ORIGINAL
ARTICLE
Cutaneous involvement in multiple myeloma (MM): A case series with clinicopathologic correlation Jozef Malysz, MD,a Giampaolo Talamo, MD,c Junjia Zhu, PhD,d Loren E. Clarke, MD,e Michael G. Bayerl, MD,a Liaqat Ali, MD,f Klaus F. Helm, MD,a,b and Catherine G. Chung, MDa,b Hershey, Pennsylvania; Salt Lake City, Utah; and Detroit, Michigan Background: Disease-specific skin lesions are rare in patients with multiple myeloma (MM). Objective: We sought to further characterize the clinical and pathologic features of patients with cutaneous involvement with MM. Methods: We identified 13 patients with cutaneous lesions of MM. Results: Cutaneous lesions consisted of pink, red, and violaceous papules, nodules, and/or plaques that varied in size. Histopathology revealed atypical plasma cells with occasional plasmablastic features. MM had aggressive biologic features and was at an advanced stage in the majority of patients. Despite aggressive management, including chemotherapy and stem-cell transplantation, most patients died of progressive disease within a few months after the development of cutaneous lesions. Limitations: The study group was relatively small. Conclusions: Cutaneous involvement with MM is associated with aggressive biologic behavior and short survival. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.12.028.) Key words: clinical settings; cutaneous plasma cell lesions; diagnostic algorithms; multiple myeloma.
M
ultiple myeloma (MM) is a rare cancer representing 1% of all malignancies. Its annual incidence is approximately 5 per 100,000.1 The incidence progressively increases with age, with approximately 90% of cases seen in patients older than 50 years, with the median age at diagnosis being 70 years. The common clinical manifestations of MM are summarized by the ‘‘CRAB’’ symptoms of hypercalcemia, renal insufficiency, anemia, and bone lesions.2 In the vast majority of cases, the malignant plasma cells remain in the bone marrow, and their proliferation leads to the development of lytic bone lesions. However, because of pathophysiologic mechanisms that are not yet fully elucidated, MM can also manifest with
extramedullary disease, where the neoplastic plasma cells infiltrate organs outside of the bone marrow. It is estimated that approximately 4% of patients with MM present with extramedullary disease, and less than 1% of them have cutaneous involvement.3 Little is known about cutaneous involvement by MM, as the medical literature describes only case reports or case series with a limited number of patients.4-7
From the Department of Pathology,a Department of Dermatology,b Department of Internal Medicine, Division of Hematology-Oncology,c and Cancer Institute,d Penn State Milton S. Hershey Medical Center; Dermatology Unit, Myriad Genetics Laboratories Inc, Salt Lake Citye; and Department of Dermatology, Wayne State University and Pinkus Dermatopathology, Detroit.f Funding sources: None. Conflicts of interest: None declared.
Accepted for publication December 13, 2015. Reprint requests: Catherine G. Chung, MD, Department of Pathology, MC H179, Penn State Milton S. Hershey Medical Center, 500 University Dr, Hershey, PA 17033. E-mail: cchung1@ hmc.psu.edu. Published online February 11, 2016. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.12.028
Abbreviations used: IHC: MM: PEMP:
immunohistochemistry multiple myeloma primary extramedullary plasmacytoma
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1 patient presenting with a large ulcerated skin mass (Fig 3). The color varied from pink-red to violaceous, and the lesions did not have a predominant anatomic distributionelesions involved the trunk, face, and upper and lower extremities. The size of lesions varied from 1 to 230 mm. Two histologic patterns of skin involvement were observed: (1) nodular and diffuse, and (2) interstitial, METHODS CAPSULE SUMMARY with most cases containing After approval from our combination of both (Fig 4). institutional review board, Cutaneous involvement with multiple All cases demonstrated we identified and reviewed myeloma is rare. involvement of the reticular data of all patients with a Cutaneous involvement with multiple dermis with sparing of the diagnosis of plasma cell myeloma should be differentiated from upper papillary dermis and disorders followed up at our solitary extramedullary plasmacytoma epidermis (ie, grenz zone). institution between January and other cutaneous plasma cell In 4 of 13 cases, there was 2006 and December 2013. In infiltrates. involvement of the subcutis. all, 675 patients with MM Cellular atypia was common; were identified; 13 of which Cutaneous involvement with multiple the spectrum of cytologic had biopsy-proven plasma myeloma occurs late in the course of the changes included easily cell neoplasms in the skin. disease, is associated with a poor recognizable plasma cells to We reviewed all clinical and prognosis, and requires aggressive areas with markedly atypical pathologic aspects of their management. morphology, which made disease. All tissue was recognition of plasma cells formalin fixed and paraffin very difficult or virtually impossible based on embedded. The tissue sections were then stained hematoxylin-eosin sections alone (Fig 5, A); in these with hematoxylin-eosin, IHC for CD138, and k and cases, plasma cell lineage was confirmed by IHC l in situ hybridization, and examined by light with CD138 (Fig 5, B). Less-differentiated lesions microscopy. demonstrated more cytologic atypia, occasional anaplastic and/or spindle-cell morphology, greater RESULTS nuclear pleomorphism, coarse chromatin, and Among 675 patients with MM, we identified 13 usually inconspicuous nucleoli. Mitotic activity was (1.9%) with skin involvement. Patient characteristics, also variable, but correlated with degree of paraprotein expression, cytogenetics, and staging differentiation, with greater than 50% mitotic index are summarized in Table I. based on Ki-67 IHC in poorly differentiated tumors. The skin was the only site of extramedullary No Russell or Dutcher bodies were identified. involvement in 5 patients. In the remaining 8 Occasional cytoplasmic vacuolization was seen. All cases, other involved organs were lymph nodes cases uniformly stained strongly with CD138. (n = 3), liver (n = 3), lungs (n = 2), kidney (n = 2), mesentery (n = 2), muscle (n = 2), pleura (n = 1), tongue (n = 1), vulva (n = 1), retro-orbital soft DISCUSSION tissues (n = 1), and cerebrospinal fluid with Cutaneous involvement by MM must be distinmyelomatous meningitis (n = 1). Cutaneous guished from other malignant and reactive plasma involvement was identified at various times during cell-rich infiltrates that may occur in the skin, most the disease course: at the time of diagnosis (n = 4), notably primary extramedullary plasmacytoma during disease progression (n = 4), and as a terminal (PEMP), primary cutaneous marginal zone lymevent (ie, within 6 months from death; n = 5). At last phoma with plasmacytic differentiation, plasmablasfollow-up, 10 of 13 patients were deceased, all tic lymphoma, cutaneous involvement by Castleman from progression of MM. Median overall survival disease, cutaneous and systemic plasmacytosis, and from the initial diagnosis of MM was 43 months pretibial lymphoplasmacytic plaque (Table II). In (range, 8-86), and median overall survival after addition, it should be noted that various infections the development of skin lesions was 8 months (eg, syphilis, Borrelia, atypical mycobacteria, and (range 3-48) (Figs 1 and 2). deep infections by fungal organisms), and benign The most common cutaneous presentation was inflammatory conditions, may contain an infiltrate in the form of papules, nodules, or plaques, with characterized by an abundance of plasma cells.8 We discuss 13 cases of MM with cutaneous involvement, identified in our database of 675 patients with MM, and review their clinical and pathologic features, including cellular morphology, immunohistochemistry (IHC), and in situ hybridization stains, which can be helpful in the recognition of this rare disorder.
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Table I. Patient characteristics Age, y
Paraprotein
ISS stage
DS stage
Gender
Race
1 2 3
74 76 76
M M M
W W W
NS NS l-Light chain
I n/a III
IIA n/a IIB
Normal n/a Normal
4
75
M
W
IgE-k
I
IIIA
Normal
5
76
M
W
IgG-k
III
IIIA
n/a
6
60
M
H
IgG-k
III
IIIB
Complex
7 8 9
53 54 56
F M F
W W W
IgD-l IgG-l l-Light chain
n/a III I
IIIA IIIA IIIA
13 Complex Normal
10
80
F
H
IgG-k
III
IIIB
n/a
11 12
74 66
F M
W W
NS IgA-k
n/a n/a
IIIA IIIA
n/a Normal
13
47
M
n/a
IgG-k
n/a
IIIA
13
Case
Metaphase cytogenetics
FISH
t(11;14), 13 n/a t(4;14), 13, 7,115, 13 Normal
Treatment
Other sites of EMD
Len-Dex, VRD, ASCT, Carf No RT, Len, Bor LNs Len-Dex, Bor, VD-PACE, ASCT LNs, retro-orbital soft tissues Dex-Thal, Bor, Dex-Len, No VD-PACE, ASCT, RT 19, 13, Dex-Bor, Len-Dex, ASCT, IM, liver, CSF, PCL atypical IgH t Thal, Bend t(11;14), VCD, VD-PACE No 13, 17p n/a VAD, ASCT, Bor-Dox, Len Tongue 13, 17p Dex-Bor, VD-PACE, ASCT 32 Lungs, liver, LNs Normal Dex-Len, Dex-Bor, ASCT, IM, pleura, Bor-Thal, Bor-Dox mesentery n/a MPT Vulva, mesentery, kidney, lung 112 Bor-Len, RT, Cy, ASCT, MPT No n/a Dex-Thal, VD-PACE, No ASCT 32, VTD n/a VAD, ASCT 32, Bor-Dex Kidney, liver
Time to skin involvement after Dx, mo
OS since skin involvement, mo
OS since Dx, mo
0 0 7
43 48 4
43 48 11
45
6
51
47
4
51
5
3
8
37 9 7
7 4 42
44 13 49
0
9
9
30 0
8 16
38 16
67
19
86
13, Monosomy 13; ASCT, autologous stem cell transplantation; Bend, bendamustine; Bor, bortezomib; Carf, carfilzomib; Cy, cyclophosphamide; Dex, dexamethasone; Dox, liposomal doxorubicin; DS, Durie-Salmon; Dx, diagnosis; EMD, extramedullary disease; F, female; FISH, fluorescence in situ hybridization; H, Hispanic; IM, intramuscular; ISS, International Staging System; Len, lenalidomide; LNs, lymph nodes; M, male; MPT, melphalan, prednisone, and Thal; n/a, not available; NS, nonsecretory; OS, overall survival; PCL, plasma cell leukemia; RT, radiation therapy; t, translocation; Thal, thalidomide; VAD, vincristine, adriamycin, and Dex; VCD, Bor, Cy, and Dex; VD-PACE, Bor, Dex, cisplatin, doxorubicin, Cy, and etoposide; VRD, Bor, Len, and Dex; VTD, Bor, Thal, and Dex; W, white.
Malysz et al 3
4 Malysz et al
Fig 1. Kaplan-Meier survival curves of 675 patients with multiple myeloma (MM) (blue line) vs 13 patients with MM and skin involvement (red line). P \ .01. Overall survival was calculated from the time of the initial diagnosis of MM.
Fig 2. Kaplan-Meier survival curves of 13 patients with multiple myeloma and skin involvement. Overall survival was calculated from the time of development of skin lesions.
The first practical step once a plasma cell neoplasm is suspected based on hematoxylin-eosin findings is to confirm the presence of plasma cells. Although cytomorphology on light microscopy may often suffice to confirm the presence of plasmas cells based on the typical basophilic eccentric nucleus and ‘‘clock face’’ chromatin distribution, IHC may confirm plasma cell lineage in poorly differentiated tumors. Plasma cells stain strongly for CD138 on IHC; all 13 cases of cutaneous MM in our current series strongly and uniformly expressed CD138 regardless of degree of cytologic differentiation. Once plasma cells are identified in the infiltrate, it is crucial to differentiate a reactive from a neoplastic process. Plasma cell clonality can be determined by using k and l light chain stains, either by IHC or in situ hybridization method. Presence of significant k or l predominance, also known as ‘‘light chain restriction,’’ is indicative of a clonal plasma cell
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process, and is not seen in reactive plasma cell-rich infiltrates (Fig 6). Of note, plasma cells are negative for CD45 (leukocyte common antigen), and may be weakly positive for cytokeratin, creating a diagnostic pitfall with possibility of erroneous interpretation as carcinoma. CD56 expression is very common in MM and may be a useful IHC marker for diagnosis; however, up to 80% of cases with plasma cell leukemia, which is a rare and very aggressive variant of MM, are CD56 . Neoplastic plasma cells are nearly always negative for CD19 and frequently negative for CD20, in contrast to other B-cell lineage neoplasms.6,9,10 Neoplastic plasma cell proliferations in skin fall into 3 clinical categories: (1) primary cutaneous plasma cell neoplasm without systemic evidence of plasma cell neoplasm (ie, PEMP); (2) cutaneous plasma cell lesions in patients with established diagnosis of MM (ie, skin metastases); and (3) cutaneous involvement from direct extension of underlying osteolytic lesions in MM. Once a clonal plasma cell lesion has been identified in the skin, it is necessary to review all clinical, laboratory, and radiologic/imaging workup, including bone-marrow biopsy, to determine the presence of systemic disease. PEMP, a diagnosis of exclusion, is appropriate in the absence of any systemic evidence of disease, including CRAB symptoms and clonal population of plasma cells on bone-marrow biopsy specimen. The prognosis of patients with PEMP is favorable with local radiation therapy; however up to 25% of these patients may have local recurrence. Progression to MM occurs in approximately 20% of these patients, and 70% remain disease-free after 10 years.11 Extramedullary involvement of the skin in MM is very rare. We identified only 13 patients in our database of 675 patients with MM, ie, a prevalence of 1.9%. Our case series confirms several findings previously reported by other groups. Although typically a late manifestation of MM, cutaneous involvement may rarely be the presenting sign of the disease.6,12 k Monoclonal immunoglobulin light chain expression is more common than l, with IgG being the most common type, followed by IgA, free light chains, IgD, and IgM.13,14 Clinically, lesions present as multiple erythematous to violaceus papules, nodules, and plaques on the trunk and less frequently the head or extremities.6,12 Our histologic findings were consistent with prior published findings, namely a nodular/diffuse pattern and/or an interstitial pattern of atypical plasma cells with involvement of the entire dermis occurring commonly, sometimes with extension into the subcutis.6,15 Cutaneous involvement by
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Fig 3. Clinical spectrum of cutaneous involvement by multiple myeloma. Violaceous nodule (A) and 23-cm exophytic mass on leg (B).
Fig 4. Representative hematoxylin-eosin infiltrate from cutaneous multiple myeloma. A, Nodular (stars) and diffuse (solid arrow) pattern: atypical plasma cells form nodules and sheetlike aggregates. B, Interstitial pattern: atypical plasma cells dissect through collagen bundles in the dermis (arrow outlines). (A and B, Hematoxylin-eosin stain; original magnifications: A, 320; B, 340.)
Fig 5. Poorly differentiated hematolymphoid cells without any distinctive plasma cell features. A, Hematoxylin-eosin stain; original magnification: 3400. B, CD138 positivity confirms plasma cell lineage.
MM generally appears at the late stage of myeloma and is an ominous clinical sign, with most of these patients surviving less than 1 year, reflecting a very aggressive biological behavior of these neoplasms once cutaneous lesions appear.10,16,17
Conclusions It is imperative to distinguish between neoplastic and nonneoplastic plasma cell lesions in the skin. Prompt comprehensive workup is required when a neoplastic plasma cell lesion is discovered to
Entity
Clinical presentation
Histologic features
Hypercalcemia, renal insufficiency, anemia, bone lesions
Sheets of plasma cells with occasional intermixed background mature lymphocytes
Immunophenotypic features
Other helpful findings
CD1381, k or l light chain restriction, background mixed T and B lymphocytes
EBER, In situ hybridization for EpsteineBarr virus; ESR, erythrocyte sedimentation rate; HHV, human herpes virus type; IFE, serum immunofixation; IL, interleukin; SPEP, serum protein electrophoresis; uIFE, urine immunofixation.
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M-protein on SPEP/IFE/uIFE in 99% of patients, marrow involvement by plasma cell dyscrasia CD1381, k or l light chain Sheets of plasma cells with occasional Primary extramedullary Solitary skin lesion without M-protein 6; no intermixed background mature plasmacytoma other clinical evidence of hypercalcemia, renal restricted, background lymphocytes multiple myeloma insufficiency, anemia, mixed T and B lymphocytes bone lesions; no marrow involvement Primary cutaneous Solitary or multiple cutaneous Predominant cell type is centrocyte-like, CD201, CD79a1, BCL 21 B M-protein in up to one monocytoid small B cell; other cells marginal zone violaceous papules, nodules, third of patients; no lymphocytes; CD1381 plasma include lymphoplasmacytoid cells and lymphoma and/or plaques with marrow involvement by cells 1 light chain restriction when scattered plasma cells; plasma cell predilection for the trunk plasma cell dyscrasia plasma cells prominent component may be prominent and upper extremities Plasmablastic lymphoma Mass occurring in oral cavity, Sheets of cells with plasmablastic/ CD20 , CD1381, CD56 ; light chain EBER1 in 70%; no M-protein rarely other mucosal sites, immunoblastic morphology restriction in rare cases or marrow involvement skin, bone, soft tissue; HIV1 or other immunodeficiency Nodular and diffuse mixed lymphocytic Mixed CD201 B cells with CD1381 Polyclonal hypergammagloCastleman disease, Lymphadenopathy, systemic infiltrate with prominent plasma cell bulinemia; elevated ESR plasma cell variant symptoms (eg, fever), plasma cells; usually polytypic, component and serum IL-6; anemia; scattered nodules and but up to one third of cases no M-protein or marrow plaques on trunk and may have k or l light involvement extremities chain restriction; HHV81 Mixed lymphocytes and plasma cells Mixed CD201 B cells and CD1381 Cutaneous and systemic Exceedingly rare, Japanese Polyclonal hypergammagloplasmacytosis individuals, numerous skin bulinemia; elevated serum plasma cells; polytypic k and l lesions, lymphadenopathy IL-6; no M-protein or light chain expression; marrow involvement HHV8 Pretibial lymphoSolitary pretibial plaque in Mixed lymphocytes and plasma cells Mixed CD201 B cells and CD1381 No associated systemic plasmacytic plaque a child symptoms or signs of plasma cells; polytypic k and l systemic disease; no light chain expression; M-protein or marrow HHV8 involvement Multiple myeloma
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Table II. Differential diagnosis of plasmacytic infiltrates in the skin
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Fig 6. In situ hybridization studies of the specimen shown in Fig 4, A, demonstrate l light chain restriction (diffuse purple staining [stars]) (A) and negative k light chain expression (absence of purple staining), confirming neoplastic clonal proliferation (B).
distinguish PEMP from cutaneous involvement by MM. In our series of 13 patients, median survival after neoplastic plasma cell skin lesion was discovered was only 8 months, despite the use of aggressive modern therapies, including stem-cell transplantation. REFERENCES 1. Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61: 212-236. 2. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757. 3. Talamo G, Farooq U, Zangari M, et al. Beyond the CRAB symptoms: a study of presenting clinical manifestations of multiple myeloma. Clin Lymphoma Myeloma Leuk. 2010;10: 464-468. 4. Alberts DS, Lynch P. Cutaneous plasmacytomas in myeloma. Relationship to tumor cell burden. Arch Dermatol. 1978;114: 1784-1787. 5. Kato N, Kimura K, Yasukawa K, et al. Metastatic cutaneous plasmacytoma: a case report associated with IgA lambda multiple myeloma and a review of the literature of metastatic cutaneous plasmacytomas associated with multiple myeloma and primary cutaneous plasmacytomas. J Dermatol. 1999;26: 587-594. 6. Requena L, Kutzner H, Palmedo G, et al. Cutaneous involvement in multiple myeloma: a clinicopathologic, immunohistochemical, and cytogenetic study of 8 cases. Arch Dermatol. 2003;139:475-486.
7. Wozney JL, Ahmed F, Bayerl MG, et al. Skin involvement in immunoglobulin E multiple myeloma. J Clin Oncol. 2009;27: 637-638. 8. Torres SM, Sanchez JL. Cutaneous plasmacytic infiltrates. Am J Dermatopathol. 1988;10:319-329. 9. Alexandrescu DT, Koulova L, Wiernik PH. Unusual cutaneous involvement during plasma cell leukemia phase in a multiple myeloma patient after treatment with thalidomide: a case report and review of the literature. Clin Exp Dermatol. 2005;30: 391-394. 10. Ballester-Martinez MA, Gonzalez-Garcia C, Fleta-Asin B, et al. Cutaneous nodules as a diagnostic clue in multiple myeloma. Am J Dermatopathol. 2013;35:377-380. 11. Ozsahin M, Tsang RW, Poortmans P, et al. Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients. Int J Radiat Oncol Biol Phys. 2006;64:210-217. 12. Shah A, Klimo P, Worth A. Multiple myeloma first observed as multiple cutaneous plasmacytomas. Arch Dermatol. 1982;118: 922-924. 13. Bayer-Garner IB, Smoller BR. The spectrum of cutaneous disease in multiple myeloma. J Am Acad Dermatol. 2003;48:497-507. 14. Patterson JW, Parsons JM, White RM, et al. Cutaneous involvement of multiple myeloma and extramedullary plasmacytoma. J Am Acad Dermatol. 1988;19:879-890. 15. Rongioletti F, Patterson JW, Rebora A. The histological and pathogenetic spectrum of cutaneous disease in monoclonal gammopathies. J Cutan Pathol. 2008;35:705-721. 16. Usmani SZ, Heuck C, Mitchell A, et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica. 2012;97:1761-1767. 17. Damaj G, Mohty M, Vey N, et al. Features of extramedullary and extraosseous multiple myeloma: a report of 19 patients from a single center. Eur J Haematol. 2004;73:402-406.
ARTICLE
Cutaneous involvement in multiple myeloma (MM): A case series with clinicopathologic correlation Jozef Malysz, MD,a Giampaolo Talamo, MD,c Junjia Zhu, PhD,d Loren E. Clarke, MD,e Michael G. Bayerl, MD,a Liaqat Ali, MD,f Klaus F. Helm, MD,a,b and Catherine G. Chung, MDa,b Hershey, Pennsylvania; Salt Lake City, Utah; and Detroit, Michigan Background: Disease-specific skin lesions are rare in patients with multiple myeloma (MM). Objective: We sought to further characterize the clinical and pathologic features of patients with cutaneous involvement with MM. Methods: We identified 13 patients with cutaneous lesions of MM. Results: Cutaneous lesions consisted of pink, red, and violaceous papules, nodules, and/or plaques that varied in size. Histopathology revealed atypical plasma cells with occasional plasmablastic features. MM had aggressive biologic features and was at an advanced stage in the majority of patients. Despite aggressive management, including chemotherapy and stem-cell transplantation, most patients died of progressive disease within a few months after the development of cutaneous lesions. Limitations: The study group was relatively small. Conclusions: Cutaneous involvement with MM is associated with aggressive biologic behavior and short survival. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.12.028.) Key words: clinical settings; cutaneous plasma cell lesions; diagnostic algorithms; multiple myeloma.
M
ultiple myeloma (MM) is a rare cancer representing 1% of all malignancies. Its annual incidence is approximately 5 per 100,000.1 The incidence progressively increases with age, with approximately 90% of cases seen in patients older than 50 years, with the median age at diagnosis being 70 years. The common clinical manifestations of MM are summarized by the ‘‘CRAB’’ symptoms of hypercalcemia, renal insufficiency, anemia, and bone lesions.2 In the vast majority of cases, the malignant plasma cells remain in the bone marrow, and their proliferation leads to the development of lytic bone lesions. However, because of pathophysiologic mechanisms that are not yet fully elucidated, MM can also manifest with
extramedullary disease, where the neoplastic plasma cells infiltrate organs outside of the bone marrow. It is estimated that approximately 4% of patients with MM present with extramedullary disease, and less than 1% of them have cutaneous involvement.3 Little is known about cutaneous involvement by MM, as the medical literature describes only case reports or case series with a limited number of patients.4-7
From the Department of Pathology,a Department of Dermatology,b Department of Internal Medicine, Division of Hematology-Oncology,c and Cancer Institute,d Penn State Milton S. Hershey Medical Center; Dermatology Unit, Myriad Genetics Laboratories Inc, Salt Lake Citye; and Department of Dermatology, Wayne State University and Pinkus Dermatopathology, Detroit.f Funding sources: None. Conflicts of interest: None declared.
Accepted for publication December 13, 2015. Reprint requests: Catherine G. Chung, MD, Department of Pathology, MC H179, Penn State Milton S. Hershey Medical Center, 500 University Dr, Hershey, PA 17033. E-mail: cchung1@ hmc.psu.edu. Published online February 11, 2016. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.12.028
Abbreviations used: IHC: MM: PEMP:
immunohistochemistry multiple myeloma primary extramedullary plasmacytoma
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1 patient presenting with a large ulcerated skin mass (Fig 3). The color varied from pink-red to violaceous, and the lesions did not have a predominant anatomic distributionelesions involved the trunk, face, and upper and lower extremities. The size of lesions varied from 1 to 230 mm. Two histologic patterns of skin involvement were observed: (1) nodular and diffuse, and (2) interstitial, METHODS CAPSULE SUMMARY with most cases containing After approval from our combination of both (Fig 4). institutional review board, Cutaneous involvement with multiple All cases demonstrated we identified and reviewed myeloma is rare. involvement of the reticular data of all patients with a Cutaneous involvement with multiple dermis with sparing of the diagnosis of plasma cell myeloma should be differentiated from upper papillary dermis and disorders followed up at our solitary extramedullary plasmacytoma epidermis (ie, grenz zone). institution between January and other cutaneous plasma cell In 4 of 13 cases, there was 2006 and December 2013. In infiltrates. involvement of the subcutis. all, 675 patients with MM Cellular atypia was common; were identified; 13 of which Cutaneous involvement with multiple the spectrum of cytologic had biopsy-proven plasma myeloma occurs late in the course of the changes included easily cell neoplasms in the skin. disease, is associated with a poor recognizable plasma cells to We reviewed all clinical and prognosis, and requires aggressive areas with markedly atypical pathologic aspects of their management. morphology, which made disease. All tissue was recognition of plasma cells formalin fixed and paraffin very difficult or virtually impossible based on embedded. The tissue sections were then stained hematoxylin-eosin sections alone (Fig 5, A); in these with hematoxylin-eosin, IHC for CD138, and k and cases, plasma cell lineage was confirmed by IHC l in situ hybridization, and examined by light with CD138 (Fig 5, B). Less-differentiated lesions microscopy. demonstrated more cytologic atypia, occasional anaplastic and/or spindle-cell morphology, greater RESULTS nuclear pleomorphism, coarse chromatin, and Among 675 patients with MM, we identified 13 usually inconspicuous nucleoli. Mitotic activity was (1.9%) with skin involvement. Patient characteristics, also variable, but correlated with degree of paraprotein expression, cytogenetics, and staging differentiation, with greater than 50% mitotic index are summarized in Table I. based on Ki-67 IHC in poorly differentiated tumors. The skin was the only site of extramedullary No Russell or Dutcher bodies were identified. involvement in 5 patients. In the remaining 8 Occasional cytoplasmic vacuolization was seen. All cases, other involved organs were lymph nodes cases uniformly stained strongly with CD138. (n = 3), liver (n = 3), lungs (n = 2), kidney (n = 2), mesentery (n = 2), muscle (n = 2), pleura (n = 1), tongue (n = 1), vulva (n = 1), retro-orbital soft DISCUSSION tissues (n = 1), and cerebrospinal fluid with Cutaneous involvement by MM must be distinmyelomatous meningitis (n = 1). Cutaneous guished from other malignant and reactive plasma involvement was identified at various times during cell-rich infiltrates that may occur in the skin, most the disease course: at the time of diagnosis (n = 4), notably primary extramedullary plasmacytoma during disease progression (n = 4), and as a terminal (PEMP), primary cutaneous marginal zone lymevent (ie, within 6 months from death; n = 5). At last phoma with plasmacytic differentiation, plasmablasfollow-up, 10 of 13 patients were deceased, all tic lymphoma, cutaneous involvement by Castleman from progression of MM. Median overall survival disease, cutaneous and systemic plasmacytosis, and from the initial diagnosis of MM was 43 months pretibial lymphoplasmacytic plaque (Table II). In (range, 8-86), and median overall survival after addition, it should be noted that various infections the development of skin lesions was 8 months (eg, syphilis, Borrelia, atypical mycobacteria, and (range 3-48) (Figs 1 and 2). deep infections by fungal organisms), and benign The most common cutaneous presentation was inflammatory conditions, may contain an infiltrate in the form of papules, nodules, or plaques, with characterized by an abundance of plasma cells.8 We discuss 13 cases of MM with cutaneous involvement, identified in our database of 675 patients with MM, and review their clinical and pathologic features, including cellular morphology, immunohistochemistry (IHC), and in situ hybridization stains, which can be helpful in the recognition of this rare disorder.
d
d
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VOLUME jj, NUMBER j
Table I. Patient characteristics Age, y
Paraprotein
ISS stage
DS stage
Gender
Race
1 2 3
74 76 76
M M M
W W W
NS NS l-Light chain
I n/a III
IIA n/a IIB
Normal n/a Normal
4
75
M
W
IgE-k
I
IIIA
Normal
5
76
M
W
IgG-k
III
IIIA
n/a
6
60
M
H
IgG-k
III
IIIB
Complex
7 8 9
53 54 56
F M F
W W W
IgD-l IgG-l l-Light chain
n/a III I
IIIA IIIA IIIA
13 Complex Normal
10
80
F
H
IgG-k
III
IIIB
n/a
11 12
74 66
F M
W W
NS IgA-k
n/a n/a
IIIA IIIA
n/a Normal
13
47
M
n/a
IgG-k
n/a
IIIA
13
Case
Metaphase cytogenetics
FISH
t(11;14), 13 n/a t(4;14), 13, 7,115, 13 Normal
Treatment
Other sites of EMD
Len-Dex, VRD, ASCT, Carf No RT, Len, Bor LNs Len-Dex, Bor, VD-PACE, ASCT LNs, retro-orbital soft tissues Dex-Thal, Bor, Dex-Len, No VD-PACE, ASCT, RT 19, 13, Dex-Bor, Len-Dex, ASCT, IM, liver, CSF, PCL atypical IgH t Thal, Bend t(11;14), VCD, VD-PACE No 13, 17p n/a VAD, ASCT, Bor-Dox, Len Tongue 13, 17p Dex-Bor, VD-PACE, ASCT 32 Lungs, liver, LNs Normal Dex-Len, Dex-Bor, ASCT, IM, pleura, Bor-Thal, Bor-Dox mesentery n/a MPT Vulva, mesentery, kidney, lung 112 Bor-Len, RT, Cy, ASCT, MPT No n/a Dex-Thal, VD-PACE, No ASCT 32, VTD n/a VAD, ASCT 32, Bor-Dex Kidney, liver
Time to skin involvement after Dx, mo
OS since skin involvement, mo
OS since Dx, mo
0 0 7
43 48 4
43 48 11
45
6
51
47
4
51
5
3
8
37 9 7
7 4 42
44 13 49
0
9
9
30 0
8 16
38 16
67
19
86
13, Monosomy 13; ASCT, autologous stem cell transplantation; Bend, bendamustine; Bor, bortezomib; Carf, carfilzomib; Cy, cyclophosphamide; Dex, dexamethasone; Dox, liposomal doxorubicin; DS, Durie-Salmon; Dx, diagnosis; EMD, extramedullary disease; F, female; FISH, fluorescence in situ hybridization; H, Hispanic; IM, intramuscular; ISS, International Staging System; Len, lenalidomide; LNs, lymph nodes; M, male; MPT, melphalan, prednisone, and Thal; n/a, not available; NS, nonsecretory; OS, overall survival; PCL, plasma cell leukemia; RT, radiation therapy; t, translocation; Thal, thalidomide; VAD, vincristine, adriamycin, and Dex; VCD, Bor, Cy, and Dex; VD-PACE, Bor, Dex, cisplatin, doxorubicin, Cy, and etoposide; VRD, Bor, Len, and Dex; VTD, Bor, Thal, and Dex; W, white.
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Fig 1. Kaplan-Meier survival curves of 675 patients with multiple myeloma (MM) (blue line) vs 13 patients with MM and skin involvement (red line). P \ .01. Overall survival was calculated from the time of the initial diagnosis of MM.
Fig 2. Kaplan-Meier survival curves of 13 patients with multiple myeloma and skin involvement. Overall survival was calculated from the time of development of skin lesions.
The first practical step once a plasma cell neoplasm is suspected based on hematoxylin-eosin findings is to confirm the presence of plasma cells. Although cytomorphology on light microscopy may often suffice to confirm the presence of plasmas cells based on the typical basophilic eccentric nucleus and ‘‘clock face’’ chromatin distribution, IHC may confirm plasma cell lineage in poorly differentiated tumors. Plasma cells stain strongly for CD138 on IHC; all 13 cases of cutaneous MM in our current series strongly and uniformly expressed CD138 regardless of degree of cytologic differentiation. Once plasma cells are identified in the infiltrate, it is crucial to differentiate a reactive from a neoplastic process. Plasma cell clonality can be determined by using k and l light chain stains, either by IHC or in situ hybridization method. Presence of significant k or l predominance, also known as ‘‘light chain restriction,’’ is indicative of a clonal plasma cell
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process, and is not seen in reactive plasma cell-rich infiltrates (Fig 6). Of note, plasma cells are negative for CD45 (leukocyte common antigen), and may be weakly positive for cytokeratin, creating a diagnostic pitfall with possibility of erroneous interpretation as carcinoma. CD56 expression is very common in MM and may be a useful IHC marker for diagnosis; however, up to 80% of cases with plasma cell leukemia, which is a rare and very aggressive variant of MM, are CD56 . Neoplastic plasma cells are nearly always negative for CD19 and frequently negative for CD20, in contrast to other B-cell lineage neoplasms.6,9,10 Neoplastic plasma cell proliferations in skin fall into 3 clinical categories: (1) primary cutaneous plasma cell neoplasm without systemic evidence of plasma cell neoplasm (ie, PEMP); (2) cutaneous plasma cell lesions in patients with established diagnosis of MM (ie, skin metastases); and (3) cutaneous involvement from direct extension of underlying osteolytic lesions in MM. Once a clonal plasma cell lesion has been identified in the skin, it is necessary to review all clinical, laboratory, and radiologic/imaging workup, including bone-marrow biopsy, to determine the presence of systemic disease. PEMP, a diagnosis of exclusion, is appropriate in the absence of any systemic evidence of disease, including CRAB symptoms and clonal population of plasma cells on bone-marrow biopsy specimen. The prognosis of patients with PEMP is favorable with local radiation therapy; however up to 25% of these patients may have local recurrence. Progression to MM occurs in approximately 20% of these patients, and 70% remain disease-free after 10 years.11 Extramedullary involvement of the skin in MM is very rare. We identified only 13 patients in our database of 675 patients with MM, ie, a prevalence of 1.9%. Our case series confirms several findings previously reported by other groups. Although typically a late manifestation of MM, cutaneous involvement may rarely be the presenting sign of the disease.6,12 k Monoclonal immunoglobulin light chain expression is more common than l, with IgG being the most common type, followed by IgA, free light chains, IgD, and IgM.13,14 Clinically, lesions present as multiple erythematous to violaceus papules, nodules, and plaques on the trunk and less frequently the head or extremities.6,12 Our histologic findings were consistent with prior published findings, namely a nodular/diffuse pattern and/or an interstitial pattern of atypical plasma cells with involvement of the entire dermis occurring commonly, sometimes with extension into the subcutis.6,15 Cutaneous involvement by
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Fig 3. Clinical spectrum of cutaneous involvement by multiple myeloma. Violaceous nodule (A) and 23-cm exophytic mass on leg (B).
Fig 4. Representative hematoxylin-eosin infiltrate from cutaneous multiple myeloma. A, Nodular (stars) and diffuse (solid arrow) pattern: atypical plasma cells form nodules and sheetlike aggregates. B, Interstitial pattern: atypical plasma cells dissect through collagen bundles in the dermis (arrow outlines). (A and B, Hematoxylin-eosin stain; original magnifications: A, 320; B, 340.)
Fig 5. Poorly differentiated hematolymphoid cells without any distinctive plasma cell features. A, Hematoxylin-eosin stain; original magnification: 3400. B, CD138 positivity confirms plasma cell lineage.
MM generally appears at the late stage of myeloma and is an ominous clinical sign, with most of these patients surviving less than 1 year, reflecting a very aggressive biological behavior of these neoplasms once cutaneous lesions appear.10,16,17
Conclusions It is imperative to distinguish between neoplastic and nonneoplastic plasma cell lesions in the skin. Prompt comprehensive workup is required when a neoplastic plasma cell lesion is discovered to
Entity
Clinical presentation
Histologic features
Hypercalcemia, renal insufficiency, anemia, bone lesions
Sheets of plasma cells with occasional intermixed background mature lymphocytes
Immunophenotypic features
Other helpful findings
CD1381, k or l light chain restriction, background mixed T and B lymphocytes
EBER, In situ hybridization for EpsteineBarr virus; ESR, erythrocyte sedimentation rate; HHV, human herpes virus type; IFE, serum immunofixation; IL, interleukin; SPEP, serum protein electrophoresis; uIFE, urine immunofixation.
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M-protein on SPEP/IFE/uIFE in 99% of patients, marrow involvement by plasma cell dyscrasia CD1381, k or l light chain Sheets of plasma cells with occasional Primary extramedullary Solitary skin lesion without M-protein 6; no intermixed background mature plasmacytoma other clinical evidence of hypercalcemia, renal restricted, background lymphocytes multiple myeloma insufficiency, anemia, mixed T and B lymphocytes bone lesions; no marrow involvement Primary cutaneous Solitary or multiple cutaneous Predominant cell type is centrocyte-like, CD201, CD79a1, BCL 21 B M-protein in up to one monocytoid small B cell; other cells marginal zone violaceous papules, nodules, third of patients; no lymphocytes; CD1381 plasma include lymphoplasmacytoid cells and lymphoma and/or plaques with marrow involvement by cells 1 light chain restriction when scattered plasma cells; plasma cell predilection for the trunk plasma cell dyscrasia plasma cells prominent component may be prominent and upper extremities Plasmablastic lymphoma Mass occurring in oral cavity, Sheets of cells with plasmablastic/ CD20 , CD1381, CD56 ; light chain EBER1 in 70%; no M-protein rarely other mucosal sites, immunoblastic morphology restriction in rare cases or marrow involvement skin, bone, soft tissue; HIV1 or other immunodeficiency Nodular and diffuse mixed lymphocytic Mixed CD201 B cells with CD1381 Polyclonal hypergammagloCastleman disease, Lymphadenopathy, systemic infiltrate with prominent plasma cell bulinemia; elevated ESR plasma cell variant symptoms (eg, fever), plasma cells; usually polytypic, component and serum IL-6; anemia; scattered nodules and but up to one third of cases no M-protein or marrow plaques on trunk and may have k or l light involvement extremities chain restriction; HHV81 Mixed lymphocytes and plasma cells Mixed CD201 B cells and CD1381 Cutaneous and systemic Exceedingly rare, Japanese Polyclonal hypergammagloplasmacytosis individuals, numerous skin bulinemia; elevated serum plasma cells; polytypic k and l lesions, lymphadenopathy IL-6; no M-protein or light chain expression; marrow involvement HHV8 Pretibial lymphoSolitary pretibial plaque in Mixed lymphocytes and plasma cells Mixed CD201 B cells and CD1381 No associated systemic plasmacytic plaque a child symptoms or signs of plasma cells; polytypic k and l systemic disease; no light chain expression; M-protein or marrow HHV8 involvement Multiple myeloma
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Table II. Differential diagnosis of plasmacytic infiltrates in the skin
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Fig 6. In situ hybridization studies of the specimen shown in Fig 4, A, demonstrate l light chain restriction (diffuse purple staining [stars]) (A) and negative k light chain expression (absence of purple staining), confirming neoplastic clonal proliferation (B).
distinguish PEMP from cutaneous involvement by MM. In our series of 13 patients, median survival after neoplastic plasma cell skin lesion was discovered was only 8 months, despite the use of aggressive modern therapies, including stem-cell transplantation. REFERENCES 1. Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61: 212-236. 2. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757. 3. Talamo G, Farooq U, Zangari M, et al. Beyond the CRAB symptoms: a study of presenting clinical manifestations of multiple myeloma. Clin Lymphoma Myeloma Leuk. 2010;10: 464-468. 4. Alberts DS, Lynch P. Cutaneous plasmacytomas in myeloma. Relationship to tumor cell burden. Arch Dermatol. 1978;114: 1784-1787. 5. Kato N, Kimura K, Yasukawa K, et al. Metastatic cutaneous plasmacytoma: a case report associated with IgA lambda multiple myeloma and a review of the literature of metastatic cutaneous plasmacytomas associated with multiple myeloma and primary cutaneous plasmacytomas. J Dermatol. 1999;26: 587-594. 6. Requena L, Kutzner H, Palmedo G, et al. Cutaneous involvement in multiple myeloma: a clinicopathologic, immunohistochemical, and cytogenetic study of 8 cases. Arch Dermatol. 2003;139:475-486.
7. Wozney JL, Ahmed F, Bayerl MG, et al. Skin involvement in immunoglobulin E multiple myeloma. J Clin Oncol. 2009;27: 637-638. 8. Torres SM, Sanchez JL. Cutaneous plasmacytic infiltrates. Am J Dermatopathol. 1988;10:319-329. 9. Alexandrescu DT, Koulova L, Wiernik PH. Unusual cutaneous involvement during plasma cell leukemia phase in a multiple myeloma patient after treatment with thalidomide: a case report and review of the literature. Clin Exp Dermatol. 2005;30: 391-394. 10. Ballester-Martinez MA, Gonzalez-Garcia C, Fleta-Asin B, et al. Cutaneous nodules as a diagnostic clue in multiple myeloma. Am J Dermatopathol. 2013;35:377-380. 11. Ozsahin M, Tsang RW, Poortmans P, et al. Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients. Int J Radiat Oncol Biol Phys. 2006;64:210-217. 12. Shah A, Klimo P, Worth A. Multiple myeloma first observed as multiple cutaneous plasmacytomas. Arch Dermatol. 1982;118: 922-924. 13. Bayer-Garner IB, Smoller BR. The spectrum of cutaneous disease in multiple myeloma. J Am Acad Dermatol. 2003;48:497-507. 14. Patterson JW, Parsons JM, White RM, et al. Cutaneous involvement of multiple myeloma and extramedullary plasmacytoma. J Am Acad Dermatol. 1988;19:879-890. 15. Rongioletti F, Patterson JW, Rebora A. The histological and pathogenetic spectrum of cutaneous disease in monoclonal gammopathies. J Cutan Pathol. 2008;35:705-721. 16. Usmani SZ, Heuck C, Mitchell A, et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica. 2012;97:1761-1767. 17. Damaj G, Mohty M, Vey N, et al. Features of extramedullary and extraosseous multiple myeloma: a report of 19 patients from a single center. Eur J Haematol. 2004;73:402-406.
