Cutaneous Plasmacytomas in Dogs: A Morphologic and Immunohis tochemical Study

Transcription

1 Vet. Pathol. 26: (1989) Cutaneous Plasmacytomas in Dogs: A Morphologic and Immunohis tochemical Study K. E. BAER, A. K. PATNAIK, S. R. GILBERTSON, AND A. I. HURVITZ Department of Pathology, The Animal Medical Center, and Cenvet Laboratory, New York, NY Abstract. Forty-nine cutaneous plasmacytomas in 46 dogs were studied. Tumors occurred at solitary sites in middle-aged to old dogs (mean age, 9.7 years) and most commonly involved the skin of the digits, lips, and ears. Initial diagnosis was made on the basis of light microscopic morphologic findings. Tumors were graded according to the extent of cellular differentiation and immunoreactivity to a panel of immunohistochemical markers (cytokeratins, canine IgG F[ab],, neurofilament, neuron-specific enolase, S-100 protein, and vimentin). Immunoreactivity was limited to antibodies directed at canine IgG F(ab)z and vimentin. Vimentin immunoreactivity was usually greater than that of canine IgG F(ab),, but there was no correlation between immunoreactivity and histologic grade of the tumors. Thirty-six of 39 dogs (92.3%) followed (mean follow-up, 13 months) were cured by surgical excision. The results of this study indicate that canine cutaneous plasmacytomas are benign neoplasms that should be included in the differential diagnosis of cutaneous round cell tumors in dogs. Canine extramedullary plasmacytomas in various sites have been reported as individual cases; some of the dogs had concomitant or subsequent multiple mye- ~ o ~ ~. The ~ morphologic J ~ J ~ and J clinical ~ ~ features ~ ~ of primary cutaneous plasmacytomas are described in a report of 11 dogs.i4 In human patients with multiple myeloma, extramedullary sites of involvement are not uncommon, but involvement of the skin is unusual.3j0,22 Cutaneous plasmacytomas without evidence of bone involvement are rare in human~.~j~s~~ Neoplasms regarded as round cell tumors in the skin of dogs include histiocytoma, cutaneous lymphoma, mast cell tumor, reticulum cell sarcoma, and trans- missible venereal tum~r.~~~~ Melanomas are included in this category by some,2o and canine cutaneous neuroendocrine turnors7j7 probably belong in this group. Cutaneous plasmacytomas have not been included in accounts of cutaneous neoplasia in dogs. 1,4,7,23,28,29 Because of morphologic and clinical similarities, it is likely that some cutaneous plasmacytomas in dogs have been misclassified as either cutaneous neuroendocrine tumors, reticulum cell sarcomas, or cutaneous lymphomas. The purpose of this study is to describe the morphologic, immunohistochemical, and clinical features of cutaneous plasmacytomas in 46 dogs. The biologic behavior of the tumors is evaluated on the basis of follow-up information available in 39 dogs. The cutaneous plasmacytomas are compared with other cutaneous neoplasms reported to have similar morphologic and clinical features. 216 Materials and Methods The cutaneous plasmacytomas studied were obtained from the surgical pathology files of the Animal Medical Center and Cenvet Laboratories. Clinical findings were obtained from the medical records and by personal communication with the referring veterinarians. Follow-up information was obtained from the medical records, by personal communication with the referring veterinarians, and by personal communication with the owners of the dogs. Excisional biopsy was done in all dogs. Specimens were fixed for 24 to 48 hours in buffered 10% formalin, processed routinely, embedded in paraffin, and sectioned at 4-6 km. Sections were stained with hematoxylin and eosin, methyl green pyronine, Congo red, and Giemsa stains. Tumors were classified as cutaneous plasmacytomas on the basis of morphologic findings on light microscopic examination. Morphologic criteria included the presence of individualized or tightly packed neoplastic cells arranged in cords and nests in the dermis, a fine reticular stromal network of capillary vessels separating the cellular cords and nests, and cytologic features consistent with neoplastic plasma cells. Cytologic features included round to oval cells with predominantly round nuclei, coarsely clumped chromatin, small, solitary nucleoli, variable amounts of amphophilic to pale basophilic cytoplasm, and low to moderate mitotic activity. The presence of binucleate and multinucleate neoplastic cells was not an essential criterion but was considered to support the diagnosis. Tumors were graded according to the extent of cellular differentiation. Grade I tumors had greater than 70% welldifferentiated neoplastic cells. Well-differentiated cells resembled normal plasma cells and had monomorphic, often eccentrically placed, round nuclei and modest amounts of

2 Cutaneous Plasmacytomas in Dogs 217 cytoplasm. Grade I1 tumors had 30-70% poorly differentiated neoplastic cells. Poorly differentiated cells were larger than well-differentiated cells. The larger cell size was attributable to larger, more pleomorphic, often eccentrically placed nuclei and more cytoplasm. Grade I11 tumors had greater than 70% poorly differentiated neoplastic cells. Additional sections of each specimen were examined for reactivity to a panel of immunohistochemical markers using standard avidin-biotin-peroxidase complex immunoperoxidase technique^.^ Primary antibodies were directed at low molecular weight cytokeratins (AEl/AE3, Hybridtech, Inc., San Diego, CA), canine IgG F(ab), (Cooper Biomedical, Inc., Malvern, PA), neurofilament (Biogenex Laboratories, Dublin, CA), neuron-specific enolase (Dako Corp., Santa Barbara, CA), S-100 protein (Dako Corp., Santa Barbara, CA), and vimentin (Biogenex Laboratories, Dublin, CA). Dilutions of the primary antibodies were 1 : 100 for cytokeratin and neuron-specific enolase, 1 : 1,000 for canine IgG F(ab),, 1 : 1,600 for S-100 protein, 1 : 3,200 for vimentin, and neurofilament was prediluted. Sections were incubated overnight in the primary antibody at 4 C, except in the case of canine IgG F(ab), which was incubated for 30 minutes at 4 C. Sections were subjected to predigestion (saponin [Sigma Chemical Co., St. Louis, MO] for neurofilament, S-100, and vimentin; pepsin [Sigma Chemical Co.] for cytokeratin and neuron-specific enolase; and trypsin [Life Technologies Inc., Grand Island, NY] for canine IgG F[ab],). Incubation in biotinylated secondary antibody and avidin-biotin complex (Vector Laboratories, Burlingame, CA) was for 30 minutes each at room temperature. The chromagen used was 3'3' diaminobenzidine tetrahydrochloride (Sigma Chemical Co., St. Louis, MO). Normal serum was substituted for the primary antibodies to serve as negative controls. Appropriate normal tissues were used as positive controls for each immunohistochemical marker. Sections were counterstained with Mayer's hematoxylin, dehydrated, and coverslipped. Immunohistochemical reactivity was graded on a scale of 0 to 3. Zero (0) was assigned to specimens with no or rare positive staining neoplastic cells. One (+ 1) was assigned to specimens with distinct positive staining in 10-30% of the neoplastic cells. Two (+2) was assigned to specimens with distinct positive staining in 30-70% of the neoplastic cells. Three (+ 3) was assigned to specimens with distinct positive staining in greater than 70% of the neoplastic cells. A similar system of grading was used for routine histochemical staining. Results Cutaneous plasmacytomas were diagnosed in 46 dogs. Site of tumor, age, and sex of the 46 dogs are given (Table 1). The dogs were middle-aged to old (mean age, 9.7 years); dogs with tumors of the lip area were slightly younger (mean age, 7.8 years). Twentyeight dogs (6 1.O%) were male (1 8 intact, ten castrated), and 18 (39.0%) were female (three intact, 15 spayed). The tumors occurred more commonly in males than females at all sites except the ear. There were 13 mixed breed dogs, five cocker spaniels, four golden retrievers, four poodles, two Airedales, two Brittany spaniels, and Table 1. Site of tumor, age, and sex in 46 dogs with cutaneous plasmacytomas.... Digit (5-15) 11 :4 Lip (5-12) 7:4 Ear (5-15) 4: 6 Other (6-15) 614 Total (5-1 5) 28: 18 two Scottish terriers. The remaining 14 dogs consisted of one each of a variety of breeds. The cutaneous plasmacytomas occurred at solitary sites in all 46 dogs. The most common site (15/46) was the skin of the digit (forelimb digit, nine; hind limb digit, six). In 11 dogs, tumors were located in the skin of the lip area (upper lip, eight; lower lip, three), and in ten dogs, the external ear (pinna, seven; ear canal, three). Tumors occurred at a variety of other sites in ten dogs, including the skin of the perianal region in two, the dorsum of the head in two, and one each in the skin of the lateral cervical region, forelimb, ventrolateral thorax, ventral abdomen, lateral thigh, and lateral stifle. The tumors were broad-based, spherical or domeshaped, and hairless; some were pedunculated. Many, especially those involving the digits, were hemorrhagic and ulcerated superficially. The tumors ranged in size from 0.3 to 2.2 cm in diameter; the mean diameter was 0.8 cm. None were encapsulated, but all were circumscribed and easily delineated from adjacent normal tissues at the time of excision. They had a relatively soft consistency, and cut surfaces were pale tan to amber or dark red and hemorrhagic. Physical examination findings did not reveal signs of systemic disease referable to cutaneous plasmacytoma in any of the dogs. Total serum protein, albumin, and globulins were evaluated in five dogs and were within normal limits. Forty-nine cutaneous plasmacytomas were examined histologically-the 46 original tumors plus one locally recurrent tumor and two tumors that subsequently recurred at new sites-and assigned a histologic grade. Grade I cutaneous plasmacytomas constituted 22.4% (11/49) of the tumors, and most were located in the skin of the lip (4/11) and ear (3/11) (Fig. 1). Grade I1 cutaneous plasmacytomas constituted 67.4% (33/49) of the tumors, and this was the most common grade at each anatomic site (Fig. 2). Grade I11 plasmacytomas accounted for the remaining 10.2% (5/49) of the tumors, and most were located in the skin of the digits (3/5) (Fig. 3). Binucleate and multinucleate neoplastic cells were common in tumors of each his-

3 218 Baer et al. Fig. 1. Cutaneous plasmacytoma, histologic grade I. Cords and nests of well-differentiated cells with monomorphic, round to oval nuclei and modest amounts of cytoplasm. HE. Fig. 2. Cutaneous plasmacytoma, histologic grade 11. Cords and nests of poorly differentiated cells with pleomorphic nuclei and abundant cytoplasm admixed with smaller, well-differentiated cells. Same magnification as Fig. 1. HE. Fig. 3. Cutaneous plasmacytoma, histologic grade 111. Cords and nests composed predominantly of poorly differentiated cells. Same magnification as Fig. 1. HE. Fig. 4. Cutaneous plasmacytoma, histologic grade 11. Abundant binucleate and multinucleate cells. Inset: Higher magnification of multinucleate cells. HE. Fig. 5. Cutaneous plasmacytoma, marked (+ 3) vimentin immunoreactivity. Granular cytoplasmic staining of neoplastic cells and occasional stromal cells. Avidin-biotin-peroxidase complex immunoperoxidase. Fig. 6. Cutaneous plasmacytoma, moderate (+ 2) canine IgG F(ab)2 immunoreactivity. Granular cytoplasmic staining limited to neoplastic cells. Avidin-biotin-peroxidase complex immunoperoxidase.

4 Cutaneous Plasmacytomas in Dogs 219 tologic grade, and in some tumors they were abundant (Fig. 4). Neoplastic cells were restricted to the dermis in most tumors. Minimal subcutaneous infiltration by neoplastic cells, unrelated to histologic grade, was detected in a few tumors. There was no evidence of epidermal infiltration by neoplastic cells. Staining with methyl green pyronine revealed moderate (29/49) to marked (5/49) cytoplasmic pyroninophylia. Several tumors (1 0/49) had minimal pyroninophylia and some (5/49) were negative. There was no correlation between pyroninophylia and histologic grade. Two tumors (both grade 11) contained intercel- Mar deposits of eosinophilic material which was congophilic, birefringent in polarized light, and presumed to be amyloid. Giemsa staining did not reveal metachromatic granules in any tumor. Various degrees (+ 1, + 2, + 3) of positive immunohistochemical reactivity for both vimentin and canine IgG F(ab), were detected in all 49 cutaneous plasmacytomas. Vimentin reactivity was greater in most tumors than that of canine IgG F(ab),. Vimentin immunoreactivity was marked (+3) in 71.4% (35/49) of the tumors and moderate (+2) in 28.6% (14/49). Vimentin immunoreactivity did not vary according to histologic grade. Canine IgG F(ab), immunoreactivity was marked (+3) in 26.5% (13/49) ofthe tumors, moderate (+2) in 47.0% (23/49), and mild (+ 1) in 26.5% (13/49). Only one of the poorly differentiated (grade 111) tumors had marked (+3) canine IgG F(ab), immunoreactivity; otherwise, the number of tumors with mild, moderate, or marked immunoreactivity was similar for the three histologic grades. Vimentin immunoreactivity was characterized by granular staining which was limited to the cytoplasm of the neoplastic cells and, occasionally, stromal cells (Fig. 5). Immunoreactivity for canine IgG F(ab), was characterized by granular staining which was limited to the cytoplasm of neoplastic cells (Fig. 6). All of the tumors were negative for immunohistochemical reactivity to cytokeratins, neurofilament, neuron-specific enolase, and S- 100, but immunoreactivity was marked (+3) in control tissues for each antibody. Post-treatment information was available in 39 of the 46 dogs; six dogs were lost and one dog died of unrelated disease 2 months after surgical excision of the cutaneous plasmacytoma. Follow-up periods ranged from 5 to 39 months (mean, 13.0 months), during which time 36 dogs (92.3%) remained free of disease. A cutaneous plasmacytoma (grade I) recurred locally in one dog 2 months after excision of the original tumor (grade I) from the skin of the dorsum of the head. This dog has remained free of disease for 6 months after excision of the recurrent tumor. Cutaneous plasmacytomas recurred at new sites in two dogs, one in the skin of the lower lip 22 months after excision of the original tumor from the upper lip, and in the other, in the skin of the perianal region 8 months after excision of the original tumor from the pinna of the ear. After excision of the second tumors, these dogs remained free of disease for 8 and 4 months, respectively. Both original tumors and both recurrent tumors were grade I1 cutaneous plasmacytomas. None of the dogs with grade I11 cutaneous plasmacytomas had local recurrence or tumor development at new sites. Discussion The morphologic features of the cutaneous plasmacytomas in this study were similar to those described for plasmacytomas in both animals and man.3j4j6,21 Various degrees of cellular differentiation were seen, as previously reported.i6s2l Although some of these tumors were dominated by poorly differentiated neoplastic cells, careful light microscopic examination revealed morphologic features adequate for a diagnosis of cutaneous plasmacytoma. The presence of binucleate and multinucleate tumor cells is consistent with plasma cell neoplasia,i6a2* and this was an almost invariable finding in the tumors of this study irrespective of histologic grade. The cytoplasmic pyroninophylia demonstrated in most of the tumors. also supported a diagnosis of plasmacytoma.21 Although minimal clinicopathological data were available, none of the dogs in this study had clinically detectable signs of multiple myeloma. The dermal location, pattern of infiltration, and lack of systemic disease referable to the tumors all indicated that these were primary dermal neoplasms rather than local extensions of deeper tumors or metastatic lesions. Immunohistochemical reactivity to a variety of antibodies was evaluated in order to substantiate the plasma cell origin of the tumors of this study. Immunohistochemical techniques employing panels of antibodies directed at different cellular components have been shown to be valuable adjuncts to routine light microscopy and to permit definitive diagnoses in most tumors."j8~20 Use of antibodies directed at vimentin, cytokeratin, neurofilament, S- 100 protein, and neuron-specific enolase as differential markers for a wide variety of neoplasms has been well document- ed.*j 1~12~18,20,26 Immunohistochemical detection of various intracellular immunoglobulins is useful in identification of neoplasms of B lymphocyte lineage.19,24,25 Immunoreactivity of the tumors in this study to vimentin and canine IgG F(ab),, in concert with the lack of immunoreactivity to the remainder of the antibodies, eliminates all but immunoglobulin-forming lymphoid neoplasms from consideration.8j 1~12,20,26 Correlation between the grade of immunoreactivity and the histologic grade of the tumors was not detected. In most tumors, vimentin immunoreactivity exceeded

5 220 Baer et al. that of canine IgG F(ab),. The generally higher grades of vimentin immunoreactivity probably resulted from consistent conservation of intermediate filament (vimentin) expression by the neoplastic cells. The generally lower and more variable grades of immunoreactivity to canine IgG F(ab), was probably due to variation in both the amount and type of immunoglobulin produced by the neoplastic cells. Some variation in immunoreactivity may have resulted from disparities in tissue handling and fixation. The results of this study indicate that cutaneous plasmacytomas in dogs are benign neoplasms that rarely recur. The results also indicate that the biologic behavior of these tumors is not affected by the anatomic site or the histologic grade. These findings are in agreement with a previous report of cutaneous plasmacytomas in 11 dogs, in which most of the tumors also involved the skin of the feet, lips, and ears, and the biologic behavior was similarly benign.i4 In man, cutaneous plasmacytoma may precede systemic manifestations of multiple myeloma by extended periods of time (1 year or more).10,22 To our knowledge, there is only one report of a dog in which a subcutaneous plasmacytoma preceded the development of multiple myeloma by almost 1 year.13 Extended follow-up will be necessary to evaluate this possibility in the dogs of this study. Morphologic and clinical features similar to those of the cutaneous plasmacytomas in this study have been reported for canine cutaneous neuroendocrine tumo~s.~j~ These are described as resembling canine histiocytomas, which have ultrastructural features similar to cutaneous neuroendocrine (Merkel cell) tumors in man.17 In some of the reported cases of canine cutaneous neuroendocrine tumors, the diagnosis was confirmed by electron microscopy; however, most were diagnosed by light microscopy. The cutaneous neuroendocrine (Merkel cell) tumors described in mansj2 share some morphologic features with both the canine cutaneous plasmacytomas of this study and the canine cutaneous neuroendocrine tu- mors reported by In contrast to reported findings in dog^,^,'^ the presence of binucleate or multinucleate tumor cells has not been described as a feature of human Merkel cell tumors.8j2 Immunohistochemical studies indicate that most are positive for neuron-specific enolase as well as either low molecular weight cytokeratin or neurofilament.8j2,26 Coexpression of cytokeratin and neurofilament has also been reported.l2,26 They are consistently negative for S- 100, vimentin, and lymphoid cell markers.'2,26 Immunohistochemical studies of canine cutaneous neuroendocrine tumors have not been reported. It is likely that some tumors in dogs diagnosed as cutaneous neuroendocrine tumors are cutaneous plasmacytomas. Cytologic features similar to those of the cutaneous plasmacytomas of this study have been reported for canine cutaneous reticulum cell sarcoma^.^ Reports are few, but cutaneous reticulum cell sarcomas have also been described as resembling histiocytomas.28 It is speculated that canine cutaneous reticulum cell sar- coma is a form of lymph~ma,~,~~ but reticulum cell sarcoma is not recognized as a form of lymphoma in man.i9 Primary cutaneous lymphomas are uncommon in dogs, and affected dogs usually die within 3 to 6 month^.^,^^^ Immunohistochemical studies of canine reticulum cell sarcomas have not been reported, although vimentin and immunoglobulin light chain immunoreactivity have been reported in canine cutaneous lymphomas.20 It is likely that some tumors in dogs diagnosed as cutaneous reticulum cell sarcomas, and possibly some diagnosed as lymphomas, are cutaneous plasmacytomas. Specific immunohistochemical markers that allow for differentiation of cutaneous plasmacytoma, cutaneous B cell lymphoma, and cutaneous manifestations of multiple myeloma in dogs are not commercially available. In our laboratory, use of the antibody directed at canine IgG F(ab), was based on its consistent specific staining of plasma cells rather than on the identification of a particular immunoglobulin type or class. In lymph nodes and other normal canine tissues, positive canine IgG F(ab)2 immunoreactivity was limited to histologically identifiable plasma cells (unpublished results). Because of immunoglobulin light chain crossreactivity, immunohistochemical reactivity to the antibody directed at the F(ab), fragment of canine IgG is not limited to the detection of formed IgG. Therefore, this marker may detect other immunoglobulin classes as well as free light chains. As such, immunoreactivity to this antibody may also be expressed in cases of multiple myeloma and some B cell lymphomas. In man, extramedullary plasmacytoma and multiple myeloma are morphologically and immunohistochemically indistinguishable and can only be differentiated on the basis of clinical ~ritera.~~,~~ Furthermore, morphologic distinction between these neoplasms and immunoblastic lymphoma is difficult in some In dogs, cutaneous plasmacytoma and the cutaneous manifestations of multiple myeloma may also be morphologically and immunohistochemically indistinguishable. Clinical features and clinicopathological data should help differentiate them. The clinical features and follow-up data in the dogs of this study indicated that the tumors were not manifestations of multiple myeloma. Routine immunohistochemical techniques are also not expected to differentiate cutaneous plasmacytomas and cutaneous lymphomas in dogs; however, these tumors are distinguishable by light microscopic morphologic and clinical features.

6 Cutaneous Plasmacytomas in Dogs 22 1 Cutaneous plasmacytomas should be included in the differential diagnosis of round cell tumors in the skin of dogs. The morphologic and clinical features of cutaneous plasmacytomas in dogs are distinctive and are sufficient for a diagnosis in most cases. The diagnosis can be further substantiated by immunohistochemical techniques using commercially available antibodies and paraffin-embedded specimens. Acknowledgements The authors thank Ms. Carol Roca and Mr. Colon Arguello for technical assistance and Ms. A. Christine MacMurray for editorial assistance. References 1 Bostock DE: Neoplasms of the skin and subcutaneous tissues in dogs and cats. Br Vet J 142:l-19, Brown NO, Nesbitt GH, Patnaik AK, MacEwen EG: Cutaneous lymphosarcoma in the dog: a disease with variable clinical and histologic manifestations. J Am Anim Hosp Assoc 16: , Canlas MS, Dillon ML, Loughrin JJ: Primary cutaneous plasmacytoma. Arch Dermatol115: , Conroy JD: Canine skin tumors. J Am Anim Hosp Assoc 19:91-114, Duncan JR, Prasse KW: Cytology of canine cutaneous round cell tumors. Mast cell tumor, histiocytoma, lymphosarcoma and transmissible venereal tumor. Vet Patho1 16~ , Funderberg M R: Adenocarcinoma subsequent to extramedullary myeloma in a German shepherd dog. Vet Med Small Anim Clin 72: , Goldschmidt MH: Dermal mesenchymal neoplasms of domestic animals. In: Proc Annu Meet, Am Acad Vet Dermatol, pp Orlando, FL, Gould VE, Moll R, Moll I, Lee I, Franke WW: Neuroendocrine (Merkel) cells of the skin: hyperplasias, dysplasias, and neoplasms. Lab Invest 52: , Hsu S-M, Raine L, Fanger H: Use of avidin-biotinperoxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29: , LaPeniere RJ, Wolfe JE, Gellin GA: Primary cutaneous plasmacytoma. Arch Dermatol 107:99-100, Leong AS-Y: Antibody probes in the diagnosis of anaplastic tumours. I. Malignant round cell tumours. Pa- thology 18~ , Leong AS-Y, Phillips GE, Pieterse AS, Milios J: Criteria for the diagnosis of primary endocrine carcinoma of the skin (Merkel cell carcinoma). A histological, immunohistochemical and ultrastructural study of 13 cases. Pathology 18: , Lester SJ, Mesfin GM: A solitary plasmacytoma in a dog with progression to a disseminated myeloma. Can Vet J 21: , hcke VM: Primary cutaneous Plasmacflomas in the dog and cat. J Small Anim Pract 28: g7 15 MacEwen EG, Patnaik AK, Johnson GF, Hurvitz AI, Erlandson R A, Lieberman PH: Extramedullary plasmacytoma of the gastrointestinal tract in two dogs. J Am Vet Med Assoc 184: , Morton LD, Barton CL, Elissalde GS, Wilson SR: Oral extramedullary plasmacytomas in two dogs. Vet Pathol 23~ , Nickoloff B J, Hill J, Weiss LM: Canine neuroendocrine carcinoma. A tumor resembling histiocytoma. Am J Dermatopathol7: , Osborn M, Weber K: Tumor diagnosis by intermediate filament typing: a novel tool for surgical pathology. Lab Invest 48: , Rosenberg SA, Berard CW, Brown BW, Burke J, Dorfman RF, Glatstein E, Hoppe RT, Simon R National Cancer Institute sponsored study of classifications of non- Hodgkin s lymphomas; summary and description of a working formulation for clinical usage. Cancer 49: , Sandusky GE, Carlton WW, Wightman KA: Diagnostic immunohistochemistry of canine round cell tumors. Vet Pathol24: , Schnitzer B, Weaver DK: Lymphoreticular disorders. In: Tumors of the Head and Neck, ed. Batsakis JG, pp Williams and Wilkins, Baltimore, MD, Shah A, Klimo P, Worth A Multiple myeloma first observed as multiple cutaneous plasmacytomas. Arch Dermatol 118: , Stannard AA, Pulley LT: Tumors of the skin and soft tissues. In: Tumors in Domestic Animals, ed. Moulton JE, 2nd ed., pp University of California Press, Berkeley, Strand WR, Banks PM, Kyle RA Anaplastic cell myeloma and immunoblastic lymphoma. Clinical, pathologic, and immunological comparison. Am J Med 76: , Strickler JG, Audeh MW, Copenhaver CM, Warnke RA: Immunophenotypic differences between plasmacytomdmultiple myeloma and immunoblastic lymphoma. Cancer 61: , Van Muijen GNP, Ruiter DJ, Warnaar SO: Intermediate filaments in Merkel cell tumors. Hum Pathol 16: , Walton GS, Gopinath C: Multiple myeloma in a dog with some unusual features. J Small Anim Pract 13: , Weiss E: International histological classification of tumours of domestic animals. VIII. Tumours of the soft (mesenchymal) tissues. Bull WHO 50: , Weiss E, Frese K International histological classification of tumours of domestic animals. VII. Tumours of the skin. Bull WHO 50:79-100, 1974 Request reprints from Dr. K. E. Baer, Department of Pathology, The Animal Medical Center, 5 10 East 62nd Street, New York, NY (USA).