Ki-1 Lymphoma: A Case Report Robert Yowell, MD, and Elizabeth Hammond, MD
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
LDS Hospital Electron Microscopy Laboratory and Department of Pathology, University of Utah, Salt Lake City, Utah 84143 USA
A case of Ki-1 lymphoma of the large cell anaplastic type with weak leukocyte common antigen expression is presented. These tumors can sometimes demonstrate confusing immunophenotypes (weak or negative leukocyte common antigen, pan T, pan B, HMB 45, and S-100. and anomalous positive epithelial membrane antigen staining), and ultrastructural examination may be requested. The tumor consisted of sheets of large malignant cells with large pleomorphic nuclei, prominent nucleoli, and a high mitotic rate. Ultrastructural examination showed pleomorphic tumor cells with irregular nuclei, large nucleoli, and abundant complex cytoplasm with varied organelles. KEY WORDS: electron microscopy, immunoperoxidase, Ki- I lymphoma, ultrastructure.
CLINICAL HISTORY
MATERIALS AND METHODS
A n otherwise healthy 19-year-old man noted a small tender mass in his right axilla approximately 4 months before admission. This progressed and became painful, indurated, and inflamed and eventually involved the right lateral chest wall. The patient was treated for cellulitis with oral antibiotics, and the lesion apparently resolved. Three weeks before admission, he noted increasing right chest wall tenderness. The skin and subcutaneous tissue became progressively inflamed and indurated, and the inflammation spread to involve the right anterior chest wall and pectoral muscle, right axilla, and right scapular region. Physical examination revealed an extensive tender region of hard induration of the right thorax and an axillary mass with a weeping, ulcerated surface. The patient was also noted to have a sparse pin dot papular rash of the trunk and lower extremities. A biopsy of the axillary mass was performed.
Portions of the axillary mass were fixed in 1 0 % buffered formalin for light microscopy and in Karnofsky fixative for ultrastructural examination. Portions of formalin-fixed tissue were also postfixed in 6-5 fixative. lmmunohistochemical studies were performed on paraffin-embedded tissue b y means of the avidin-biotinperoxidase technique with antibodies against Ki-I antigen (BerH21, leukocyte common antigen (LCA), epithelial membrane antigen (EMA), pan-T-cell antigen (L601, pan-6-cell antigen (L261, melanoma-specific antigen (HMB-45), and S-100 protein. For ultrastructural examination, tissue was postfixed in osmium, dehydrated in graded acetones, and embedded in epoxy resin. Ultrathin sections from selected tumor blocks were stained with lead citrate and uranyl acetate.
RESULTS Gross Pathology The axillary mass consisted of occasional small, gray-white nodules up t o 1.5 cm in
Address correspondence to R Yowell
Copyright
Ultrastructural Pathology, 16: 1 1 - 16, 1992 Hemisphere Publishing Corporation
0 1992 by
11
12
R. Yowell and E. Hammond
diameter in axillary fibrofatty connective tissues.
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
Light Microscopy Microscopic examination demonstrated a malignant neoplasm composed of sheets of large malignant cells possessing large pleomorphic nuclei with prominent nucleoli and relatively abundant cytoplasm. Frequent tumor cells with wreathlike nuclei were seen. Frequent mitoses were present, and occasional multinucleated cells were observed (Fig. 1). Differential diagnosis included large cell lymphoma, melanoma, and metastatic undifferentiated carcinoma.
Immunohistochemistry Strong membraneous staining with BerH2 was obtained. Positivity with EMA was also found. Initial staining for LCA was equivocal, but repeat staining on tissue postfixed in B-5 fixative was positive in a moderate number of tumor cells. Staining
for pan-B, pan-T, HMB-45, and S-100 protein was negative.
Electron Microscopy Ultrastructural examination showed pleomorphic tumor cells w i t h irregularly shaped nuclei and large nucleoli. The abundant, often eccentric, tumor cell cytoplasm contained numerous polysomes; stacked profiles of rough endoplasrnic reticulum; occasional variably sized, electron-dense, membrane-bound granules; scattered variably sized clear vesicles; and common Golgi regions, often within nuclear concavities or in the center of a wreathlike circle of nuclear lobes. Profiles of smooth endoplasmic reticulum were common. Rare rudimentary junctions occasionally joined tumor cells, but no desmosomes were observed. Melanosomes were not present (Figs. 2 and 3).
DISCUSSION Several reports have recently described various aspects of Ki-1-positive large cell
FIG. 1 Light micrograph. The axillary mass was composed of sheets of cells containing abundant cytoplasm with common paranuclear clearing and common wreathlike nuclei, prominent nucleoli, and frequent mitoses. Hematoxylin and eosin, x 400.
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
Ki-1 Lymphoma
13
FIG. 2 Electron micrograph. Sheets of pleomorphic tumor cells contain abundant, often eccentric cytoplasm and common irregular nuclei with prominent nucleoli,
x 5,000. non-Hodgkin lymphoma. The morphology, immunophenotype, ultrastructure, cytogenetics, and clinical behavior of K i - I positive lymphomas are heterogeneous. The Ki-I antigen was originally detected on the Hodgkin disease-derived cell line L428.' This membrane antigen is composed of a 90-kD precursor and associated 15-kD and 30-kD moieties.* BerH2 antibody recognizes a Ki-1-related epitope preserved in formalin-fixed tissue^.^ Ki-1 antigen has been shown to be expressed by embryonal carcinoma4 in addition to hematopoietic tissues, including ReedSternberg cells in Hodgkin disease and malignant cells in the recently described anaplastic large cell (ALC) l y m p h ~ m a . ' , ~ Two patterns of Ki- 1-positive lymphomas have been recognized.6 One pattern consists of ALC lymphoma (Ki-l-positive ALC lymphoma), which generally presents at a lower stage, is held by some investiga-
tors to be more common in young patients, and has a better prognosis than the second morphologic pattern.6-8 On the basis of a limited number of cases, Ki-1-positive ALC lymphoma has been shown to possess a unique cytogenetic abnormality ( 2 : 5 reciprocal tran~location).~ This pattern is characterized by large pleomorphic cells often showing sinus infiltration with partial node replacement and sparing of B-cell areas. Cells frequently contain paranuclear clearing, large prominent nucleoli, and common wreathlike nuclei. Reed-Sternberg-like cells with inclusionlike nucleoli can be seen. Mitotic activity is high, and delicate collagenous bands between nests of tumor cells are frequently seen; plasma cells are common. The cytologic characteristics of this variant of Ki-1 lymphoma are identical to those observed in cutaneous Ki-1-positive ALC lymphoma and regressing atypical histiocytosis.''
R. Yowell and E. Hammond
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
14
FIG. 3 Electron micrograph. Large tumor cell with markedly irregular nuclear profile and cytoplasm containing occasional lysosomes, profiles of smooth endoplasmic reticulum, and numerous polysomes, x 10,000.
The second morphologic group of Ki-I lymphomas is composed of relatively monomorphous cells with less pronounced nuclear pleomorphism, delicate nucleoli, absence of paranuclear clearing, uncommon multinucleated giant cells, rare cells with wreathlike nuclei, and rare ReedSternberg-like cells. This variant does not possess the characteristic chromosomal translocation observed in the anaplastic ~ariant.~ The majority (70%) of Ki-I-positive lymphomas express T-cell antigens, often in an aberrant pattern with common loss of differentiation markers. A small proportion (20%) express neither B-cell nor T-cell antigens, and B-cell lineage is uncommon (0% t o 10%). Most cases have been reported as expressing HLA-DR, Tac (an interleukin-2 receptor), and T-9 (a transferrin receptor).” The infiltrates of cutaneous K i - I -positive ALC lymphomas have all been of T-cell phenotype.”
Confusion regarding diagnosis can arise from the fact that LCA expression may be weak or absent, especially in paraffin-embedded tissue. Ki-I -positive lymphomas have been reported t o be LCA negative in up t o 30% of cases.” In addition, EMA positivity has been reported in many cases (from 58%6 t o 10O%l2 of cases). Leu-MI expression is uniformly negative. Ultrastructurally, Ki- 1-positive ALC lymphomas are characterized as having pleomorphic, cleaved, or multisegmented nuclei and generally multiple nucleoli. The abundant cytoplasm contains a welldeveloped Golgi apparatus, prominent polysomes, and variable numbers of lysosomes. In some cases the neoplastic cells may contain secondary lysosomes, suggesting histiocyte d i f f e r e n t i a t i ~ n . ’ ~Ultra.’~ structural morphometry demonstrated a nuclear size comparable t o that of other large cell lymphomas but a higher nuclear
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
Ki-1 Lymphoma
contour index, indicating greater nuclear irregularity than other lymphoma^.'^ Clinically, Ki- 1-positive ALC lymphoma can occur in all age groups and has been described not infrequently in children and adolescent^.^'^ Cutaneous Ki- 1-positive ALC lymphoma is manifest more often in an older population (mean age in 1 5 previously reported cases,” 60 years). Chott et aI6 found that fewer patients with the anaplastic variant presented with stage Ill or IV disease compared t o those with the monomorphous variant ( 2 7 % and 73%, respectively) and that the mean survival with the anaplastic variant was greater than that with the monomorphous variant (13months and 4 months, respectively). There was no difference between the anaplastic variant and the monomorphous variant with respect to age, although younger patients had a better prognosis. These investigators found bone marrow involvement in 30% of patients, which occurred exclusively in patients older than 40 years of age. Similar lack of marrow involvement in a series of 1 9 young patients with K i - l positive ALC lymphoma was reported by Agnarsson and Kadin.’ A similar survival advantage for the anaplastic variant was found among the 1 0 cases studied by Bitter et al,’ where 4 of 5 patients with ALC lymphoma were alive in complete remission after 1 0 to 2 7 months of follow-up, whereas 3 of 4 patients with Ki-I-positive non-ALC lymphoma died within 17 months of follow-up. The differential diagnostic considerations in Ki-1-positive lymphoma include anaplastic carcinoma, malignant histiocytic tumors, regressing atypical histiocytosis, syncytial variant of nodular sclerosing Hodgkin disease, and malignant melanoma. In general, anaplastic carcinoma can be distinguished from Ki-1-positive ALC lymphoma by the use of epithelial markers such as cytokeratins; thus immunologic studies as well as the clinical history should establish the correct diagnosis. In cases where marker studies are equivocal, electron microscopy can provide a resolution. A key ultrastructural distinction between anaplastic carcinoma and Ki- 1-
15 positive ALC lymphoma is the lack of epithelial junctions in lymphoma. Malignant histiocytosis may have similar pathologic features, including atypical large histiocytic cells demonstrating a sinusoidal pattern of infiltration and partial node effacement. Ultrastructural distinction between these lesions may not be possible, but malignant histiocytosis frequently has a different clinical presentation with frequent liver, spleen, and marrow involvement. The lack of histiocytic immunophenotypic markers could rule out this entity. Regressing atypical histiocytosis is a misnomer because these tumors express T-cell markers in addition t o Ki-1 antigen. Kaudewitz et allo express the view that this entity represents a clinical variant of Ki-I -positive ALC lymphoma presenting in skin. It may occasionally be difficult t o distinguish Ki-I-positive ALC lymphoma from the syncytial variant of nodular sclerosing Hodgkin disease. If the tumor has large numbers of Reed-Sternberg-like cells, prominent fibrous bands, and a pleomorphic inflammatory cell infiltrate, these t w o entities could be confused. Skin involvement would favor Ki-I lymphoma. Immunophenotyping would in most cases distinguish these t w o entities. Mascarel et all6 reported Leu-MI positivity in ReedSternberg cells in 5 5 of 7 3 cases (75%) of nodular sclerosing Hodgkin disease, whereas this antigen is typically absent from Ki-1-positive lymphomas. LCA is commonly but not invariably present in Ki1-positive lymphoma, whereas it is rarely expressed by Reed-Sternberg cells. EMA is commonly expressed in Ki-1-positive ALC lymphoma, whereas this antigen is rarely expressed in nodular sclerosing Hodgkin disease. The ultrastructural distinction between malignant melanoma and Ki-1-positive lymphoma can be difficult. The nuclear features are similar, and these tumors both commonly have abundant cytoplasm with pleomorphic cellular organelles. The presence of surface microvillous processes would favor malignant melanoma. The presence of melanosomes would establish
R. Yowell and E. Hammond
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
16 the diagnosis of melanoma, but in amelanotic melanoma these structures can be quite rare. S-100 protein staining is useful because the vast majority of melanomas are positive for this antigen, whereas Ki-lpositive lymphomas have not been reported as staining with this antigen. Ki-I lymphoma may give confusing immunoperoxidase results, with LCA staining commonly being negative, both T-cell and B-cell markers occasionally being negative, and EMA staining often being positive. Because of this confusing immunoperoxidase profile, these tumors may on occasion be submitted for ultrastructural evaluation. Although Ki-I lymphomas are not usually diagnosed by electron microscopy, pathologists and electron microscopists need t o be cognizant of this entity, which should be included in the differential diagnosis of ALC tumors. An awareness of the characteristic morphologic and immunophenotypic pattern of this interesting lymphoma should allow accurate diagnosis, even when the clinical presentation is atypical.
REFERENCES Schwab U.Stein H, Gerdes J, et al. Production of a monoclonal antibody specific for Hodgkin's and Reed-Sternberg cells of Hodgkin's disease and a subset of normal lymphoid cells. Nature (London). 1982;299:65-66. Stein H. Immunologic and tissue culture studies in Hodgkin's disease: investigation and diagnosis. Am J Surg Pathol. 1987; 11: 148149. Schwarting R, Gerdes J, Durkop H, et al. BERH2: a new anti-Ki-I (CD30) monoclonal antibody directed at a Formol-resistant epitope. Blood. 1989;74: 1678-1 689. Pallesen G, Hamilton-Dutoit S. Ki-I (CD301 antigen is regularly expressed by tumor cells of embryonal carcinoma. Am J Pathol. 1988; 133~446-450.
5. Stein H, Mason DY, Gerdes J, et al. The expression of the Hodgkin's disease associated antigen Ki-I in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985;66:848-858. 6. Chott A, Kaserer K, Augustin I, et al. Ki-I positive large cell lymphoma: a clinicopathologic study of 41 cases. Am J Surg Pathol. 1990; 14:439-448. 7. Agnarsson B, Kadin M. Ki-I positive large cell lymphoma: a morphologic and immunologic study of 1 9 cases. A m J Surg Pathol. 1988;12:264-274. 8. Kadin M, Sako D, Berliner N, et al. Childhood Ki-I lymphoma presenting with skin lesions and peripheral lymphadenopathy. Blood. 1986;68:1042-1049. 9. Bitter M, Franklin W, Larson R, et al. Morphology in Ki-I (CD30)-positive non-Hodgkin's lymphoma is correlated with clinical features and the presence of a unique chromosomal abnormality, t(2;5)(p23;q35). Am J Surg Pathol. 1990; 14:305-316. 10. Kaudewitz P, Stein H, Dallenbach F, et al. Primary and secondary cutaneous Ki- 1 (CD30') anaplastic large cell lymphomas. Am J Pathol. 1989;135:359-367. 1 1. Suchi T, Lennert K, Tu L-Y, et al. Histopathology and histochemistry of peripheral T cell lymphomas: a proposal for their classification. J Clin Pathol. 1987;40:995-1015. 12. Fujimoto J, Hata J, lshii E, et al. Ki-1 lymphomas in childhood: immunohistochemical analysis and the significance of epithelial membrane antigen (EMA) as a new marker. Virchows Arch A. 1988;412:307-314. 13. Erlandson R. Filippa D. Unusual non-Hodgkin's lymphomas and true histiocytic lymphomas. Ultrastruct Pathol. 1989; 13:249-273. 14. Burns B, Cripps C, Dardick I. A case of Ki-1 large cell "anaplastic" lymphoma with ultrastructural features. Hum Pathol. 1989;20:393-396. 15. Burns 6 , Dardick I. Ki-1 positive non-Hodgkin's lymphomas. Am J Clin Pathol. 1990;93:327-332. 16. Mascarel I, Trojani M, Eghbali H, et al. Prognostic value of phenotyping by Ber-H2, Leu-1 , EMA in Hodgkin's disease. Arch Pathol Lab Med. 1990; 114:953-955. +
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
LDS Hospital Electron Microscopy Laboratory and Department of Pathology, University of Utah, Salt Lake City, Utah 84143 USA
A case of Ki-1 lymphoma of the large cell anaplastic type with weak leukocyte common antigen expression is presented. These tumors can sometimes demonstrate confusing immunophenotypes (weak or negative leukocyte common antigen, pan T, pan B, HMB 45, and S-100. and anomalous positive epithelial membrane antigen staining), and ultrastructural examination may be requested. The tumor consisted of sheets of large malignant cells with large pleomorphic nuclei, prominent nucleoli, and a high mitotic rate. Ultrastructural examination showed pleomorphic tumor cells with irregular nuclei, large nucleoli, and abundant complex cytoplasm with varied organelles. KEY WORDS: electron microscopy, immunoperoxidase, Ki- I lymphoma, ultrastructure.
CLINICAL HISTORY
MATERIALS AND METHODS
A n otherwise healthy 19-year-old man noted a small tender mass in his right axilla approximately 4 months before admission. This progressed and became painful, indurated, and inflamed and eventually involved the right lateral chest wall. The patient was treated for cellulitis with oral antibiotics, and the lesion apparently resolved. Three weeks before admission, he noted increasing right chest wall tenderness. The skin and subcutaneous tissue became progressively inflamed and indurated, and the inflammation spread to involve the right anterior chest wall and pectoral muscle, right axilla, and right scapular region. Physical examination revealed an extensive tender region of hard induration of the right thorax and an axillary mass with a weeping, ulcerated surface. The patient was also noted to have a sparse pin dot papular rash of the trunk and lower extremities. A biopsy of the axillary mass was performed.
Portions of the axillary mass were fixed in 1 0 % buffered formalin for light microscopy and in Karnofsky fixative for ultrastructural examination. Portions of formalin-fixed tissue were also postfixed in 6-5 fixative. lmmunohistochemical studies were performed on paraffin-embedded tissue b y means of the avidin-biotinperoxidase technique with antibodies against Ki-I antigen (BerH21, leukocyte common antigen (LCA), epithelial membrane antigen (EMA), pan-T-cell antigen (L601, pan-6-cell antigen (L261, melanoma-specific antigen (HMB-45), and S-100 protein. For ultrastructural examination, tissue was postfixed in osmium, dehydrated in graded acetones, and embedded in epoxy resin. Ultrathin sections from selected tumor blocks were stained with lead citrate and uranyl acetate.
RESULTS Gross Pathology The axillary mass consisted of occasional small, gray-white nodules up t o 1.5 cm in
Address correspondence to R Yowell
Copyright
Ultrastructural Pathology, 16: 1 1 - 16, 1992 Hemisphere Publishing Corporation
0 1992 by
11
12
R. Yowell and E. Hammond
diameter in axillary fibrofatty connective tissues.
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
Light Microscopy Microscopic examination demonstrated a malignant neoplasm composed of sheets of large malignant cells possessing large pleomorphic nuclei with prominent nucleoli and relatively abundant cytoplasm. Frequent tumor cells with wreathlike nuclei were seen. Frequent mitoses were present, and occasional multinucleated cells were observed (Fig. 1). Differential diagnosis included large cell lymphoma, melanoma, and metastatic undifferentiated carcinoma.
Immunohistochemistry Strong membraneous staining with BerH2 was obtained. Positivity with EMA was also found. Initial staining for LCA was equivocal, but repeat staining on tissue postfixed in B-5 fixative was positive in a moderate number of tumor cells. Staining
for pan-B, pan-T, HMB-45, and S-100 protein was negative.
Electron Microscopy Ultrastructural examination showed pleomorphic tumor cells w i t h irregularly shaped nuclei and large nucleoli. The abundant, often eccentric, tumor cell cytoplasm contained numerous polysomes; stacked profiles of rough endoplasrnic reticulum; occasional variably sized, electron-dense, membrane-bound granules; scattered variably sized clear vesicles; and common Golgi regions, often within nuclear concavities or in the center of a wreathlike circle of nuclear lobes. Profiles of smooth endoplasmic reticulum were common. Rare rudimentary junctions occasionally joined tumor cells, but no desmosomes were observed. Melanosomes were not present (Figs. 2 and 3).
DISCUSSION Several reports have recently described various aspects of Ki-1-positive large cell
FIG. 1 Light micrograph. The axillary mass was composed of sheets of cells containing abundant cytoplasm with common paranuclear clearing and common wreathlike nuclei, prominent nucleoli, and frequent mitoses. Hematoxylin and eosin, x 400.
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
Ki-1 Lymphoma
13
FIG. 2 Electron micrograph. Sheets of pleomorphic tumor cells contain abundant, often eccentric cytoplasm and common irregular nuclei with prominent nucleoli,
x 5,000. non-Hodgkin lymphoma. The morphology, immunophenotype, ultrastructure, cytogenetics, and clinical behavior of K i - I positive lymphomas are heterogeneous. The Ki-I antigen was originally detected on the Hodgkin disease-derived cell line L428.' This membrane antigen is composed of a 90-kD precursor and associated 15-kD and 30-kD moieties.* BerH2 antibody recognizes a Ki-1-related epitope preserved in formalin-fixed tissue^.^ Ki-1 antigen has been shown to be expressed by embryonal carcinoma4 in addition to hematopoietic tissues, including ReedSternberg cells in Hodgkin disease and malignant cells in the recently described anaplastic large cell (ALC) l y m p h ~ m a . ' , ~ Two patterns of Ki- 1-positive lymphomas have been recognized.6 One pattern consists of ALC lymphoma (Ki-l-positive ALC lymphoma), which generally presents at a lower stage, is held by some investiga-
tors to be more common in young patients, and has a better prognosis than the second morphologic pattern.6-8 On the basis of a limited number of cases, Ki-1-positive ALC lymphoma has been shown to possess a unique cytogenetic abnormality ( 2 : 5 reciprocal tran~location).~ This pattern is characterized by large pleomorphic cells often showing sinus infiltration with partial node replacement and sparing of B-cell areas. Cells frequently contain paranuclear clearing, large prominent nucleoli, and common wreathlike nuclei. Reed-Sternberg-like cells with inclusionlike nucleoli can be seen. Mitotic activity is high, and delicate collagenous bands between nests of tumor cells are frequently seen; plasma cells are common. The cytologic characteristics of this variant of Ki-1 lymphoma are identical to those observed in cutaneous Ki-1-positive ALC lymphoma and regressing atypical histiocytosis.''
R. Yowell and E. Hammond
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
14
FIG. 3 Electron micrograph. Large tumor cell with markedly irregular nuclear profile and cytoplasm containing occasional lysosomes, profiles of smooth endoplasmic reticulum, and numerous polysomes, x 10,000.
The second morphologic group of Ki-I lymphomas is composed of relatively monomorphous cells with less pronounced nuclear pleomorphism, delicate nucleoli, absence of paranuclear clearing, uncommon multinucleated giant cells, rare cells with wreathlike nuclei, and rare ReedSternberg-like cells. This variant does not possess the characteristic chromosomal translocation observed in the anaplastic ~ariant.~ The majority (70%) of Ki-I-positive lymphomas express T-cell antigens, often in an aberrant pattern with common loss of differentiation markers. A small proportion (20%) express neither B-cell nor T-cell antigens, and B-cell lineage is uncommon (0% t o 10%). Most cases have been reported as expressing HLA-DR, Tac (an interleukin-2 receptor), and T-9 (a transferrin receptor).” The infiltrates of cutaneous K i - I -positive ALC lymphomas have all been of T-cell phenotype.”
Confusion regarding diagnosis can arise from the fact that LCA expression may be weak or absent, especially in paraffin-embedded tissue. Ki-I -positive lymphomas have been reported t o be LCA negative in up t o 30% of cases.” In addition, EMA positivity has been reported in many cases (from 58%6 t o 10O%l2 of cases). Leu-MI expression is uniformly negative. Ultrastructurally, Ki- 1-positive ALC lymphomas are characterized as having pleomorphic, cleaved, or multisegmented nuclei and generally multiple nucleoli. The abundant cytoplasm contains a welldeveloped Golgi apparatus, prominent polysomes, and variable numbers of lysosomes. In some cases the neoplastic cells may contain secondary lysosomes, suggesting histiocyte d i f f e r e n t i a t i ~ n . ’ ~Ultra.’~ structural morphometry demonstrated a nuclear size comparable t o that of other large cell lymphomas but a higher nuclear
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
Ki-1 Lymphoma
contour index, indicating greater nuclear irregularity than other lymphoma^.'^ Clinically, Ki- 1-positive ALC lymphoma can occur in all age groups and has been described not infrequently in children and adolescent^.^'^ Cutaneous Ki- 1-positive ALC lymphoma is manifest more often in an older population (mean age in 1 5 previously reported cases,” 60 years). Chott et aI6 found that fewer patients with the anaplastic variant presented with stage Ill or IV disease compared t o those with the monomorphous variant ( 2 7 % and 73%, respectively) and that the mean survival with the anaplastic variant was greater than that with the monomorphous variant (13months and 4 months, respectively). There was no difference between the anaplastic variant and the monomorphous variant with respect to age, although younger patients had a better prognosis. These investigators found bone marrow involvement in 30% of patients, which occurred exclusively in patients older than 40 years of age. Similar lack of marrow involvement in a series of 1 9 young patients with K i - l positive ALC lymphoma was reported by Agnarsson and Kadin.’ A similar survival advantage for the anaplastic variant was found among the 1 0 cases studied by Bitter et al,’ where 4 of 5 patients with ALC lymphoma were alive in complete remission after 1 0 to 2 7 months of follow-up, whereas 3 of 4 patients with Ki-I-positive non-ALC lymphoma died within 17 months of follow-up. The differential diagnostic considerations in Ki-1-positive lymphoma include anaplastic carcinoma, malignant histiocytic tumors, regressing atypical histiocytosis, syncytial variant of nodular sclerosing Hodgkin disease, and malignant melanoma. In general, anaplastic carcinoma can be distinguished from Ki-1-positive ALC lymphoma by the use of epithelial markers such as cytokeratins; thus immunologic studies as well as the clinical history should establish the correct diagnosis. In cases where marker studies are equivocal, electron microscopy can provide a resolution. A key ultrastructural distinction between anaplastic carcinoma and Ki- 1-
15 positive ALC lymphoma is the lack of epithelial junctions in lymphoma. Malignant histiocytosis may have similar pathologic features, including atypical large histiocytic cells demonstrating a sinusoidal pattern of infiltration and partial node effacement. Ultrastructural distinction between these lesions may not be possible, but malignant histiocytosis frequently has a different clinical presentation with frequent liver, spleen, and marrow involvement. The lack of histiocytic immunophenotypic markers could rule out this entity. Regressing atypical histiocytosis is a misnomer because these tumors express T-cell markers in addition t o Ki-1 antigen. Kaudewitz et allo express the view that this entity represents a clinical variant of Ki-I -positive ALC lymphoma presenting in skin. It may occasionally be difficult t o distinguish Ki-I-positive ALC lymphoma from the syncytial variant of nodular sclerosing Hodgkin disease. If the tumor has large numbers of Reed-Sternberg-like cells, prominent fibrous bands, and a pleomorphic inflammatory cell infiltrate, these t w o entities could be confused. Skin involvement would favor Ki-I lymphoma. Immunophenotyping would in most cases distinguish these t w o entities. Mascarel et all6 reported Leu-MI positivity in ReedSternberg cells in 5 5 of 7 3 cases (75%) of nodular sclerosing Hodgkin disease, whereas this antigen is typically absent from Ki-1-positive lymphomas. LCA is commonly but not invariably present in Ki1-positive lymphoma, whereas it is rarely expressed by Reed-Sternberg cells. EMA is commonly expressed in Ki-1-positive ALC lymphoma, whereas this antigen is rarely expressed in nodular sclerosing Hodgkin disease. The ultrastructural distinction between malignant melanoma and Ki-1-positive lymphoma can be difficult. The nuclear features are similar, and these tumors both commonly have abundant cytoplasm with pleomorphic cellular organelles. The presence of surface microvillous processes would favor malignant melanoma. The presence of melanosomes would establish
R. Yowell and E. Hammond
Ultrastruct Pathol Downloaded from informahealthcare.com by Mcgill University on 11/04/14 For personal use only.
16 the diagnosis of melanoma, but in amelanotic melanoma these structures can be quite rare. S-100 protein staining is useful because the vast majority of melanomas are positive for this antigen, whereas Ki-lpositive lymphomas have not been reported as staining with this antigen. Ki-I lymphoma may give confusing immunoperoxidase results, with LCA staining commonly being negative, both T-cell and B-cell markers occasionally being negative, and EMA staining often being positive. Because of this confusing immunoperoxidase profile, these tumors may on occasion be submitted for ultrastructural evaluation. Although Ki-I lymphomas are not usually diagnosed by electron microscopy, pathologists and electron microscopists need t o be cognizant of this entity, which should be included in the differential diagnosis of ALC tumors. An awareness of the characteristic morphologic and immunophenotypic pattern of this interesting lymphoma should allow accurate diagnosis, even when the clinical presentation is atypical.
REFERENCES Schwab U.Stein H, Gerdes J, et al. Production of a monoclonal antibody specific for Hodgkin's and Reed-Sternberg cells of Hodgkin's disease and a subset of normal lymphoid cells. Nature (London). 1982;299:65-66. Stein H. Immunologic and tissue culture studies in Hodgkin's disease: investigation and diagnosis. Am J Surg Pathol. 1987; 11: 148149. Schwarting R, Gerdes J, Durkop H, et al. BERH2: a new anti-Ki-I (CD30) monoclonal antibody directed at a Formol-resistant epitope. Blood. 1989;74: 1678-1 689. Pallesen G, Hamilton-Dutoit S. Ki-I (CD301 antigen is regularly expressed by tumor cells of embryonal carcinoma. Am J Pathol. 1988; 133~446-450.
5. Stein H, Mason DY, Gerdes J, et al. The expression of the Hodgkin's disease associated antigen Ki-I in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985;66:848-858. 6. Chott A, Kaserer K, Augustin I, et al. Ki-I positive large cell lymphoma: a clinicopathologic study of 41 cases. Am J Surg Pathol. 1990; 14:439-448. 7. Agnarsson B, Kadin M. Ki-I positive large cell lymphoma: a morphologic and immunologic study of 1 9 cases. A m J Surg Pathol. 1988;12:264-274. 8. Kadin M, Sako D, Berliner N, et al. Childhood Ki-I lymphoma presenting with skin lesions and peripheral lymphadenopathy. Blood. 1986;68:1042-1049. 9. Bitter M, Franklin W, Larson R, et al. Morphology in Ki-I (CD30)-positive non-Hodgkin's lymphoma is correlated with clinical features and the presence of a unique chromosomal abnormality, t(2;5)(p23;q35). Am J Surg Pathol. 1990; 14:305-316. 10. Kaudewitz P, Stein H, Dallenbach F, et al. Primary and secondary cutaneous Ki- 1 (CD30') anaplastic large cell lymphomas. Am J Pathol. 1989;135:359-367. 1 1. Suchi T, Lennert K, Tu L-Y, et al. Histopathology and histochemistry of peripheral T cell lymphomas: a proposal for their classification. J Clin Pathol. 1987;40:995-1015. 12. Fujimoto J, Hata J, lshii E, et al. Ki-1 lymphomas in childhood: immunohistochemical analysis and the significance of epithelial membrane antigen (EMA) as a new marker. Virchows Arch A. 1988;412:307-314. 13. Erlandson R. Filippa D. Unusual non-Hodgkin's lymphomas and true histiocytic lymphomas. Ultrastruct Pathol. 1989; 13:249-273. 14. Burns B, Cripps C, Dardick I. A case of Ki-1 large cell "anaplastic" lymphoma with ultrastructural features. Hum Pathol. 1989;20:393-396. 15. Burns 6 , Dardick I. Ki-1 positive non-Hodgkin's lymphomas. Am J Clin Pathol. 1990;93:327-332. 16. Mascarel I, Trojani M, Eghbali H, et al. Prognostic value of phenotyping by Ber-H2, Leu-1 , EMA in Hodgkin's disease. Arch Pathol Lab Med. 1990; 114:953-955. +
