J Clin Aesthet Dermatol. 2021;14(3):24–27.
by Luke Maxfield, DO; Jarett Casale, BS; Muneeb Shah, DO; Mikél E. Muse, DO; and Dana Baigrie, DO
Drs. Maxfield, Shah, and Muse are with Campbell University at Sampson Regional Medical Center in Clinton, North Carolina. Mr. Casale is with Campbell University School of Osteopathic Medicine in Raleigh, North Carolina. Dr. Baigrie is with Atlantic Dermatology in Wilmington, North Carolina.
FUNDING: No funding was provided for this article.
DISCLOSURES: The authors report no conflicts of interest relevant to the content of this article.
ABSTRACT: Cutaneous plasmacytosis is a rare disease that presents clinically with multiple red-brown papules and plaques with minimal to no epidermal change. Histopathologic findings include a perivascular dermal infiltration of polyclonal plasma cells. The etiology of cutaneous plasmacytosis is unknown, but hypothesized to be due to persistent or repeated antigenic stimulation. Ehrlichia represents a family of obligate intracellular bacteria that have been associated with the development of plasma cell dyscrasias in the veterinary literature. We present a case of a 67-year-old male patient with the development of progressively worsening cutaneous plasmacytosis following prolonged hospitalization secondary to ehrlichiosis sepsis. The patient initially presented with isolated cutaneous involvement and normal laboratory findings that eventually progressed to include multiple laboratory abnormalities, including anemia, hyperproteinemia, and elevated serum creatinine. Further diagnostic workup was declined by the patient despite evidence of progression to systemic plasmacytosis or multiple myeloma.
Key words: Cutaneous, systemic, plasmacytosis, plasmacytoma, gamma, polyclonal, hypergammaglobulinemia, gammopathy, ehrlichia, ehrlichiosis, chaffeensis, human, monocytotropic, myeloma, multiple, monoclonal
Cutaneous plasmacytosis is a rare disease of unknown etiology that may represent an indolent systemic process. Most cases have been reported in middle-aged men of Japanese descent.1,2 The lesions of cutaneous plasmacytosis typically present as multiple red-brown papules and plaques with little epidermal change. The diagnosis is made by histopathology, which demonstrates dense dermal perivascular infiltrates of mature polyclonal plasma cells without atypia.2 Systemic plasmacytosis is characterized by cutaneous plasmacytosis with concomitant lymphadenopathy and polyclonal hypergammaglobulinemia.3 Data on the treatment options for cutaneous plasmacytosis are limited, with no current standardized treatment protocol.4
Ehrlichia chaffeensis is an obligate intracellular bacterium transmitted to humans by tick bite and is responsible for human monocytotropic ehrlichiosis (HME).5 A hallmark feature of early HME includes multilineage cytopenias, including leukopenia in most patients within the first week after infection. This phase is typically followed by lymphocytosis during the recovery period.6
We discuss a patient who presented with hyperpigmented, annular, coalescing papules and plaques that began after prolonged hospitalization due to ehrlichiosis septic shock. Biopsies were performed, and histopathologic and immunohistochemical examination confirmed a diagnosis of cutaneous plasmacytosis. The patient declined treatment, and the cutaneous lesions continued to progress. Follow-up laboratory testing revealed multiorgan involvement suggestive of systemic plasmacytosis or multiple myeloma. This rare presentation of cutaneous plasmacytosis in an African-American patient after ehrlichiosis infection highlights a rare association between these two entities and the potential for progression to systemic involvement.
A 67-year-old African-American man with a recent history of prolonged hospitalization due to septic shock secondary to E. chaffeensis infection presented for the evaluation of a hyperpigmented rash involving both legs. The physical examination revealed hyperpigmented coalescing annular papules and plaques on both lower extremities (Figure 1). The patient had previously been diagnosed with biopsy-proven granuloma annulare; however, the lesions progressed despite treatment with topical corticosteroids, intralesional corticosteroids, rifampin, doxycycline, and dapsone.
Two punch biopsies were performed on the right lateral leg. Complete blood count (CBC), comprehensive metabolic panel (CMP), and a lipid panel taken at this time yielded results within normal limits. Histopathology revealed a dense dermal infiltrate of lymphocytes, histiocytes, and plasma cells (Figure 2). Immunohistochemical analysis of these cells showed small aggregates of CD20+ B-cells, CD3+ T-cells, low Ki-67 activity, and CD-30 negativity (Figure 3). Kappa and lambda light chain in-situ hybridization showed polyclonal plasma cells consistent with cutaneous lymphoid hyperplasia (Figure 3). The patient refused further diagnostic workup and testing despite being counseled about the risks of underlying systemic disease.
The patient agreed to follow up for laboratory testing two years after initial presentation. Physical examination revealed expansion of the initial lesions (Figure 4). Noteworthy findings on repeat CBC and CMP included a hemoglobin concentration of 12.1g/dL (<13.2g/dL), creatinine level of 1.61ng/dL, and estimated glomerular filtration rate (eGFR) of 51mL/min/1.73m2. Serum protein electrophoresis showed a total protein level of 8.9g/dL (>8.1g/dL), elevated immunoglobulin G level of 2,658mg/dL (>1,618 mg/dL), elevated gamma globulin level of 2.4g/dL (>1.7g/dL), alpha-1 globulin level of 0.4g/dL (>0.3g/dL), alpha-2 globulin level of 1.0g/dL (>0.9g/dL), and E. chaffeensis immunoglobulin G 1:256 dilution consistent with prior exposure. Urine studies, including electrophoresis, revealed no protein abnormalities.
Despite evidence of systemic plasmacytosis or multiple myeloma, the patient declined further studies, including renal ultrasound, bone marrow biopsy, and repeat kappa/lambda light chain assay.
Cutaneous plasmacytosis has a very low prevalence, with only 118 reported cases worldwide.1 The disease has a higher epidemiological presence in Asia, especially in the Japanese population. The mean and median age of onset is 37 years old, with a typical age of onset of between 20 to 62 years old; however, pediatric cases have been reported in the literature.7,8 The pathophysiology of cutaneous and systemic plasmacytosis is poorly understood, but cases of cutaneous and systemic plasmacytosis have been reported with latent or chronic infections and are thought to be due to persistent microbial-antigenic stimulation.9 In our patient, preceding ehrlichiosis might have been the source of antigenic stimulation leading to the development of cutaneous plasmacytosis.
E. chaffeensis was first identified on a peripheral smear in 1986, and its epidemiology has not been well-studied in human populations to date.6 E. chaffeensis is an obligate intracellular bacterium that enters the body by tick bite, most commonly from Amblyomma americanum, also known as the lone star tick.6 Once in the bloodstream, E. chaffeensis infects monocytes and macrophages and spreads systemically to cause HME.5,6 The most common symptoms of HME include fever, headache, myalgia, anorexia, and nausea. Abnormal laboratory studies from HME include multiple electrolyte abnormalities together with multilineage cytopenias during the initial phase of illness. The mechanism for the observed cytopenias is hypothesized to stem from peripheral sequestration and phagocytosis of leukocytes, erythrocytes, and platelets.5 During the recovery period after infection, a relative and absolute lymphocytosis is seen in most patients, representing a hyperproliferative expansion of activated T-cells.6
Previous observational studies have hypothesized a link between E. chaffeensis infection and the development of bone marrow disorders, including leukemia, multiple myeloma, aplastic anemia, and polycythemia vera.10,11 Several case reports and case series in the veterinary literature have reported an association between ehrlichiosis and the subsequent development of plasma cell dyscrasias in canines.11–13 These cases include canines with an active or previous history of ehrlichiosis followed by the development of polyclonal or monoclonal gammopathy, including multiple myeloma.11,14,15 To our knowledge, this is the first reported human case of plasmacytosis after a near-fatal ehrlichiosis infection.
The clinical presentation of cutaneous plasmacytosis involves multiple asymptomatic to mildly pruritic red-brown papules and plaques with minimal to no epidermal change. The lesions are most commonly seen on the trunk and can mimic pigmented pityriasis rosea.4 If systemic involvement is present, a triad of cutaneous lesions, lymphadenopathy, and polyclonal hypergammaglobulinemia is typically seen.3 In addition to lymphadenopathy, other visceral sites of plasmacytic involvement may include the bone marrow, lungs, liver, kidneys, or spleen.9
The diagnosis of cutaneous plasmacytosis is typically determined by histopathological analysis and aided by immunohistochemical staining from a biopsy specimen. Histopathology shows dense dermal perivascular plasma cell infiltration without significant atypia.2 Plasma cell infiltrates seen in cutaneous plasmacytosis represent a polyclonal infiltration, while a monoclonal infiltration of plasma cells should raise suspicion for marginal-zone B-cell lymphoma.16 Other histopathological findings may include increased numbers of mast cells together with variable lymphocytes and histiocytes.2 There is evidence to suggest that interleukin-6 (IL-6) activation of B-cells may play a pathophysiological role in cutaneous plasmacytosis due to increased deposition of IL-6 and IL-6 messenger RNA in lesional skin relative to in uninvolved skin.17,18
Laboratory findings associated with systemic plasmacytosis include polyclonal hypergammaglobulinemia with a kappa:lambda ratio in a normal range or with kappa overexpression.19 Although the hypergammaglobulinemia seen in cutaneous and systemic plasmacytosis typically involves all immunoglobulins, immunoglobulin G elevation has the strongest association with constitutional symptoms and extracutaneous involvement.7 Clinical signs and symptoms are used to guide systemic screening studies for extracutaneous plasmacytic involvement.
Treatment of cutaneous and systemic plasmacytosis is difficult, with variable efficacy. In the treatment of cutaneous lesions, intralesional corticosteroids have been shown to be moderately beneficial. Other studied treatments for cutaneous lesions include topical calcineurin inhibitors, phototherapy including psoralen with ultraviolet A light, radiotherapy, and intralesional interferon-gamma.2 Treatment with calcineurin inhibitors has demonstrated mixed efficacy, with one study citing complete clinical and histological remission with pimecrolimus treatment, while others have reported less promising results.20,21 Psoralen with ultraviolet A light therapy has been shown to halt cutaneous disease progression and flatten existing lesions.1 Treatment for systemic involvement has shown mixed clinical efficacy with systemic corticosteroids and alkylating chemotherapeutic agents. In one study, the chemotherapy agent thalidomide was used to successfully treat cutaneous and systemic plasmacytosis with no adverse effects.22
The clinical course of cutaneous and systemic plasmacytosis, as demonstrated in our patient, is typically progressive, with systemic manifestations occurring years to decades after the initial presentation of cutaneous lesions. Our case exemplifies the importance of establishing the diagnosis of this rare disease entity and the poorly understood progression of the disease. The relationship between cutaneous plasmacytosis and other related neoplastic diseases such as leukemia or multiple myeloma has not yet been elucidated and remains a research topic of interest. Our patient’s cutaneous disease preceded systemic involvement and shows evidence of progression to systemic plasmacytosis, monoclonal gammopathy of uncertain significance, or multiple myeloma. The preceding history of severe HME infection warrants further investigation in humans to establish a link between these two entities previously described in the canine literature.
- Mok ZR, Tan ES, Chong WS. Treatment of cutaneous plasmacytosis with mask-bath PUVA: a therapeutic option. Australas J Dermatol. 2015;58(1):e1–e4.
- Han XD, Lee SSJ, Tan SH, et al. Cutaneous plasmacytosis: a clinicopathologic study of a series of cases and their treatment outcomes. Am J Dermatopathol. 2018;40(1):36–42.
- Watanabe S. Systemic plasmacytosis. A syndrome of peculiar multiple skin eruptions, generalized lymphadenopathy, and polyclonal hypergammaglobulinemia. Arch Dermatol. 1986;122(11):1314–1320.
- Bares J, Wang A, Pavlidakey P, et al. Cutaneous plasmacytosis resembling pityriasis rosea in a 66-year-old white woman: a rare disease presenting in an unusual patient demographic. JAAD Case Rep. 2017;3(1):78–81.
- Walker DH. Ehrlichia under our noses and no one notices. Arch Virol Suppl. 2005;(19): 147–156.
- Paddock CD, Childs JE. Ehrlichia chaffeensis: a prototypical emerging pathogen. Clin Microbiol Rev. 2003;16(1):37–64.
- Uhara H, Saida T, Ikegawa S, et al. Primary cutaneous plasmacytosis: report of three cases and review of the literature. Dermatology. 1994;189(3):251–255.
- On HR, Lee SE, Kim YC, Kim SC. Isolated benign primary cutaneous plasmacytosis in a child. Pediatr Dermatol. 2014;31(6):e120–e121.
- Haque M, Hou JS, Hisamichi K, et al. Cutaneous and systemic plasmacytosis vs. cutaneous plasmacytic Castleman disease: review and speculations about pathogenesis. Clin Lymphoma Myeloma Leuk. 2011;11(6): 453–461.
- Kallick CA, Friedman DA, Nyindo MB. Could ehrlichial infection cause some of the changes associated with leukemia, myelodysplastic diseases and autoimmune disorders, and offer antibiotic treatment options?. Med Hypotheses. 2015;85(6):891–893.
- Geigy C, Riond B, Bley CR, et al. Multiple myeloma in a dog with multiple concurrent infectious diseases and persistent polyclonal gammopathy. Vet Clin Pathol. 2013;42(1): 47–54.
- Giraudel JM, Pagès JP, Guelfi JF. Monoclonal gammopathies in the dog: a retrospective study of 18 cases (1986–1999) and literature review. J Am Anim Hosp Assoc. 2002;38(2):135–147.
- Breitschwerdt EB, Woody BJ, Zerbe CA, et al. Monoclonal gammopathy associated with naturally occurring canine ehrlichiosis. J Vet Intern Med. 1987;1(1):2–9.
- Baba K, Itamoto K, Amimoto A, et al. Ehrlichia canis infection in two dogs that emigrated from endemic areas. J Vet Med Sci. 2012;74(6): 775–778.
- Varela F, Font X, Valladares JE, Alberola J. Thrombocytopathia and light-chain proteinuria in a dog naturally infected with Ehrlichia canis. J Vet Intern Med. 1997;11(5):309–311.
- Lu PH, Shih, LY, Yang CH, Kuo TT. Cutaneous plasmacytosis: a clinicopathologic study of 12 cases in Taiwan revealing heterogeneous underlying causes. Int J Dermatol. 2015;54(10):1132–1137.
- Kanbe N, Kurosawa M, Akimoto S, et al. Systemic plasmacytosis with deposition of interleukin (IL)-6 and elevated expression of IL-6 mRNA in the skin lesions. Br J Dermatol. 1998;138(4):721–723.
- Boostrom BO, Moore AS, DeRegis CJ, et al. Canine cutaneous plasmacytosis: 21 cases (2005–2015). J Vet Intern Med. 2017;31(4):1074–1080.
- Ma L, Leonard A, Kamino H, Meehan S. Cutaneous and systemic plasmacytosis. J Cutan Pathol. 2008;32(1):102–102.
- Hafner C, Hohenleutner U, Babilas P, et al. Targeting T cells to hit B cells: successful treatment of cutaneous plasmacytosis with topical pimecrolimus. Dermatology. 2006;213(2):163–165.
- Miura H, Itami S, Yoshikawa K. Treatment of facial lesion of cutaneous plasmacytosis with tacrolimus ointment. J Am Acad Dermatol. 2003;49(6):1195–1196.
- Fang S, Shan K, & Chen AJ. Cutaneous and systemic plasmacytosis on the face: effective treatment of a case using thalidomide. Oncol Lett. 2016;11(3):1923–1925.