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Neural invasion in intraductal carcinoma of the breast
HUMAN PATHOLOGY
Volume 23, No. 2 (February
Schwann cell origin of the tumor is also supported by the presence of discontinuous basal lamina.” Basal lamina has been found in five of eight tumors ultrastructurally examined by Enzinger et al’ and in all three tumors examined by Miettinen.’ Abundant intermediate filaments also were present in the previously studied tumors.‘.’ Primitive cell junctions, which were readily found in the tumor described here, were present only in one of the three tutnors reported by Miettinen,’ but were not found in the tumors described by Enzinger et al.’
.1. Nakamura y, Becker- I.E. Mxks A: S-I 00 protein in 1umor\ of cartilage and bone. An immonohisrochernical study. Cancer 52; 1820-l 8?4. 1983 5 Mrmuli VA, Brown EF. Gould VE: Glial fibrillq acidic protein (GFAP) inlmunr)rearlivity in peripheral nerve sheath tumors. Ultrastruct Pathol 7:X9275, 1984 6. (Gould VE, Mall R, Mall I. et al: The inrermediatr filament complement uf the specttxm of nerve sheath neoplasms. I.ah Invest 55:463-474, 1986 7. Kawahara E. Oda Y, Ooi A, et al: Exp~rssion of glial librillary acids< protein (GFAP) in peripheral nerw sheath ~UIIIOI-S. .4 comparative study of irnmunureactivity of GFAP. vimentin, S-100 protein. and neurofilament in 38 schwnnwna~ and 18 neurofihromas. Am J Surg Pathol I?: 1 15-120. 1988 8. Gray MH. Rosenberg AE, Dickersin GR, et 4: Cilia1 fibrillq acidic protein and kerarin expression by benign and malignant nerve shrath uncra. HUM PATHOI.PO:lO89-1096, 1989 9. Wick MR, Swanson PE. Srhelthauer BW. et al: Malignant peripheral nerve sheath tumor. An immurrohistochen~i~al studs of 64 cases Am J Clin Path<>187:425-43X 1987 IO. l.odding P, Kindblorn I.(;, AngervaIl I.: Epithelioid mahgnan~ srhw;irlnoma. A study of 14 cases. Virchows Arch [A] 409:433-451, 1986 1 I. Bornstein I’, Sage H: Strnctul-ally distinct collagen types. Ann Rex Biochem 49:957-1003. 1980 12. Dickersin GR: ‘The electron microscopic q~txt~um (,f rwvz sheath tumars L’ltrastruct l’athol 11:103-146. 19X7
REFERENCES 1. Etumger FM, Weiss SW. l.idng CY: Ossifying fibromywid tunw~ of soft parts. A clinicopathological analysis of 59 c;1scs. Am J Surg Path4 IS:81 7-827. 1989 2. Miettinen M: Ossifying hbromyxoid tumw of soft parts. Additional observations of a distinctive soft tissue tumor. Am J Clin Pathol95: 14%149, 1991 3. Weiss SW, Langloss JM. Enzinger FM: Value of S-100 protein in the diagnosis of soft tissue tumws with particular reference to benign xnd malignant Schwann cell tumors. Lab lnvrst 49:?99-308. 1983
NEURAL
INVASION
IN INTRADUCTAL
WILLIAM Y. W. TSANG. MBBS, AND JOHN
CARCINOMA
K. C. CHAN,
1992)
OF THE BREAST
MBBS, MRCPAT~~. FCAP
Although perineural invasion in a malignancy jkvors the diagnosis of invasive over in situ carcinoma, we report a rate of cribriform intraduct carcinoma of the breast showingperineural invasion. The in situ nature of the lesion is supported by the finding of an intact uctin-positive myoepithelial cell layer around the cribriform growths and the presentation of lobular architecture. HUM PATHOL.23:202201. Copyright 0 1992 by W.B. Saunders Cornparty Cribriform intraduct carcinoma of the breast is a premalignant/preinvasive lesion characterized by proliferation of monotonous hyperchromatic round cells forming round-contoured regular spaces within pre-existing ductal and lobular lumina.’ This lesion should be distinguished from invasive cribriform carcinoma, which is cytologically and histologically similar except for the presence of invasion.‘-4 We report a unique case showing perineural invasion, which was confirmed immunohistochemically to be a purely in situ lesion. This phenomenon, to our knowledge, has not been described before. CASE REPORT A previously healthy, f&year-old woman presented with a recently discovered mass in the left breast. The mass measured 2 cm in diameter and was located in the lower outer quadrant. The right breast was normal. Fine needle aspiration of the mass yielded a diagnosis of ductal carcinoma, and modified radical mastectomy was performed 2 weeks later. In the mastectomy specimen, a hard white nodule measuring 2 X 1 X 1 cm was found 2 cm below and lateral to the nipple. The adjacent breast tissue was firm. Microscopic ex-
amination showed cribriform intraduct carcinoma with no evidence of stromal invasion. The entire lesion was interpreted as being in situ because the cribriform structures were round and conformed to the contours as well as the boundaries of expanded lobular units, there was no extension between the lobules, and a desmoplastic stroma was absent (Fig 1, left). Furthermore, staining for muscle-specific actin (HHF 35; Enzo Biochem, New York, NY) using the avidin-biotin-peroxidase technique showed a complete rim of positive cells around all the cribriform structures (Fig 1, right). The actin-positive cells conformed to the location, morphology, and immunophenotype of residual myoepithelial cells, and could be distinguished from the actin-positive stromal myofibroblasts, which were not as closely applied to the cribriform structures and which lacked cytoplasmic processes enveloping the intraductal epithelial cells. The cribriform intraduct carcinoma also showed extensive involvement of the breast tissue beyond the main tumor mass; in some areas, it cancerized lobules with pre-existing sclerosing adenosis. Near the deep resection margin, perineural infiltration was identified within one lobule composed of several cribriform structures with architectural and cytologic features no different from the surrounding in situ carcinoma (Fig 2, left). The nerves were closely apposed to or surrounded by the smooth-contoured neoplastic units (Fig 3), which were focally surrounded by attenuated myoepithelial cells. Complete rings of actin-positive myoepithelial cells could also be demonstrated around these units (Fig 2, right). The axillary lymph nodes were free of metastasis. DISCUSSION
From the Institute of Pathology, Queen Elizabeth Hospital, Hong Kong. Accepted for publication April 25, 1991. Kqy woruk breast tumor. intraductal carcinoma, perineural invasion. Address correspondence and reprint requests to William Y. W. Tsang, MBBS, Institute of Pathology, Queen Elizabeth Hospital, Wylie Rd. Kowloon, Hong Kong. Copvrieht 0 1992 bv W.B. Saunders Comoanv 00‘%677/92/230~-0021$5.00/0 1 ’
Carcinoma in situ of the breast is characterized by proliferation of tumor cells within pre-existing ductal and lobular spaces without stromal invasion and, thus, preservation of the lobular architecture. However, considerable distortion of architecture may occur due to sclerosis, expansion of the lobules, or cancerization of sclerosing adenosis, making distinction from invasive carcinomas difficult.‘,“-’ One helpful distin-
202
CASE STUDIES
FIGURE 1. (Left) Scanning view of the breast nodule, featuring round cribriform units conforming to the contour as well as the boundaries of expanded pre-existing lobules. (Hematoxylin-eosin stain; magnification X14.) (Right) The cribriform structures are surrounded by complete rings of actin-positive residual myoepithelial cells. (lmmunoperoxidase for musclespecific actin; magnification #135.)
cause the lobular architecture is preserved. the crlbriform structures are smooth-contoured and appear I o be within the confines of normal ductal boundaries, and a convincing actinpositive residual myoepithelial layer can be demonstratrd around the cribriform units (including those showing pcrineural invasion). This tumor does not rrprrsent an invasive cribriform carcinoma, which is characterized by haphazardly disposed cribriform units with no respect for lobular boundaries as well as frequent presence of nests with angular contour and a cellular desmoplastic stroma.‘.’ It is rviclent from previous reports that the growth pattern of invasive cribriform carcinoma can be readily recognked as taring invasive because
guishing fcaturc is the identification of a complete or near-l) complete residual myoepithelial layer around the units, which strongly favors the diagnosis of in situ over invasive carcinomas,” although the myoepithelial layer may be completely abselrt in cases of advanced carcinoma in situ.’ The myoepithelial in conventional sections as an outer-cells c-an be recognized most layer- of clear polygonal, plump spindlecl, or attenuated cdls, ht can sometimes he very difficult to visualire. lmmunostaining l’or muscle-specific actin is extremely helpful in highlighting thesr myoepithelial cells.“,!’ III the present case, despite the presence of perineural invasion. we interpret the tumor to be in situ carcinoma he-
FIGURE 2. (Left) Two discrete, smooth-contoured lobules showing involvement by cribriform intraductal carcinoma, with perineural invasion in the lower lobule (arrows). (Hematoxylin-eosin stain; magnification X26.) (Right) The cribriform units of the lobule sbIown in the lower field of the left panel are surrounded by actin-positive myoepitheli’al cells. (Immunoperoxidase for musclespecific actin: magnification X39.)
203
HUMAN PATHOLOGY
Volume 23, No. 2 (February
1992)
perplastic prostate gland, vasitis nodosa. skin following excisionai biopsy, keratoacanthoma, trichofblliculoma, endomeof neural triosis, and normal pancreas.“‘-‘-’ ’ The mechanism invasion in these conditions is not clear, and various possibilities include active epithelial proliferation in a plane of low resistance (perineural spaces), mechanical implantation, aberrant regeneration of biopsy-traumatized epithelium, aberrant development of epithelial or neural tissue, and active proliferation of nerves into epithelial structures.“‘~” In our case, with a history of fine needle aspiration, mechanical implantation and posttraumatic neural overgrowth appear to he possible explanations. However, we do not favor these possibilities because changes attributable to the previous aspiration were not present in the focus of interest, and the nerves do not exhibit features of traumatic neuroma.
REFERENCES 1. Page DL, Anderson IJ, Rogers 1.M’ ( ..,I( irrotna 111situ ((IIS), 111l’agr DI.. Anderson TF (eds): Diagnostic Hiatopathology o1 the Bt-east. Edinburgh, LtK, Churchill Livingstone. 1990. pp 1.57-192 2. Page DL, Anderson TJ, Sakamoto (:: Infiltrating c,trrinoma: M+jw hirtologi,lral types. in Page 1~1.. Attdrr-sort TJ (eds): Diagnostic Histopathology of the Breast. Edinburgh. UK, Churchill Li~ittgstotte. 1990, pp 193-235 3. Venable JG. Schwartz AM. Silverbcrg SC: Infiltrating cribriform carcinoma of the breast: A distinctive clinicopathotogic etrttty. H~:M PATH~I. 21: 333-338, 1990 4. Page Dl., Dixon JM. Anders~m I J, ct al: lttv.tsivr
FIGURE 3. Higher magnification of the region indicated by the upper arrow in Fig 2, left, showing neural invasion by cribriform intraductal carcinoma. (Hematoxylin-eosin stain: magnification X190.)
all the cases had previously been diagnosed as infiltrative ductal carcinoma of nonspecific type. 3.4 Furthermore, residual myoepithelial cells are not found around epithelial islands in invasive carcinoma.6,” Perineural invasion has not been described for carcinoma in situ of the breast and for in situ carcinomas of other organs. We suspect that previous cases showing such a phenomenon might have been interpreted as invasive carcinoma. It should not be too surprising to find perineural invasion in in situ carcinomas because this is a recognized phenomenon in a variety of benign and proliferative lesions, such as fibrocystic disease and sclerosing adenosis of the breast, normal and hy-
204
Volume 23, No. 2 (February
Schwann cell origin of the tumor is also supported by the presence of discontinuous basal lamina.” Basal lamina has been found in five of eight tumors ultrastructurally examined by Enzinger et al’ and in all three tumors examined by Miettinen.’ Abundant intermediate filaments also were present in the previously studied tumors.‘.’ Primitive cell junctions, which were readily found in the tumor described here, were present only in one of the three tutnors reported by Miettinen,’ but were not found in the tumors described by Enzinger et al.’
.1. Nakamura y, Becker- I.E. Mxks A: S-I 00 protein in 1umor\ of cartilage and bone. An immonohisrochernical study. Cancer 52; 1820-l 8?4. 1983 5 Mrmuli VA, Brown EF. Gould VE: Glial fibrillq acidic protein (GFAP) inlmunr)rearlivity in peripheral nerve sheath tumors. Ultrastruct Pathol 7:X9275, 1984 6. (Gould VE, Mall R, Mall I. et al: The inrermediatr filament complement uf the specttxm of nerve sheath neoplasms. I.ah Invest 55:463-474, 1986 7. Kawahara E. Oda Y, Ooi A, et al: Exp~rssion of glial librillary acids< protein (GFAP) in peripheral nerw sheath ~UIIIOI-S. .4 comparative study of irnmunureactivity of GFAP. vimentin, S-100 protein. and neurofilament in 38 schwnnwna~ and 18 neurofihromas. Am J Surg Pathol I?: 1 15-120. 1988 8. Gray MH. Rosenberg AE, Dickersin GR, et 4: Cilia1 fibrillq acidic protein and kerarin expression by benign and malignant nerve shrath uncra. HUM PATHOI.PO:lO89-1096, 1989 9. Wick MR, Swanson PE. Srhelthauer BW. et al: Malignant peripheral nerve sheath tumor. An immurrohistochen~i~al studs of 64 cases Am J Clin Path<>187:425-43X 1987 IO. l.odding P, Kindblorn I.(;, AngervaIl I.: Epithelioid mahgnan~ srhw;irlnoma. A study of 14 cases. Virchows Arch [A] 409:433-451, 1986 1 I. Bornstein I’, Sage H: Strnctul-ally distinct collagen types. Ann Rex Biochem 49:957-1003. 1980 12. Dickersin GR: ‘The electron microscopic q~txt~um (,f rwvz sheath tumars L’ltrastruct l’athol 11:103-146. 19X7
REFERENCES 1. Etumger FM, Weiss SW. l.idng CY: Ossifying fibromywid tunw~ of soft parts. A clinicopathological analysis of 59 c;1scs. Am J Surg Path4 IS:81 7-827. 1989 2. Miettinen M: Ossifying hbromyxoid tumw of soft parts. Additional observations of a distinctive soft tissue tumor. Am J Clin Pathol95: 14%149, 1991 3. Weiss SW, Langloss JM. Enzinger FM: Value of S-100 protein in the diagnosis of soft tissue tumws with particular reference to benign xnd malignant Schwann cell tumors. Lab lnvrst 49:?99-308. 1983
NEURAL
INVASION
IN INTRADUCTAL
WILLIAM Y. W. TSANG. MBBS, AND JOHN
CARCINOMA
K. C. CHAN,
1992)
OF THE BREAST
MBBS, MRCPAT~~. FCAP
Although perineural invasion in a malignancy jkvors the diagnosis of invasive over in situ carcinoma, we report a rate of cribriform intraduct carcinoma of the breast showingperineural invasion. The in situ nature of the lesion is supported by the finding of an intact uctin-positive myoepithelial cell layer around the cribriform growths and the presentation of lobular architecture. HUM PATHOL.23:202201. Copyright 0 1992 by W.B. Saunders Cornparty Cribriform intraduct carcinoma of the breast is a premalignant/preinvasive lesion characterized by proliferation of monotonous hyperchromatic round cells forming round-contoured regular spaces within pre-existing ductal and lobular lumina.’ This lesion should be distinguished from invasive cribriform carcinoma, which is cytologically and histologically similar except for the presence of invasion.‘-4 We report a unique case showing perineural invasion, which was confirmed immunohistochemically to be a purely in situ lesion. This phenomenon, to our knowledge, has not been described before. CASE REPORT A previously healthy, f&year-old woman presented with a recently discovered mass in the left breast. The mass measured 2 cm in diameter and was located in the lower outer quadrant. The right breast was normal. Fine needle aspiration of the mass yielded a diagnosis of ductal carcinoma, and modified radical mastectomy was performed 2 weeks later. In the mastectomy specimen, a hard white nodule measuring 2 X 1 X 1 cm was found 2 cm below and lateral to the nipple. The adjacent breast tissue was firm. Microscopic ex-
amination showed cribriform intraduct carcinoma with no evidence of stromal invasion. The entire lesion was interpreted as being in situ because the cribriform structures were round and conformed to the contours as well as the boundaries of expanded lobular units, there was no extension between the lobules, and a desmoplastic stroma was absent (Fig 1, left). Furthermore, staining for muscle-specific actin (HHF 35; Enzo Biochem, New York, NY) using the avidin-biotin-peroxidase technique showed a complete rim of positive cells around all the cribriform structures (Fig 1, right). The actin-positive cells conformed to the location, morphology, and immunophenotype of residual myoepithelial cells, and could be distinguished from the actin-positive stromal myofibroblasts, which were not as closely applied to the cribriform structures and which lacked cytoplasmic processes enveloping the intraductal epithelial cells. The cribriform intraduct carcinoma also showed extensive involvement of the breast tissue beyond the main tumor mass; in some areas, it cancerized lobules with pre-existing sclerosing adenosis. Near the deep resection margin, perineural infiltration was identified within one lobule composed of several cribriform structures with architectural and cytologic features no different from the surrounding in situ carcinoma (Fig 2, left). The nerves were closely apposed to or surrounded by the smooth-contoured neoplastic units (Fig 3), which were focally surrounded by attenuated myoepithelial cells. Complete rings of actin-positive myoepithelial cells could also be demonstrated around these units (Fig 2, right). The axillary lymph nodes were free of metastasis. DISCUSSION
From the Institute of Pathology, Queen Elizabeth Hospital, Hong Kong. Accepted for publication April 25, 1991. Kqy woruk breast tumor. intraductal carcinoma, perineural invasion. Address correspondence and reprint requests to William Y. W. Tsang, MBBS, Institute of Pathology, Queen Elizabeth Hospital, Wylie Rd. Kowloon, Hong Kong. Copvrieht 0 1992 bv W.B. Saunders Comoanv 00‘%677/92/230~-0021$5.00/0 1 ’
Carcinoma in situ of the breast is characterized by proliferation of tumor cells within pre-existing ductal and lobular spaces without stromal invasion and, thus, preservation of the lobular architecture. However, considerable distortion of architecture may occur due to sclerosis, expansion of the lobules, or cancerization of sclerosing adenosis, making distinction from invasive carcinomas difficult.‘,“-’ One helpful distin-
202
CASE STUDIES
FIGURE 1. (Left) Scanning view of the breast nodule, featuring round cribriform units conforming to the contour as well as the boundaries of expanded pre-existing lobules. (Hematoxylin-eosin stain; magnification X14.) (Right) The cribriform structures are surrounded by complete rings of actin-positive residual myoepithelial cells. (lmmunoperoxidase for musclespecific actin; magnification #135.)
cause the lobular architecture is preserved. the crlbriform structures are smooth-contoured and appear I o be within the confines of normal ductal boundaries, and a convincing actinpositive residual myoepithelial layer can be demonstratrd around the cribriform units (including those showing pcrineural invasion). This tumor does not rrprrsent an invasive cribriform carcinoma, which is characterized by haphazardly disposed cribriform units with no respect for lobular boundaries as well as frequent presence of nests with angular contour and a cellular desmoplastic stroma.‘.’ It is rviclent from previous reports that the growth pattern of invasive cribriform carcinoma can be readily recognked as taring invasive because
guishing fcaturc is the identification of a complete or near-l) complete residual myoepithelial layer around the units, which strongly favors the diagnosis of in situ over invasive carcinomas,” although the myoepithelial layer may be completely abselrt in cases of advanced carcinoma in situ.’ The myoepithelial in conventional sections as an outer-cells c-an be recognized most layer- of clear polygonal, plump spindlecl, or attenuated cdls, ht can sometimes he very difficult to visualire. lmmunostaining l’or muscle-specific actin is extremely helpful in highlighting thesr myoepithelial cells.“,!’ III the present case, despite the presence of perineural invasion. we interpret the tumor to be in situ carcinoma he-
FIGURE 2. (Left) Two discrete, smooth-contoured lobules showing involvement by cribriform intraductal carcinoma, with perineural invasion in the lower lobule (arrows). (Hematoxylin-eosin stain; magnification X26.) (Right) The cribriform units of the lobule sbIown in the lower field of the left panel are surrounded by actin-positive myoepitheli’al cells. (Immunoperoxidase for musclespecific actin: magnification X39.)
203
HUMAN PATHOLOGY
Volume 23, No. 2 (February
1992)
perplastic prostate gland, vasitis nodosa. skin following excisionai biopsy, keratoacanthoma, trichofblliculoma, endomeof neural triosis, and normal pancreas.“‘-‘-’ ’ The mechanism invasion in these conditions is not clear, and various possibilities include active epithelial proliferation in a plane of low resistance (perineural spaces), mechanical implantation, aberrant regeneration of biopsy-traumatized epithelium, aberrant development of epithelial or neural tissue, and active proliferation of nerves into epithelial structures.“‘~” In our case, with a history of fine needle aspiration, mechanical implantation and posttraumatic neural overgrowth appear to he possible explanations. However, we do not favor these possibilities because changes attributable to the previous aspiration were not present in the focus of interest, and the nerves do not exhibit features of traumatic neuroma.
REFERENCES 1. Page DL, Anderson IJ, Rogers 1.M’ ( ..,I( irrotna 111situ ((IIS), 111l’agr DI.. Anderson TF (eds): Diagnostic Hiatopathology o1 the Bt-east. Edinburgh, LtK, Churchill Livingstone. 1990. pp 1.57-192 2. Page DL, Anderson TJ, Sakamoto (:: Infiltrating c,trrinoma: M+jw hirtologi,lral types. in Page 1~1.. Attdrr-sort TJ (eds): Diagnostic Histopathology of the Breast. Edinburgh. UK, Churchill Li~ittgstotte. 1990, pp 193-235 3. Venable JG. Schwartz AM. Silverbcrg SC: Infiltrating cribriform carcinoma of the breast: A distinctive clinicopathotogic etrttty. H~:M PATH~I. 21: 333-338, 1990 4. Page Dl., Dixon JM. Anders~m I J, ct al: lttv.tsivr
FIGURE 3. Higher magnification of the region indicated by the upper arrow in Fig 2, left, showing neural invasion by cribriform intraductal carcinoma. (Hematoxylin-eosin stain: magnification X190.)
all the cases had previously been diagnosed as infiltrative ductal carcinoma of nonspecific type. 3.4 Furthermore, residual myoepithelial cells are not found around epithelial islands in invasive carcinoma.6,” Perineural invasion has not been described for carcinoma in situ of the breast and for in situ carcinomas of other organs. We suspect that previous cases showing such a phenomenon might have been interpreted as invasive carcinoma. It should not be too surprising to find perineural invasion in in situ carcinomas because this is a recognized phenomenon in a variety of benign and proliferative lesions, such as fibrocystic disease and sclerosing adenosis of the breast, normal and hy-
204