (Fig. 3c), and mitotic figures were occasionally observed. Most of the tumor cells gave an immunohistochemically positive reaction for prolactin by the indirect immunoperoxidase method performed on formalin-fixed, paraffinembedded material (Fig. 4). However, NSE, chromogranin A, keratin and other anterior pituitary hormones were negative in the tumor cells. The compressed and remaining non-neoplastic anterior pituitary cells were
seen at the tumor periphery. Electron microscopy revealed that the polygonal nuclei of the tumor cells contained frequent large nucleoli, while the cytoplasm possessed a large number of mitochondria. Occasional scattered secretory granules about 100 nm in diameter were seen in the cytoplasm (Fig. 5). Misplaced exostosis, frequently seen in prolactinoma, was obscure because of poor fixation influenced by the long postmortem time and use of a respirator. Similar tumor cells were observed in the tumor nodules on the basal skull. The meninges showed diffuse infiltration of numerous neutrophils. The cerebrum, cerebellum and other parts of the central nervous system showed diffuse
834
lnvasive Prolactinoma (Onoda et a / . )
Figure 3. a : Low-power view of the pituitary tumor showing a solid growth pattern with downward extrasellar growth and destruction of the floor (HE). b : The tumor is solid and vascular (HE). c : High power view of the tumor cells shows prominent nuclear pleomorphism and multinucleation with occasional mitotic figures (HE).
835
Acta Pathologica Japonica 42 (11) : 1992
ischemic change due to use of the respirator.
DISCUSSION
Figure 4. lmmunohistochemically, most of the tumor cells show granular staining for prolactin in the cytoplasm.
Pituitary gland tumors are classified as malignant (or invasive) adenoma or pituitary carcinoma. The first category is considered to show cellular atypia and invasive growth without distant metastasis, and it is generally agreed that the second category shows distant metastasis independent of the degree of cellular atypia (1). It is widely accepted that in pituitary tumors there is no correlation between cellular atypia and biological behavior such as invasion and metastasis. There have been some fatal cases of pituitary tumors with local invasion (2-7). and therefore local and destructive invasion of adjacent tissue may be one of the parameters of clinica I malignancy. To our knowledge, on the basis of endocrinological characteristics, five cases of prolactin-secreting or prolactin-containing malignant tumors have been reported; one case was locally invasive(l), one presented
Figure 5. Electron microscopically, tumor cells, affected by previous use of a respirator and postmortem change, contain occasional scattered small secretory granules about 100 nm in diameter (arrows) in the cytoplasm.
836
lnvasive Prolactinoma (Onoda et a / . )
extracranial distant metastasis (8) and others showed brain and vertebral metastases (9-1 1). In the present case, the serum prolactin level was not measured because of the fact that pituitary tumor was not suspected initially, and the rapid clinical course. The light microscopic findings were quite similar t o the previously reported case (l), i.e., marked vascularization and hypercellularity with prominent nuclear pleomorphism. Ultrastructurally, scattered secretory granules were compatible with sparsely granulated pituitary adenoma, although the staining was not the typical Golgi pattern (11, 12). There were no evident findings of malignancy except for the large nucleoli. A review of previous literature revealed no particular cytologic distinction between non-invasive and invasive adenoma (13). According t o previous reports, the prognosis of invasive pituitary adenoma was variable with survival times ranging from about 4 days t o 11 years (2, 4, 7). A case quite similar to ours was reported by Martins ef a/. ( 2 ) : a 51-year-old healthy but obese m a n had been asymptomatic until 4 days prior t o death, when he experienced severe headache. The immediate cause of death was marked hemorrhage in the tumor. Marked downward invasive growth in contrast t o slight upward growth is a common feature among these rapidly fatal tumors, and it seems that such invasive pituitary tumors with prominent downward growth produce no particular symptoms. In our present case, infection probably f r o m the site of invasion and causing suppurative meningitis was a significant finding. It may be reasonable t o propose that the infection originated f r o m the site of tumor invasion in the sinus o r upper pharynx. To our knowledge, there has been no reported case of meningitis associated with invasive pituitary tumor resulting in a rapid clinical course. The data suggest that infection and hemorrhage should be considered as poor prognostic factors in cases of invasive pituitary adenoma.
REFERENCES 1. Kovacs K and Horvath E. Tumor of Pituitary Gland.
AFIP, Washington, D.C., 1986: 217-224. 2. Martins AN, Hayes GJ, and Kampe LG. lnvasive pituitary adenomas. J Neurosurg 22 : 268-276, 1965. 3. Shimizu T, Fukushima N, Ebihara Y, and Kameya T. An autopsy case of pituitary carcinoma. Byori to Rinsho 3: 441-447, 1985 (in Japanese with English abstract). 4. Negishi K, Suzuki T, Masuda Y, et a/. Two autopsy cases of primary pituitary carcinoma. No to Shinkei 40: 491-496, 1988 (in Japanese with English abstract). 5. Wise EL and Brown HA. Pituitary adenomas: Carcinomas and craniopharyngiomas. Surg Gynecol Obstet 101 : 185-193, 1955. 6. Nishikawa A, Kawai T, Fuji M, et a/. Two autopsy cases of malignant pituitary adenoma with special reference to ultrastructural and cytochemical studies. No to Shinkei 35: 175-183, 1983 (in Japanese with English abstract). 7. Newton TH, Burhenne HJ, and Palubinskas AJ. Primary carcinoma of the pituitary. Am J Roentgen01 87: 110-120, 1962. 8. Scheithauer BW, Randall RV, Laws ER Jr, et a / . Prolactin cell carcinoma of the pituitary : Clinicopathologic, immunohistochemical and ultrastructural study of a case with cranial and extracranial metastasis. Cancer 55 : 598-604, 1985. 9. Cohen H, Diengdoh JV, Thomas DGT, and Himsworth RL. An intracranial metastasis from PRL secreting pituitary tumor. Clin Endocrinol 18 : 259-264, 1983. 10. Martin NA, Hales M, and Wilson CB. Cerebellar metas. tasis from a prolactinoma during treatment with bromocriptine. J Neurosurg 55 : 615-61 9, 1981. 11. Hoi Sang V and Johnson C. Metastatic prolactin-secreting pituitary adenoma. Hum Pathol 15 : 94-96, 1984. 12. Kameya T, Tsumuraya M, Adachi I, et a/. Ultrastructure, immunohistochemistry and hormone release of pituitary adenoma in relation to prolactin production. Virchows Arch [Pathoi Anat] 387: 31-46, 1980. 13. Kameya T. lmmunocytochemistry and electron microscopy of pituitary adenomas. Byori to Rinsho 8 : 871-878, 1990 (in Japanese). 14. Landort AM. Ultrastructure of human sella tumors: Correlations of clinical findings and morphology. Malignant pituitary tumors. Acta Neurochir (Wien) [suppl] 22: 94-103, 1973.
0 1992 The Japanese Society of
Pathology
An Autopsy Case of lnvasive Pituitary Adenoma (Prolactinoma) with Rapid Fatal Clinical Course Due to Streptococcal Meningitis
Noboru Onodal, Yutaka Kamezu2, Shigeharu Takagi2, Yukito Shinohara2, and R. Yoshiyuki Osamural
A 44-year-old male suffered epistaxis and headache of sudden onset and was diagnosed as having suppurative meningitis due to streptococci. Four days after the onset of symptoms, he died despite treatment with antibiotics. Destruction and ballooning of the sella turcica was revealed by a plain head X-ray examination during the clinical course. At autopsy, a massive tumorous lesion extended from the ballooned sella turcica to the paranasal cavities, nasopharynx and facial bone, and this had resulted in suppurative meningitis. The tumor was also disseminated to the basal skull. The tumor cells possessed prominent nuclear atypia and were immunohistochemically positive for prolactin. This was diagnosed as a case of pituitary adenoma with markedly invasive pathological findings and a rapid and fatal clinical course. Acta Pathol Jpn
42 : 832-836,1992. Key words : Pituitary carcinoma,
Pituitary adenoma, Prolactin, Meningitis, lmmunohistochemistry
Primary malignant pituitary tumors are rare. The distinction between invasive pituitary adenoma and pituitary carcinoma is sometimes difficult if the patient has no extracranial metastases. In this report, we describe a case of pituitary tumor with intracranial dissemination and marked extra-sellar invasion, which showed a rapid and fatal clinical course due to streptococcal meningitis. The literature on similar cases is also reviewed.
Received January 29, 1992. Accepted for publication June 1, 1992. Departments of 'Pathology and *Internal Medicine V, Tokai University School of Medicine, Isehara. Mailing address : Noboru Onoda M.D., Department of Pathology, Tokai University School of Medicine, Boseidai, Isehara, Kanagawa 259-1 1, Japan.
CASEREPORT A 44-year-old male video cameraman, who had been working without difficulty, developed sudden epistaxis and headache. Two days later, high fever appeared, followed by clouding of consciousness. He was then referred to the emergency department of Tokai University Hospital. Physical examination revealed signs of meningeal irritation and intracranial hypertension. Numerous neutrophils were present in the cerebrospinal fluid, and group A streptococci were cultured from it. He was therefore diagnosed as having intracranial hypertension due to acute streptococcal meningitis. However, four days after onset, he died of cerebral herniation despite treatment with antibiotics and mannitol. Destruction and ballooning of the sella turcica were evident at the time of admission (Fig. I), but no histological, hormonal or immunological studies were performed because of the rapid clinical course.
AUTOPSY FINDINGS Autopsy was performed 17 h after death. The patient was 1 6 7 c m in height and weighed 81 kg. There were no apparent signs of Cushing's syndrome or gynecomastia. The edematous brain weighed 1,100 g and showed bilateral tonsillar herniation. Diffuse suppurative inflammation was seen in the subarachnoidal space of the cerebrum. Group A streptococci were also detected in postmortem cultures of cerebrospinal fluid. A 3 x 3 x 2 - c m firm, gray tumor was seen in the ballooned hypophyseal fossa. The tumor had grown downward, destroying the thin-walled fossa, and filling the maxillary sinuses and upper pharynx (Figs. 2, 3a). Small implanted tumor nodules were also seen on the basal skull. The extracranial organs were free of distant
Acta Pathologica Japonica 42 (11): 1992
833
Figure 1. Marked ballooning of the sella turcica associated with destruction of the floor is seen in a plain X-ray film (a). A round suprasellar tumor is revealed by computed tomography (b, arrows).
Intra-(thin arrows) and extrasellar solid tumors, including dissemination to the skull base, are evident (thick arrows).
Figure 2. Sagittal section of the pituitary tumor.
metastasis. Histologically, the main tumor was solid, vascular and composed of neoplastic cells possessing hyperchromatic round nuclei and eosinophilic cytoplasm (Fig. 3b). Pleomorphic and multinucleated cells were noted (Fig. 3c), and mitotic figures were occasionally observed. Most of the tumor cells gave an immunohistochemically positive reaction for prolactin by the indirect immunoperoxidase method performed on formalin-fixed, paraffinembedded material (Fig. 4). However, NSE, chromogranin A, keratin and other anterior pituitary hormones were negative in the tumor cells. The compressed and remaining non-neoplastic anterior pituitary cells were
seen at the tumor periphery. Electron microscopy revealed that the polygonal nuclei of the tumor cells contained frequent large nucleoli, while the cytoplasm possessed a large number of mitochondria. Occasional scattered secretory granules about 100 nm in diameter were seen in the cytoplasm (Fig. 5). Misplaced exostosis, frequently seen in prolactinoma, was obscure because of poor fixation influenced by the long postmortem time and use of a respirator. Similar tumor cells were observed in the tumor nodules on the basal skull. The meninges showed diffuse infiltration of numerous neutrophils. The cerebrum, cerebellum and other parts of the central nervous system showed diffuse
834
lnvasive Prolactinoma (Onoda et a / . )
Figure 3. a : Low-power view of the pituitary tumor showing a solid growth pattern with downward extrasellar growth and destruction of the floor (HE). b : The tumor is solid and vascular (HE). c : High power view of the tumor cells shows prominent nuclear pleomorphism and multinucleation with occasional mitotic figures (HE).
835
Acta Pathologica Japonica 42 (11) : 1992
ischemic change due to use of the respirator.
DISCUSSION
Figure 4. lmmunohistochemically, most of the tumor cells show granular staining for prolactin in the cytoplasm.
Pituitary gland tumors are classified as malignant (or invasive) adenoma or pituitary carcinoma. The first category is considered to show cellular atypia and invasive growth without distant metastasis, and it is generally agreed that the second category shows distant metastasis independent of the degree of cellular atypia (1). It is widely accepted that in pituitary tumors there is no correlation between cellular atypia and biological behavior such as invasion and metastasis. There have been some fatal cases of pituitary tumors with local invasion (2-7). and therefore local and destructive invasion of adjacent tissue may be one of the parameters of clinica I malignancy. To our knowledge, on the basis of endocrinological characteristics, five cases of prolactin-secreting or prolactin-containing malignant tumors have been reported; one case was locally invasive(l), one presented
Figure 5. Electron microscopically, tumor cells, affected by previous use of a respirator and postmortem change, contain occasional scattered small secretory granules about 100 nm in diameter (arrows) in the cytoplasm.
836
lnvasive Prolactinoma (Onoda et a / . )
extracranial distant metastasis (8) and others showed brain and vertebral metastases (9-1 1). In the present case, the serum prolactin level was not measured because of the fact that pituitary tumor was not suspected initially, and the rapid clinical course. The light microscopic findings were quite similar t o the previously reported case (l), i.e., marked vascularization and hypercellularity with prominent nuclear pleomorphism. Ultrastructurally, scattered secretory granules were compatible with sparsely granulated pituitary adenoma, although the staining was not the typical Golgi pattern (11, 12). There were no evident findings of malignancy except for the large nucleoli. A review of previous literature revealed no particular cytologic distinction between non-invasive and invasive adenoma (13). According t o previous reports, the prognosis of invasive pituitary adenoma was variable with survival times ranging from about 4 days t o 11 years (2, 4, 7). A case quite similar to ours was reported by Martins ef a/. ( 2 ) : a 51-year-old healthy but obese m a n had been asymptomatic until 4 days prior t o death, when he experienced severe headache. The immediate cause of death was marked hemorrhage in the tumor. Marked downward invasive growth in contrast t o slight upward growth is a common feature among these rapidly fatal tumors, and it seems that such invasive pituitary tumors with prominent downward growth produce no particular symptoms. In our present case, infection probably f r o m the site of invasion and causing suppurative meningitis was a significant finding. It may be reasonable t o propose that the infection originated f r o m the site of tumor invasion in the sinus o r upper pharynx. To our knowledge, there has been no reported case of meningitis associated with invasive pituitary tumor resulting in a rapid clinical course. The data suggest that infection and hemorrhage should be considered as poor prognostic factors in cases of invasive pituitary adenoma.
REFERENCES 1. Kovacs K and Horvath E. Tumor of Pituitary Gland.
AFIP, Washington, D.C., 1986: 217-224. 2. Martins AN, Hayes GJ, and Kampe LG. lnvasive pituitary adenomas. J Neurosurg 22 : 268-276, 1965. 3. Shimizu T, Fukushima N, Ebihara Y, and Kameya T. An autopsy case of pituitary carcinoma. Byori to Rinsho 3: 441-447, 1985 (in Japanese with English abstract). 4. Negishi K, Suzuki T, Masuda Y, et a/. Two autopsy cases of primary pituitary carcinoma. No to Shinkei 40: 491-496, 1988 (in Japanese with English abstract). 5. Wise EL and Brown HA. Pituitary adenomas: Carcinomas and craniopharyngiomas. Surg Gynecol Obstet 101 : 185-193, 1955. 6. Nishikawa A, Kawai T, Fuji M, et a/. Two autopsy cases of malignant pituitary adenoma with special reference to ultrastructural and cytochemical studies. No to Shinkei 35: 175-183, 1983 (in Japanese with English abstract). 7. Newton TH, Burhenne HJ, and Palubinskas AJ. Primary carcinoma of the pituitary. Am J Roentgen01 87: 110-120, 1962. 8. Scheithauer BW, Randall RV, Laws ER Jr, et a / . Prolactin cell carcinoma of the pituitary : Clinicopathologic, immunohistochemical and ultrastructural study of a case with cranial and extracranial metastasis. Cancer 55 : 598-604, 1985. 9. Cohen H, Diengdoh JV, Thomas DGT, and Himsworth RL. An intracranial metastasis from PRL secreting pituitary tumor. Clin Endocrinol 18 : 259-264, 1983. 10. Martin NA, Hales M, and Wilson CB. Cerebellar metas. tasis from a prolactinoma during treatment with bromocriptine. J Neurosurg 55 : 615-61 9, 1981. 11. Hoi Sang V and Johnson C. Metastatic prolactin-secreting pituitary adenoma. Hum Pathol 15 : 94-96, 1984. 12. Kameya T, Tsumuraya M, Adachi I, et a/. Ultrastructure, immunohistochemistry and hormone release of pituitary adenoma in relation to prolactin production. Virchows Arch [Pathoi Anat] 387: 31-46, 1980. 13. Kameya T. lmmunocytochemistry and electron microscopy of pituitary adenomas. Byori to Rinsho 8 : 871-878, 1990 (in Japanese). 14. Landort AM. Ultrastructure of human sella tumors: Correlations of clinical findings and morphology. Malignant pituitary tumors. Acta Neurochir (Wien) [suppl] 22: 94-103, 1973.
