A c t a P a t h . Jap. 29(4): 597-606, 1979
MALIGNANT NEUROFIBROMA WITH GLANDULAR DIFFERENTIATION (GLANDULAR SCHWANNOMA)
Osaniu TAKAHARA, Iwao NAKAYAMA, Shigeo YOKOYAMA*, Akira MORIUCHI*,Hiroo MuTA**, and Yuzo UCHIDA** Department of Pathology, Medical College of Oita, Oita and Department of Central Diagnostic Laboratory* and Surgery**, Nagasaki University School of Medicine, Nagasaki (Received on Oct. 12, 1978)
A case of malignant shwannoma is reported with unusual elements in an 89-year-old female. A large mass was located in the subcutaneous tissue of the right lateral chest wall and measured 5 cm in the greatest diameter. Histologically the tumor was composed of neurofibroma and malignant schwannoma with glandular differentiation. Neurofibroma characterized by numerous hyaline neural nodules was located in the peripheral portion of the tumor, whereas malignant schwannoma occupied a large part of the central portion of the tumor. The glandular elements observed in some areas of malignant schwannoma consisted of cuboidal and columnar shaped cells and were arranged in tubular or tubulo-medullary fashion in which rosettes o r pseudorosettes were found. Mucicarminophilic material was observed, both in the cytoplasm and in the lumen. Seven reported cases of peripheral nerve tumor with glandular differentiation are reviewed briefly. ACTA PATH. JAP. 29: 597-606, 1979.
Introduction
It is well known that malignant schwannoma occurs more frequently in patients with von Recklinghausen's disease than benign schwannomaa. The neoplastic cells originating from schwann cells have the potential for differentiation into several tissues such as o s t e ~ i d ~ ~chondroid2117, s ~ ~ ~ ~ ' , striated muscle3~e~10~15J6, and glands lined by several types of epithelial cells1,415~*~17 as a component of the tumor. However, cases of malignant schwannomas with foci of rhabdomyosarcoma (malignant Triton tumor) or glandular elements (glandular schwannoma) are extremely rare. GARRE' was the first to describe a case of malignant neurofibroma containing numerous glands lined by cuboidal cells, in a 31-year-old female in 1892, and used the term of glandular schwannoma. Subsequently 8 cases of similar tumor including the present case have appeared in the world literature. These glandular schwannomas definitely differ from peripheral tumor of primitive neuroectoderm6, because 6 of the 8 reported cases represented pre-existing neurofibroma and the majority of the neoplastic ~
~
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%rlr, e F4 sg, *ffl @A, l4El 13 Mailing address: Dr. Osamu TAKAHARA, Department of Pathology, Medical College of Oita. 1506 Ooaza Toi, Hazama-cho, Oita-gun, Oita. 597
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tissue was composed of spindle shaped cells, in which the glandular elements were embedded here and there throughout the tumor. This paper describes a case of malignant schwannoma in an 89-year-old female, which is considered to have arisen by transformation from benign neurofibroma, with differentiation to glandular elements, and in addition the literature is reviewed. Case Report
An 89-year-old female was admitted to the hospital on May 17, 1973 because of a tumor in her right lateral chest wall. She noticed a small tumor in her right lateral chest wall a t 13 years of age, however, there was no medical treatment because there was neither clinical signs nor evidence of progressive growth of the tumor. During the past two years the tumor grew progressively and attained a large size, measuring 5 cm in diameter. On physical examination, there were numerous abnormal pigmentations on the skin of the back. The tumor was located in the subcutaneous tissue of the right lateral chest wall and showed no adhesion to the underlying tissue and skin. X-ray examination of the chest showed no metastatic lesion. Laboratory examination revealed a hemoglobin of 13.0 gldl, hematocrit of 40.5y0, red blood cell count of 4,200,000/mms and white blood cell count of 6,900/mms. Serum proteins were 6.3 g/dl with albumin of 52%, a,-globulin of 6%. a,-globulin of 14%, fl-globulin of 13% and y-globulin of 15%. Serum chemistry revealed total bilirubin of 0.23 mg%, serum-GOT of 33 S.F.E., serum-GPT of 20 S.F.E., alkaline phosphatase of 12.9 Bod. U., serum cholesterol of 208 mg%, mucoprotein of 10.3 mg% and LDH of 355U. Urea N was 20.4 mg%. Electrolytes were Na of 144 mEq/l, K of 4.1 mEq/l, and C1 of 105 mEq/l. At operation a large tumor measuring 5 cm in diameter was extirpated with no difficulty from the right lateral chest wall. Primary healing progressed with no sign of recurrence during her hospitalization. She was readmitted to the hospital on March 27, 1974, because of recurrence of the tumor. Four months after the first operation she had a small recurrent tumor just beneath the incisional scar of the first operation. Thereafter the tumor grew very rapidly and attained a large size measuring 5 . 0 ~ 4.5 cm. On physical examination the tumor was located in the subcutaneous tissue just beneath the previous incisional scar and showed partial adhesion to skin but it was easily movable from the underlying soft tissue. The skin covering the tumor was reddish in color with dilated capillaries. The superficial lymph nodes were not palpable. X-ray examination of the chest on April 1, 1974 revealed a well circumscribed lesion indicative of metastatic tumor in the right middle lobe. During 4 months of hospitalization the tumor in the right middle lobe increased in size and measured 5 5 ~ 45 mm on the chest X-ray film. On April 12, 1974 the recurrent tumor of the right lateral chest wall was amputated with no difficulty. The patient died a t home on August 12, 1974. An autopsy wag not performed.
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Macroscopic and Microscopic Observation The tumor removed from the right lateral chest wall a t the first operation was covered by seemingly normal skin and located in the subcutaneous tissue as a well circumscribed spherical mass measuring 5 cm in the greatest diameter. It was not encapsulated by connective tissue and showed no evidence of direct connection with peripheral nerve. Multiple-cut-surfaces of the tumor showed homogeneous or nodular lesions of gray-white tissue. Peripheral portion of the tumor was more glistening than the central portion which appeared to exhibit an expansive growth toward the periphery and consisted of white fibrous tissue. There was an irregular shaped lesion with fragile light yellow white tissue located in the upper portion of the tumor (Fig. 1). It was well demarcated from the surrounding tumor tissue.
Fig. 1. Gross appearance of the primary tumor resected from the left lateral chest wall a t the first operation. The tumor shows a well-circumscribed spherical mass measuring 5 cm in the greatest diameter. On cut-section i t consists of white-gray tissue except for a portion (arrow) which is fragile light yellow white tissue. Fig. 2. Gross appearance of the recurrent tumor. It is a wellcircumscribed mass measuring 5.0 x 4.5 cm located just beneath the skin and consists of white-gray tissue.
The recurrent tumor adhered partly to the overlying skin and was a well circumscribed spherical mass located in the subcutaneous tissue and measured 5.0 x 4.5 cm. On multiple cut sections the gross appearance of the tumor was essentially similar to that of the central portion of primary tumor except for a nodular lesion consisting of fragile tissue (Fig. 2). For histological examination, the tumor removed from the right lateral chest wall at the first and second operation was fixed in 10% neutral formalin. Numerous tissues
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Fig. 3. Photograph shows a portion of neurofibroma composed of numerous hyaline neural nodules resembling tactile corpusc~es. X 300. Fig. 4. A portion of malignant schwannoma. The tumor is composed of relatively loose streaming fascicles of slender spindle cells. X 1100. Figs. 5-6. High cellular area of malignant schwannoma. Spindle-shaped cells with hyperchromatic nucleus arranged in interlacing fascicles. Some areas composed of high cellularity appear to be lobulated by neoplastic tissue with lower cellularity. Several nuclear mitoses are seen. Fig. 5: x 900, Fig. 6 ; x 300.
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were taken from both tumors and embedded in paraffin. Sections from paraffin embedded tissues were stained with hematoxylin-eosin (H-E),Van Gieson, Masson’s trichrome, periodic acid Schiff (PAS), Snook’s silver, alcian blue, mucicarmine and phosphotungstic acid hematoxylin (PTAH). By microscopic observation the primary tumor was composed of several different tissues. The skin covering the tumor showed an essentially normal structure of the epidermis. However, the deeper dermis contained a tumor consisting of slender or wavy loose spindle cells in which there were numerous hyaline neural nodules resembling tactile corpuscles (Fig. 3) and occasionally sweat glands. The histological features corresponded to neurofibroma. Identical structures of neurofibroma were also observed in the peripheral portion of the primary tumor. This neurofibromatous area exhibited direct continuity with the malignant tumor which showed evidence of high cellularity , nuclear atypism and abnormal mitoses. The malignant neoplasm differed somewhat in its cellularity from one field to another. The tumor tissue with low cellularity was composed of loose streaming fascicles of slender spindle cells (Fig. 4) and mainly located in the peripheral portion of the tumor where benign and malignant elements of the tumor were intermingled, whereas the central portion of the tumor showed high cellularity and comprised interlacing fascicles of spindle cells with indistinct cell boundaries (Fig. 5 ) . In some areas the tumor tissue with high cellularity appeared to be separated by neoplastic tissue with low cellularity (Fig. 6). The nucleus of these spindle shaped cells was hyperchromatic and showed numerous mitoses (Fig. 5). There was no evidence of nuclear palisading in the malignant neoplastic tissue. Although several hyaline neural nodules were observed in the intermingled area of benign and malignant neoplasm, they were not found in the central portion of the malignant tumor. The malignant neoplastic tissue contained several large cells arranged either singly or in groups. They were plump spindle or round in shape and had a large nucleus with a prominent nucleolus and abundant acidophilic cytoplasm showing negative reaction for PTAH and Nissle’s stains (Fig. 7). As an occasional finding, metaplastic osteoid tissue was observed in the malignant tumor. These histological characteristics of the malignant tumor coincide well with malignant schwannoma and suggest a malignant transformation from pre-existing neurofihroma. Several glandular structures were embedded in some areas of the malignant schwannoma. Most of the glandular structures were arranged in a medullary fashion which was separated by fibrocapillary stroma. There appeared rosettes and pseudorosettes in this area, although typical blepharoplasts were not clear (Figs. 8-9). Some glands were tubular and contained intraluminal mucicarminophilic material (Fig. 10). Large cystic lesions were filled with PAS positive, colloid-like material and were covered by single or psuedostratified columnar cells having a continuous basement membrane a t the basal surface. These glandular structures appeared to be composed of identical cells which were non-ciliated cuboidal or high columnar. The nuclei in
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many of the glandular cells were round or oval, and hyperchromatic. A few mitotic figures were seen. The cytoplasm of the glanduar cells was often clear or acidophilic with positive reaction after mucicarmine and PAS staining. The histological picture of the recurrent tumor was identical to that of malignant schwannoma observed in the central portion of the primary tumor, although it was devoid of glandular elements. Discussion
It is well known that neurofibroma has some potential for malignant transformation, which is referred to as malignant schwannoma. Malignant schwannoma arises more frequently from neurofibromatosis than from benign schwannomas. Therefore pre-existing neurofibroma or direct connection of the tumor with the peripheral nerve is particularly important for pathological diagnosis of malignant s~hwannoma'~~'~. The present 89-year-old patient noticed a small tumor in her right lateral chest wall a t 13 years of age. There were neither clinical signs nor any evidence of progressive growth for 76 years. Seventy-six years after the onset of illness, the tumor grew progressively, attaining 5 cm in the largest diameter and showed recurrence and pulmonary metastasis 4 months after the first operation. On histological examination the peripheral portion of the primary tumor exhibited typical neurofibroma containing numerous hyaline neural nodules, whereas the central portion showed several patterns composed mainly of spindle-shaped cells with evidence of malignancy such as high cellularity, cellular atypism and atypical nuclear mitoses. This malignant tumor corresponds well to malignant schwannoma with evidence of pre-existing neurofibroma and histological shift from benign to malignant structures. It is also well known that schwannoma and neurofibroma can demonstrate metaplastic changes of neoplastic cells t o several mesenchymal elements. The most frequently encountered metaplastic elements in the peripheral nerve tumor are chondroid and osteoid tissue. In addition to these benign elements there have appeared several reports of schwannoma exhibiting foci of r h a b d o m y o s a r c ~ m a ~ chondrosar~~~~~, coma2, and liposarcoma2. These unusual elements observed in the tumor arising from peripheral nerve are the result of a metaplastic potential of the Schwann cells which are derived from neuroectodermal neural crest and can differentiate to mesoectoderm during embryonic differentiation'P. Therefore it is possible that peripheral nerve tumors ~.
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Fig. 7. Photograph shows a portion of malignant schwannoma containing plump spindle or round cells with acidophilic cytoplasm and a large nucleus with a prominent nucleolus. They are negative with PTAH and Nissl's stains. x 1600. Figs. 8-9. Glandular elements in malignant schwannoma. Cuboidal shaped cells having a hyperchromatic round nucleus and a scanty cytoplasm arranged in a medullo-tubular fashion separated by fibrocapillary stroma. There are rosettes and pseudorosettes in the glandular structure. Some mitoses are seen in the glandular cells (arrow). Fig. 8: x 300, Fig. 9: x 700. Fig. 10. In some areas the glandular elements show a tubular arrangement composed of high columnar-shaped cells with intraluminal and intracytoplasmic muricarminophilic material. x 300.
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occasionally contain foci of rhabdomyosarcoma, chondrosarcoma and liposarcoma. Furthermore, unusual cases of malignant schwannonia show differentiation along the epithelial line. Eight cases of such tumors including the present one have appeared in the literature, since GARRE5 first described a case using the term of glandular schwannoma. There appears to be some sex predilection in the patients with glandular schwannoma; 6 patients were female and 2 male. Five of the 8 cases had clinicopathological evidence of von Recklinghausen's disease. The majority of the patients noticed the lesion between 15 and 35 years of age, although the youngest patient was an 8-year-old girl and the oldest an 89-year-old female. Anatomical distribution of the tumor included the neck4, arm8, chest wall, peritoneum17and retroperitone~ml~. The size of these tumors differed considerably from one case to another and ranged from 1 cm in diameter to 15 cni. Five of the 8 patients died with clinical recurrence or metastasis t o the lung within several months to ten years, although there were three patients who were alive more than 4 years after the 0 p e r a t i o n ~ 1 ~ 1 ~Histological 1~~. feature of glandular schwannoma resembles t o some extent that of peripheral tumor of primitive neuroectoderm. However, they are quite different one to the other, because 7 cases of glandular schwannoma showed histological features of malignant neurofibroma51~1~1l~ as the predominant element of the tumor and in one case glandular structures were embedded in atypical pigmented nevoid schwannoma17. Furthermore it is necessary to differentiate glandular schwannoma from synovial sarcoma with the presence of biphasic elements. In the present case the tumor showed no progressive growth for 76 years and on histological examination exhibited a feature of typical nwrofibroma in the peripheral portion of the tumor in addition to biphasic elements. These facts coincide with neither clinical nor histological behavior of synovial sarcoma. Histological features of the glandular component in the reported cases developing within malignant schwannoma differ somewhat from one case to another. In the present case glandular structures were characterized by rosette or pseudorosette formation as well as by a tubular and cystic arrangement with intraluminal mucicarminophilic material. These glands were composed of nonciliated cuboidal to high columnar cells having nuclear pleomorphism with mitotic figures. In the review described by WOOD RIFT^', the glands were most commonly lined by nonciliated cuboidal and/or pseudostratified columnar epithelial cells with clear cytoplasm and nuclear mitoses. Each of the tumor containing clear cells showed mucin in glandular lumina and two glands contained well formed goblet cells which were not observed in the present case. In other reported cases the feature of the glandular element resembled that of medulloepitheliomas and ependymomall. There are sweral possible hypotheses to explain the appearance of glandular elements in the peripheral nerve tumor. GAR RE^ considered that glandular elements represented a developmental carry-over of the central canal of the spinal cord into peripheral nerve. FORAKER4 thought that the glands were heterotopic ependymal tissue. H O R K I Nreferred ~ to these tumor as peripheral medulloepithelioma.
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Using several lines of evidence, WOODRUFT" has reported that epithelial elements found in glandular schwannoma arise from Schwann cells or mesoectodermal cells intrinsic t o peripheral nerve. His evidence leading to the above conclusions is as follows; l), the metaplastic potential of malignant schwannoma as shown by formation of rhabdomyosarcoma and chondrosarcoma; 2) the lack of histologic identity of the glands in these schwannomas to any normal glandular tissue, including ependymal tissue; 3) Schwann cells in the vicinity of glands undergo enlargement and line slit-like spaces with possibility for transition of these structure to well-formed glands; 4) presence of malignant schwannoma which displayed within its substance the intermingling of osteogenic sarcoma, rhabdomyosarcoma and numerous atypical mucin-secreting glands. The glandular elements in the present case somewhat resembled ependymoma with the presence of rosettes and pseudorosettes. However, glandular cells showed positive reaction for mucicarmine and PAS stains in the cytoplasm and lumen, and typical blepharoplast was not observed. These findings indicate that the glandular elements in the present case are not derived conclusively from ependyma but are assumed to represent differentiation of Schwann cells into some embryonic tissue. Furthermore in the previously reported cases glandular elements contained well-developed goblet cells. These facts, therefore, demonstrate some possibility that the neoplastic cells of malignant schwannoma have metaplastic potential for forming glandular elements, although we suggest that further studies must be carried out before the histogenesis of the glandular elements in the peripheral nerve tumors can be clarified completely. References 1. COHN,I.: Epithelial neoplasms of peripheral and cranial nerve. Report of three cases: review of the literature. Arch. Surg. 17: 117-160, 1928. 2. D'AQOSTINO,A.N., SOULE, E.H., and MILLER, R.M.: Primary malignant neoplaem of
3.
4. 5. 6.
7. 8. 9.
nerve (malignant neurilemomas) in patient without manifestation of multiple neurofibromatosis (von Recklinghausen's disease). Cancer 16: 1003-1014, 1963. D'AQOSTINO,A.N., SOULE,E.H., and MILLER,R.H.: Sarcomas of the peripheral nerve and somatic soft tissues associated with mutiple nuerofibromatosis (von Becklinghausen's disease). Cancer 16: 1015-1027, 1963. FORAKER, A.G.: Glandlike elements in a peripheral neurosarcoma. Cancer 1 : 286-293, 1947. GARRB,C.: Uber Sekundar Maligne Neurome. Beitr. Z. klin. Chir. Z. 9: 465-495, 1892. HARKIN,J.C. and REED,R.J.: Tumor of the peripheral nerve system. I n atlas of tumor pathology. Second series, Fascicle 3, Washington D.C. Armed Forces Institute of Pathology, 1968: P 144. HARRISON,R.G. : Neuroblast versus sheath cell in the development of peripheral nerves. J. Comp. Neurol. 37: 123-194, 1924. LARFORD, J.A. and COHN,I.: Ependymal neoplasm of the median nerve, with case report. South. Med. J. 20: 273-278, 1927. MASSON,P. and MARTIN,J.F.: Rhabdomyomes des nerb. Bull. Assoc. Pr. Cancer 27: 751-
767, 1938. E.: Rhabdomyoma del nervo ishiatico. Arch. Sci. Med. (Torino). 19: 113-135, 1895. 10. ORLANDI, 11. PENFIELD,W.: The malignant tumor of the peripheral nerves. Am. J. Cancer 25: 1-36,1935. 12. RUSSELL,D.S. and RUBINSTEIN,L.J.: Pathology of tumor of the nerve system. London, England, Edward Arnold Ltd. 1959. 13. STOUT,A.P. and MURRAY,M.R.: Neuroepithelioma of the radial nerve with a study of it's
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behavior in vitro. Rev. Can. Biol. 1: 651-659, 1942. 14. STOUT,A.P.: Tumors of the peripheral nervous system. In atlas of tumor pathology. Fascicle 6, Washington D.C. Armed Foroes Institute of Pathology. 1949. 15. WHITE, J.R.: Survival in malignant schwannoma. An 18-year study. Cancer 27: 720729, 1971. 18. WOODRUFT, F.W. JR.: PeriJ.M., CHERNIK,N.L., SMITH,M.C., MILLETT,W.B., and FOOTE, pheral nerve tumor with rhabdomyosarcomatous differentiation (Malignant Triton Tumor). Cancer 32: 426-439, 1973. 17. WOODRUFT, J.M. : Peripheral nerve tumor showing glandular differentiation (glandular schwannoma). Cancer 37: 2399-2413, 1976. L.E., FONT,R.L., and ANDERSON, S.R. : Rhabdomyosarcomatous differentia18. ZIMMERMAN, tion in malignant intraocular medulloepitheliomas. Canrer 30: 817-835, 1972.
MALIGNANT NEUROFIBROMA WITH GLANDULAR DIFFERENTIATION (GLANDULAR SCHWANNOMA)
Osaniu TAKAHARA, Iwao NAKAYAMA, Shigeo YOKOYAMA*, Akira MORIUCHI*,Hiroo MuTA**, and Yuzo UCHIDA** Department of Pathology, Medical College of Oita, Oita and Department of Central Diagnostic Laboratory* and Surgery**, Nagasaki University School of Medicine, Nagasaki (Received on Oct. 12, 1978)
A case of malignant shwannoma is reported with unusual elements in an 89-year-old female. A large mass was located in the subcutaneous tissue of the right lateral chest wall and measured 5 cm in the greatest diameter. Histologically the tumor was composed of neurofibroma and malignant schwannoma with glandular differentiation. Neurofibroma characterized by numerous hyaline neural nodules was located in the peripheral portion of the tumor, whereas malignant schwannoma occupied a large part of the central portion of the tumor. The glandular elements observed in some areas of malignant schwannoma consisted of cuboidal and columnar shaped cells and were arranged in tubular or tubulo-medullary fashion in which rosettes o r pseudorosettes were found. Mucicarminophilic material was observed, both in the cytoplasm and in the lumen. Seven reported cases of peripheral nerve tumor with glandular differentiation are reviewed briefly. ACTA PATH. JAP. 29: 597-606, 1979.
Introduction
It is well known that malignant schwannoma occurs more frequently in patients with von Recklinghausen's disease than benign schwannomaa. The neoplastic cells originating from schwann cells have the potential for differentiation into several tissues such as o s t e ~ i d ~ ~chondroid2117, s ~ ~ ~ ~ ' , striated muscle3~e~10~15J6, and glands lined by several types of epithelial cells1,415~*~17 as a component of the tumor. However, cases of malignant schwannomas with foci of rhabdomyosarcoma (malignant Triton tumor) or glandular elements (glandular schwannoma) are extremely rare. GARRE' was the first to describe a case of malignant neurofibroma containing numerous glands lined by cuboidal cells, in a 31-year-old female in 1892, and used the term of glandular schwannoma. Subsequently 8 cases of similar tumor including the present case have appeared in the world literature. These glandular schwannomas definitely differ from peripheral tumor of primitive neuroectoderm6, because 6 of the 8 reported cases represented pre-existing neurofibroma and the majority of the neoplastic ~
~
-
m, Rcll
.
%rlr, e F4 sg, *ffl @A, l4El 13 Mailing address: Dr. Osamu TAKAHARA, Department of Pathology, Medical College of Oita. 1506 Ooaza Toi, Hazama-cho, Oita-gun, Oita. 597
&6w
;R#, rpcll
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tissue was composed of spindle shaped cells, in which the glandular elements were embedded here and there throughout the tumor. This paper describes a case of malignant schwannoma in an 89-year-old female, which is considered to have arisen by transformation from benign neurofibroma, with differentiation to glandular elements, and in addition the literature is reviewed. Case Report
An 89-year-old female was admitted to the hospital on May 17, 1973 because of a tumor in her right lateral chest wall. She noticed a small tumor in her right lateral chest wall a t 13 years of age, however, there was no medical treatment because there was neither clinical signs nor evidence of progressive growth of the tumor. During the past two years the tumor grew progressively and attained a large size, measuring 5 cm in diameter. On physical examination, there were numerous abnormal pigmentations on the skin of the back. The tumor was located in the subcutaneous tissue of the right lateral chest wall and showed no adhesion to the underlying tissue and skin. X-ray examination of the chest showed no metastatic lesion. Laboratory examination revealed a hemoglobin of 13.0 gldl, hematocrit of 40.5y0, red blood cell count of 4,200,000/mms and white blood cell count of 6,900/mms. Serum proteins were 6.3 g/dl with albumin of 52%, a,-globulin of 6%. a,-globulin of 14%, fl-globulin of 13% and y-globulin of 15%. Serum chemistry revealed total bilirubin of 0.23 mg%, serum-GOT of 33 S.F.E., serum-GPT of 20 S.F.E., alkaline phosphatase of 12.9 Bod. U., serum cholesterol of 208 mg%, mucoprotein of 10.3 mg% and LDH of 355U. Urea N was 20.4 mg%. Electrolytes were Na of 144 mEq/l, K of 4.1 mEq/l, and C1 of 105 mEq/l. At operation a large tumor measuring 5 cm in diameter was extirpated with no difficulty from the right lateral chest wall. Primary healing progressed with no sign of recurrence during her hospitalization. She was readmitted to the hospital on March 27, 1974, because of recurrence of the tumor. Four months after the first operation she had a small recurrent tumor just beneath the incisional scar of the first operation. Thereafter the tumor grew very rapidly and attained a large size measuring 5 . 0 ~ 4.5 cm. On physical examination the tumor was located in the subcutaneous tissue just beneath the previous incisional scar and showed partial adhesion to skin but it was easily movable from the underlying soft tissue. The skin covering the tumor was reddish in color with dilated capillaries. The superficial lymph nodes were not palpable. X-ray examination of the chest on April 1, 1974 revealed a well circumscribed lesion indicative of metastatic tumor in the right middle lobe. During 4 months of hospitalization the tumor in the right middle lobe increased in size and measured 5 5 ~ 45 mm on the chest X-ray film. On April 12, 1974 the recurrent tumor of the right lateral chest wall was amputated with no difficulty. The patient died a t home on August 12, 1974. An autopsy wag not performed.
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Macroscopic and Microscopic Observation The tumor removed from the right lateral chest wall a t the first operation was covered by seemingly normal skin and located in the subcutaneous tissue as a well circumscribed spherical mass measuring 5 cm in the greatest diameter. It was not encapsulated by connective tissue and showed no evidence of direct connection with peripheral nerve. Multiple-cut-surfaces of the tumor showed homogeneous or nodular lesions of gray-white tissue. Peripheral portion of the tumor was more glistening than the central portion which appeared to exhibit an expansive growth toward the periphery and consisted of white fibrous tissue. There was an irregular shaped lesion with fragile light yellow white tissue located in the upper portion of the tumor (Fig. 1). It was well demarcated from the surrounding tumor tissue.
Fig. 1. Gross appearance of the primary tumor resected from the left lateral chest wall a t the first operation. The tumor shows a well-circumscribed spherical mass measuring 5 cm in the greatest diameter. On cut-section i t consists of white-gray tissue except for a portion (arrow) which is fragile light yellow white tissue. Fig. 2. Gross appearance of the recurrent tumor. It is a wellcircumscribed mass measuring 5.0 x 4.5 cm located just beneath the skin and consists of white-gray tissue.
The recurrent tumor adhered partly to the overlying skin and was a well circumscribed spherical mass located in the subcutaneous tissue and measured 5.0 x 4.5 cm. On multiple cut sections the gross appearance of the tumor was essentially similar to that of the central portion of primary tumor except for a nodular lesion consisting of fragile tissue (Fig. 2). For histological examination, the tumor removed from the right lateral chest wall at the first and second operation was fixed in 10% neutral formalin. Numerous tissues
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Fig. 3. Photograph shows a portion of neurofibroma composed of numerous hyaline neural nodules resembling tactile corpusc~es. X 300. Fig. 4. A portion of malignant schwannoma. The tumor is composed of relatively loose streaming fascicles of slender spindle cells. X 1100. Figs. 5-6. High cellular area of malignant schwannoma. Spindle-shaped cells with hyperchromatic nucleus arranged in interlacing fascicles. Some areas composed of high cellularity appear to be lobulated by neoplastic tissue with lower cellularity. Several nuclear mitoses are seen. Fig. 5: x 900, Fig. 6 ; x 300.
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were taken from both tumors and embedded in paraffin. Sections from paraffin embedded tissues were stained with hematoxylin-eosin (H-E),Van Gieson, Masson’s trichrome, periodic acid Schiff (PAS), Snook’s silver, alcian blue, mucicarmine and phosphotungstic acid hematoxylin (PTAH). By microscopic observation the primary tumor was composed of several different tissues. The skin covering the tumor showed an essentially normal structure of the epidermis. However, the deeper dermis contained a tumor consisting of slender or wavy loose spindle cells in which there were numerous hyaline neural nodules resembling tactile corpuscles (Fig. 3) and occasionally sweat glands. The histological features corresponded to neurofibroma. Identical structures of neurofibroma were also observed in the peripheral portion of the primary tumor. This neurofibromatous area exhibited direct continuity with the malignant tumor which showed evidence of high cellularity , nuclear atypism and abnormal mitoses. The malignant neoplasm differed somewhat in its cellularity from one field to another. The tumor tissue with low cellularity was composed of loose streaming fascicles of slender spindle cells (Fig. 4) and mainly located in the peripheral portion of the tumor where benign and malignant elements of the tumor were intermingled, whereas the central portion of the tumor showed high cellularity and comprised interlacing fascicles of spindle cells with indistinct cell boundaries (Fig. 5 ) . In some areas the tumor tissue with high cellularity appeared to be separated by neoplastic tissue with low cellularity (Fig. 6). The nucleus of these spindle shaped cells was hyperchromatic and showed numerous mitoses (Fig. 5). There was no evidence of nuclear palisading in the malignant neoplastic tissue. Although several hyaline neural nodules were observed in the intermingled area of benign and malignant neoplasm, they were not found in the central portion of the malignant tumor. The malignant neoplastic tissue contained several large cells arranged either singly or in groups. They were plump spindle or round in shape and had a large nucleus with a prominent nucleolus and abundant acidophilic cytoplasm showing negative reaction for PTAH and Nissle’s stains (Fig. 7). As an occasional finding, metaplastic osteoid tissue was observed in the malignant tumor. These histological characteristics of the malignant tumor coincide well with malignant schwannoma and suggest a malignant transformation from pre-existing neurofihroma. Several glandular structures were embedded in some areas of the malignant schwannoma. Most of the glandular structures were arranged in a medullary fashion which was separated by fibrocapillary stroma. There appeared rosettes and pseudorosettes in this area, although typical blepharoplasts were not clear (Figs. 8-9). Some glands were tubular and contained intraluminal mucicarminophilic material (Fig. 10). Large cystic lesions were filled with PAS positive, colloid-like material and were covered by single or psuedostratified columnar cells having a continuous basement membrane a t the basal surface. These glandular structures appeared to be composed of identical cells which were non-ciliated cuboidal or high columnar. The nuclei in
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many of the glandular cells were round or oval, and hyperchromatic. A few mitotic figures were seen. The cytoplasm of the glanduar cells was often clear or acidophilic with positive reaction after mucicarmine and PAS staining. The histological picture of the recurrent tumor was identical to that of malignant schwannoma observed in the central portion of the primary tumor, although it was devoid of glandular elements. Discussion
It is well known that neurofibroma has some potential for malignant transformation, which is referred to as malignant schwannoma. Malignant schwannoma arises more frequently from neurofibromatosis than from benign schwannomas. Therefore pre-existing neurofibroma or direct connection of the tumor with the peripheral nerve is particularly important for pathological diagnosis of malignant s~hwannoma'~~'~. The present 89-year-old patient noticed a small tumor in her right lateral chest wall a t 13 years of age. There were neither clinical signs nor any evidence of progressive growth for 76 years. Seventy-six years after the onset of illness, the tumor grew progressively, attaining 5 cm in the largest diameter and showed recurrence and pulmonary metastasis 4 months after the first operation. On histological examination the peripheral portion of the primary tumor exhibited typical neurofibroma containing numerous hyaline neural nodules, whereas the central portion showed several patterns composed mainly of spindle-shaped cells with evidence of malignancy such as high cellularity, cellular atypism and atypical nuclear mitoses. This malignant tumor corresponds well to malignant schwannoma with evidence of pre-existing neurofibroma and histological shift from benign to malignant structures. It is also well known that schwannoma and neurofibroma can demonstrate metaplastic changes of neoplastic cells t o several mesenchymal elements. The most frequently encountered metaplastic elements in the peripheral nerve tumor are chondroid and osteoid tissue. In addition to these benign elements there have appeared several reports of schwannoma exhibiting foci of r h a b d o m y o s a r c ~ m a ~ chondrosar~~~~~, coma2, and liposarcoma2. These unusual elements observed in the tumor arising from peripheral nerve are the result of a metaplastic potential of the Schwann cells which are derived from neuroectodermal neural crest and can differentiate to mesoectoderm during embryonic differentiation'P. Therefore it is possible that peripheral nerve tumors ~.
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Fig. 7. Photograph shows a portion of malignant schwannoma containing plump spindle or round cells with acidophilic cytoplasm and a large nucleus with a prominent nucleolus. They are negative with PTAH and Nissl's stains. x 1600. Figs. 8-9. Glandular elements in malignant schwannoma. Cuboidal shaped cells having a hyperchromatic round nucleus and a scanty cytoplasm arranged in a medullo-tubular fashion separated by fibrocapillary stroma. There are rosettes and pseudorosettes in the glandular structure. Some mitoses are seen in the glandular cells (arrow). Fig. 8: x 300, Fig. 9: x 700. Fig. 10. In some areas the glandular elements show a tubular arrangement composed of high columnar-shaped cells with intraluminal and intracytoplasmic muricarminophilic material. x 300.
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occasionally contain foci of rhabdomyosarcoma, chondrosarcoma and liposarcoma. Furthermore, unusual cases of malignant schwannonia show differentiation along the epithelial line. Eight cases of such tumors including the present one have appeared in the literature, since GARRE5 first described a case using the term of glandular schwannoma. There appears to be some sex predilection in the patients with glandular schwannoma; 6 patients were female and 2 male. Five of the 8 cases had clinicopathological evidence of von Recklinghausen's disease. The majority of the patients noticed the lesion between 15 and 35 years of age, although the youngest patient was an 8-year-old girl and the oldest an 89-year-old female. Anatomical distribution of the tumor included the neck4, arm8, chest wall, peritoneum17and retroperitone~ml~. The size of these tumors differed considerably from one case to another and ranged from 1 cm in diameter to 15 cni. Five of the 8 patients died with clinical recurrence or metastasis t o the lung within several months to ten years, although there were three patients who were alive more than 4 years after the 0 p e r a t i o n ~ 1 ~ 1 ~Histological 1~~. feature of glandular schwannoma resembles t o some extent that of peripheral tumor of primitive neuroectoderm. However, they are quite different one to the other, because 7 cases of glandular schwannoma showed histological features of malignant neurofibroma51~1~1l~ as the predominant element of the tumor and in one case glandular structures were embedded in atypical pigmented nevoid schwannoma17. Furthermore it is necessary to differentiate glandular schwannoma from synovial sarcoma with the presence of biphasic elements. In the present case the tumor showed no progressive growth for 76 years and on histological examination exhibited a feature of typical nwrofibroma in the peripheral portion of the tumor in addition to biphasic elements. These facts coincide with neither clinical nor histological behavior of synovial sarcoma. Histological features of the glandular component in the reported cases developing within malignant schwannoma differ somewhat from one case to another. In the present case glandular structures were characterized by rosette or pseudorosette formation as well as by a tubular and cystic arrangement with intraluminal mucicarminophilic material. These glands were composed of nonciliated cuboidal to high columnar cells having nuclear pleomorphism with mitotic figures. In the review described by WOOD RIFT^', the glands were most commonly lined by nonciliated cuboidal and/or pseudostratified columnar epithelial cells with clear cytoplasm and nuclear mitoses. Each of the tumor containing clear cells showed mucin in glandular lumina and two glands contained well formed goblet cells which were not observed in the present case. In other reported cases the feature of the glandular element resembled that of medulloepitheliomas and ependymomall. There are sweral possible hypotheses to explain the appearance of glandular elements in the peripheral nerve tumor. GAR RE^ considered that glandular elements represented a developmental carry-over of the central canal of the spinal cord into peripheral nerve. FORAKER4 thought that the glands were heterotopic ependymal tissue. H O R K I Nreferred ~ to these tumor as peripheral medulloepithelioma.
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Using several lines of evidence, WOODRUFT" has reported that epithelial elements found in glandular schwannoma arise from Schwann cells or mesoectodermal cells intrinsic t o peripheral nerve. His evidence leading to the above conclusions is as follows; l), the metaplastic potential of malignant schwannoma as shown by formation of rhabdomyosarcoma and chondrosarcoma; 2) the lack of histologic identity of the glands in these schwannomas to any normal glandular tissue, including ependymal tissue; 3) Schwann cells in the vicinity of glands undergo enlargement and line slit-like spaces with possibility for transition of these structure to well-formed glands; 4) presence of malignant schwannoma which displayed within its substance the intermingling of osteogenic sarcoma, rhabdomyosarcoma and numerous atypical mucin-secreting glands. The glandular elements in the present case somewhat resembled ependymoma with the presence of rosettes and pseudorosettes. However, glandular cells showed positive reaction for mucicarmine and PAS stains in the cytoplasm and lumen, and typical blepharoplast was not observed. These findings indicate that the glandular elements in the present case are not derived conclusively from ependyma but are assumed to represent differentiation of Schwann cells into some embryonic tissue. Furthermore in the previously reported cases glandular elements contained well-developed goblet cells. These facts, therefore, demonstrate some possibility that the neoplastic cells of malignant schwannoma have metaplastic potential for forming glandular elements, although we suggest that further studies must be carried out before the histogenesis of the glandular elements in the peripheral nerve tumors can be clarified completely. References 1. COHN,I.: Epithelial neoplasms of peripheral and cranial nerve. Report of three cases: review of the literature. Arch. Surg. 17: 117-160, 1928. 2. D'AQOSTINO,A.N., SOULE, E.H., and MILLER, R.M.: Primary malignant neoplaem of
3.
4. 5. 6.
7. 8. 9.
nerve (malignant neurilemomas) in patient without manifestation of multiple neurofibromatosis (von Recklinghausen's disease). Cancer 16: 1003-1014, 1963. D'AQOSTINO,A.N., SOULE,E.H., and MILLER,R.H.: Sarcomas of the peripheral nerve and somatic soft tissues associated with mutiple nuerofibromatosis (von Becklinghausen's disease). Cancer 16: 1015-1027, 1963. FORAKER, A.G.: Glandlike elements in a peripheral neurosarcoma. Cancer 1 : 286-293, 1947. GARRB,C.: Uber Sekundar Maligne Neurome. Beitr. Z. klin. Chir. Z. 9: 465-495, 1892. HARKIN,J.C. and REED,R.J.: Tumor of the peripheral nerve system. I n atlas of tumor pathology. Second series, Fascicle 3, Washington D.C. Armed Forces Institute of Pathology, 1968: P 144. HARRISON,R.G. : Neuroblast versus sheath cell in the development of peripheral nerves. J. Comp. Neurol. 37: 123-194, 1924. LARFORD, J.A. and COHN,I.: Ependymal neoplasm of the median nerve, with case report. South. Med. J. 20: 273-278, 1927. MASSON,P. and MARTIN,J.F.: Rhabdomyomes des nerb. Bull. Assoc. Pr. Cancer 27: 751-
767, 1938. E.: Rhabdomyoma del nervo ishiatico. Arch. Sci. Med. (Torino). 19: 113-135, 1895. 10. ORLANDI, 11. PENFIELD,W.: The malignant tumor of the peripheral nerves. Am. J. Cancer 25: 1-36,1935. 12. RUSSELL,D.S. and RUBINSTEIN,L.J.: Pathology of tumor of the nerve system. London, England, Edward Arnold Ltd. 1959. 13. STOUT,A.P. and MURRAY,M.R.: Neuroepithelioma of the radial nerve with a study of it's
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behavior in vitro. Rev. Can. Biol. 1: 651-659, 1942. 14. STOUT,A.P.: Tumors of the peripheral nervous system. In atlas of tumor pathology. Fascicle 6, Washington D.C. Armed Foroes Institute of Pathology. 1949. 15. WHITE, J.R.: Survival in malignant schwannoma. An 18-year study. Cancer 27: 720729, 1971. 18. WOODRUFT, F.W. JR.: PeriJ.M., CHERNIK,N.L., SMITH,M.C., MILLETT,W.B., and FOOTE, pheral nerve tumor with rhabdomyosarcomatous differentiation (Malignant Triton Tumor). Cancer 32: 426-439, 1973. 17. WOODRUFT, J.M. : Peripheral nerve tumor showing glandular differentiation (glandular schwannoma). Cancer 37: 2399-2413, 1976. L.E., FONT,R.L., and ANDERSON, S.R. : Rhabdomyosarcomatous differentia18. ZIMMERMAN, tion in malignant intraocular medulloepitheliomas. Canrer 30: 817-835, 1972.
