Plasma Cell Disorders

In classical terms, a plasma cell is a terminally differentiated B lymphocyte, and a myeloma cell is its neoplastically transformed progeny. These are simplistic definitions, for plasma cell disorders (PCDs) are a complex group comprising a diverse spectrum of benign conditions to cancers known as myeloma-related disorders (MRDs).¹

Multiple myeloma (MM) is the primogenitor of the PCD. First reported in humans in 1844, it is a cancer that has become synonymous with skeletal involvement.² A multistep transformation model had been hypothesized for the development of myeloma in humans. The myeloma cell is believed to be derived from a somatically mutated and isotype-switched, postgerminal center B cell corresponding to a long-lived plasma cell.³ Intramedullary plasma cells develop karyotypic instability and form immortalized clone(s). As clone numbers increase, a premalignant bone marrow MRD becomes evident. As clonal cells evolve, there is morphological transition with concomitant cancerous myeloma features, the development of multiple myeloma and eventual extension of extramedullary metastases.⁴

Historical diagnostic criteria applied in human patients emphasizing the centrality of bone involvement were widely adopted in the diagnosis of feline myeloma.

Numerous other disorders of plasma cells, both neoplastic and nonneoplastic, have been recognized over time. Three disorders in particular provide further illustration of the historical background to PCD, namely; extramedullary plasmacytoma (EMP), monoclonal gammopathy of undetermined significance (MGUS), and immunoglobulin amyloidosis (IA).

Extramedullary plasmacytomas are tumors of plasma cells arising in soft tissues and not involving the bone marrow. In humans, they are considered rare tumors constituting approximately 5% of all MRDs; they can progress to MM in a small proportion of people.⁵

Blurred diagnostic distinctions occur not only among different MRDs but also among nonneoplastic, preneoplastic, and neoplastic PCDs. Kyle⁶ introduced the term “monoclonal gammopathy of undetermined significance (MGUS)” in 1978 after observing that a proportion of asymptomatic human patients with a monoclonal protein and no discernible neoplasia have a higher risk of going on to develop MRD such as MM, Waldenström's macroglobulinemia, and IA.

In 1971, it was established that the amyloid fibrils of primary amyloidosis were comprised of immunoglobulin (Ig) light chains.⁷ Note that biopsies from patients with IA typically show significant abnormal protein deposition (amyloid), but the appearance of plasma cells is either not evident or low in density within the tissue of interest and elsewhere such as bone marrow. In general historical terms, IA has perhaps more often been considered within the context of the protein conformation diseases (see Pathology of Protein Deposition Diseases) and less in relation to MRD.

The first authors to describe a case of feline myeloma were Holzworth and Meier in 1957.⁸ Since then, over 130 cats with a variety of MRDs have been described in the form of case studies or small case series.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 Many have been reported through the prism of myeloma as defined in humans. However it appears that extramedullary involvement may be more common in cats and that the diagnostic criteria for myeloma should be reviewed.1, 62 The largest peer-reviewed case series thus far describes 26 cats.1, 62

Epidemiology

In three large series of feline neoplasms, MRD accounted for 0.0012% (n = 3248),¹⁴ 0.0025% (n = 395),¹⁸ and up to 0.9% (n = 1491)⁴⁶ of all malignancies. For comparison, MRDs account for just over 1% of all tumors in dogs and in humans.⁶³ Within the subset of hematological neoplasia, MRDs account for 1.9% (n = 670) of affected cats, and 10% of affected humans.46, 64

Reported sex distributions in feline MRD are 50% female: 50% male in one study, and 44% female: 56% male in another.1, 46 For comparison, in humans, myeloma is more common in males (61%).⁶⁵

In the cat, the majority of MRD cases have been reported in domestic shorthair cats and in older cats (reported medians of 12 to 14 years with a range from 4 to 18 years).1, 46

Etiology

The etiology of feline MRDs is relatively unexplored. In one study, the entire medical record was obtained for all reported cats and specifically assessed for evidence of historic or concurrent chronic antigenic stimulation. Only two of 24 cats had evidence of chronic inflammation.¹ In the same study, the entire vaccination history of all patients was examined, with no indication of an association with MRD.¹

Overall, 37 cases of feline MRD have been assessed for feline infectious peritonitis (FIP), including feline coronavirus serology which was either negative or low-titer. The presence of feline leukemia virus was examined in 47 cases by either p27 antigen enzyme-linked immunosorbent assay (ELISA) or direct immunofluorescence assay, and only a single test in a single case was positive.⁵⁹ Similarly, the ELISA test for the antibody to feline immunodeficiency virus was carried out in 44 cats revealing two cases with single-test positive results.50, 56 A role of chronic infection in the establishment of some feline MRDs should not be ruled out. For example, infection of susceptible mice with Abelson murine leukemia virus and other retroviral constructs hastens the development of plasma cell neoplasia.⁶⁶ In human MRD patients, most have no definable etiology. However, connections to MRD have been reported for ionizing radiation,⁶⁷ petroleum-related products,⁶⁸ medicinal mineral oil,⁶⁹ Epstein-Barr virus in isolation or in combination with human immunodeficiency virus,70, 71 as well as hereditary factors.⁷²

Clinical Features

Cats with MRD may be free of clinical signs at the time of presentation, and diagnostic investigations may be mounted as a result of incidental findings on a routine blood analysis. Nonspecific clinical signs described in feline myeloma include lethargy, weakness, reduced appetite, vomiting, and diarrhea.¹ Alternatively, a number of common clinical manifestations arise which may be pathogenetically summarized as:

• (i)focal problems attributable to local cellular infiltration of plasma cells or myeloma cells (an infiltrative lesion or mass development) such as bone lysis, organomegaly, or mass.
• (ii)focal problems attributable to the consequences of clonal plasma cell protein production (i.e., focal light chain amyloid or Ig deposition).
• (iii)systemic problems attributable to the consequences of plasma cell protein production (e.g., renal insufficiency, reciprocal humoral immunoparesis, coagulopathy, hyperviscosity, amyloidosis, or Ig deposition diseases).
• (iv)systemic problems attributable to damage arising from widespread local cellular infiltration of myeloma cells (e.g., hypercalcemia from widespread osteolysis).

The following clinical features are commonly ascribed to myeloma: anemia, renal dysfunction, hypercalcemia, intramedullary involvement, extramedullary involvement, hyperviscosity, neurological signs, coagulopathy, immunosuppression, and other clinical signs.

Anemia

A nonregenerative, normocytic normochromic anemia is common in feline MRD (46% to 75% in the larger case series).1, 48 The pathogenesis of anemia can be multifactorial, including altered bone marrow microenvironment, myelophthisis, hypoerythropoietinemia in association with myeloma-related renal dysfunction, blood loss due to coagulopathies, and immune-mediated hemolytic anemia.73, 74

Renal Dysfunction

Renal insufficiency affected 21% to 25% of feline MRD cases in the two largest case series, the pathogenesis of which can be multifactorial.1, 48 An interstitial nephritis arises from the development of light chain casts.⁷⁵ Myeloma-associated hypercalcemia and hyperviscosity can induce renal failure. Renal IA has been reported.¹⁷ A report consistent with noncongophilic Ig deposition disease causing renal failure has recently been described.⁷⁶ Proteinuria has been reported, and this can arise through intercurrent glomerulonephropathy.¹ Medication usage (e.g., bisphosphonates, nonsteroidal anti-inflammatory drugs, some chemotherapeutics) can exacerbate the renal failure.

Hypercalcemia

Hypercalcemia has been reported in 8% to 20% of feline MRD cases.1, 48 Neoplasia induced bone lysis is a key pathogenetic mechanism.⁷⁷ Elevated parathyroid hormone-related peptide is likely to be a mechanism in some cases of feline MRD as has been reported in feline lymphoma.⁷⁸ Ideally, ionized calcium should be measured since this is the functionally active element within plasma.

Intramedullary Involvement

Bone pain due to osteolysis has been a key feature in the historical understanding of MM in humans. However, in contrast, it may not be as common a feature in feline MRD.¹ In one feline MRD series, lameness was reported in 16% of cases, but none of the patients with reported lameness had radiographic evidence for bone lysis.¹ In other reports, lameness and/or skeletal pain and radiographic evidence for bone lysis have been described.11, 48 Assessing bone pain poses difficulties in cats, and it is likely underestimated by both owners and clinicians.

Extramedullary Involvement

Extramedullary involvement is frequently apparent at the time of initial presentation in feline MRD.¹ This is in contrast to humans, where extramedullary involvement is rarely a presenting feature, and instead is usually associated with metastatic progression from the intramedullary compartment.⁷⁹ The spleen, liver, and skin are commonly affected organs in cats, but a wide range of organ systems either singly or in combination with multiorgan involvement (including bone marrow) have been reported.1, 48

Hyperviscosity

The risk of hyperviscosity syndrome (HVS) rises with increasing levels of serum monoclonal protein. It also increases with certain types of monoclonal protein (e.g., most commonly with IgM, but also IgA, and some subclasses of IgG).⁸⁰ Hyperviscosity syndrome can cause neurological signs, visual changes including blindness due to retinal hemorrhage or detachment, renal failure, hypertrophic cardiomyopathy, cardiac failure, thromboembolic disease, and bleeding diathesis.13, 19, 24, 28, 31, 56, 59

Neurological Signs

Central neurological signs have been reported in 13% of cats with MRD.¹ A wide range of neurological signs have been reported including behavioral changes, seizures, tremors, ataxia, and paresis.24, 25, 26, 27, 31, 32, 46, 58 The pathogenesis of most neurological signs is attributed to tumor mass effect, be that intracranial, spinal cord, or nerve compression. Hyperviscosity, hypercalcemia, meningeal involvement, and peripheral neuropathies have also been reported as potential causes for the neurologic signs.

Coagulopathy

Serum monoclonal proteins interfere with coagulation cascade, endothelial, and platelet function. Hyperviscosity and reduced capillary flow exacerbate clotting problems. Both bleeding and thrombotic problems can be observed.⁸¹ Bleeding disorders including epistaxis, oral bleeding, melena, hyphema, and retinal hemorrhages have been reported in feline MRD.1, 29, 48, 56

Immunosuppression

Numerous mechanisms for reduced cellular and humoral immunity have been described in human myeloma patients. These include numerical and functional abnormalities of dendritic cells, T cells, and Natural killer cells. Reciprocal humoral immunoparesis (reduced levels of polyclonal Igs as a result of the high serum monoclonal protein level) predisposes patients to infection by encapsulated bacteria, in particular organisms associated with pneumonia.⁸² Many myeloma therapies worsen this immunosuppression. Infections are the principal cause of death and a leading cause of morbidity in human myeloma patients.⁸³ Immunosuppression and infection are likely under-recognized in feline patients. Severe or fatal infections have been reported in a few individual feline MRD cases (e.g., respiratory tract infection, sepsis, severe fungal infections, and pyothorax).17, 19, 24, 36, 48, 58

Other Clinical Signs

A diversity of other signs have been reported in association with feline MRD, including constipation in a case with small intestinal plasma cell masses,²⁷ iridal color change with intraocular involvement,⁴⁵ pleural effusion,28, 30, 36 facial edema,¹⁹ lymphadenomegaly,⁴⁸ glaucoma with iridal in­­volvement,³⁵ and chronic nasal discharge with sinonasal involvement.⁵³

Diagnostic Investigations

Initial investigations will follow the presenting features of PCD patients who, as previously stated, may display protean clinical signs. The route to diagnosis is typically achieved through the following two pathways: discovery of hyperglobulemia and investigation of a lesion or mass.

Discovery of Hyperglobulinemia

The appropriate next stage test is serum protein electrophoresis (SPE, see Clinical Pathology of Gammopathies). Regardless of whether the globulin rise is poly- or monoclonal, where there are “significantly” elevated globulins or where progressive elevations over time have been demonstrated, these patients should have their clinical history and examination reviewed. Efforts to localize and identify possible lesion(s) associated with the hyperglobulinemia are indicated. Where SPE indicates a monoclonal protein, biopsy of soft tissue lesions (particularly of the liver, spleen, or skin masses), skeletal lesions, and/or bone marrow sampling, including aspirate(s) and core trephine(s) are warranted.

Investigation of a Lesion or Mass

The lesion may be macroscopically visible or an imaging discovery such as organomegaly or a skeletal lesion. Usually the lesion of interest will be sampled, although individual clinical judgment will be used where a surrogate sampling site associated with a lower risk of morbidity is necessary or desirable. Diagnosis is initiated by a tentative cytological or histopathological report of plasma cell lesions and/or amyloid. In the case of the former, it is essential to demonstrate the presence or absence of plasma cell clonality in the tissue of interest (see Achieving a Pathological Diagnosis in Myeloma-Related Disorders). In the case of amyloid like lesions, amyloid typing confirms the diagnosis of IA.

Once a PCD is suspected, patients should have any outstanding clinical issues re-evaluated. For example, is hyperviscosity suspected? Hyperviscosity syndrome is a clinical diagnosis based on demonstration of an elevated serum monoclonal protein in conjunction with appropriate clinical signs, in particular ophthalmic signs. While viscosity can be measured in serum, plasma, or whole blood, it is not typically used for diagnosis, and instead has been used for monitoring of patients undergoing plasmapheresis.⁸⁴ In the event of suspected HVS, are concurrent neurological signs or cardiovascular problems such as heart murmurs in association with hypertrophic cardiomyopathy present? If water intake and/or urine output are thought to be abnormal, then have renal function, calcium status, and urinalysis been assessed? If pallor is present, has any anemia been characterized? If bleeding has been reported, has coagulation been assessed? Could bone pain be a possibility in the patient, with or without imaging evidence of bone lesions? What is the confidence level that a lesion is solitary, or is there evidence for multifocal involvement? Are additional imaging studies indicated? A description of some of the tests that may be considered in feline MRD is given in Table 55-1 .

Table 55-1.

Investigations That Can Be Indicated in the Diagnosis of Plasma Cell Disorders

Tests	What to Look for
Ophthalmological examination	Retinal hemorrhage, retinal vessel distension and tortuosity, aneurysms
Blood pressure	Appropriate ocular signs in the absence of hypertension is consistent with hyperviscosity syndrome
Hematology	Anemia, thrombocytopenia, plasma cells in peripheral blood
Biochemistry	Hyperglobulinemia, azotemia, hypercalcemia, liver function
Rule out FIP	Coronavirus titers, alpha-1 acid glycoprotein along with other aspects of the clinical picture, plus tissue analysis
Serum gammopathy	Serum protein electrophoresis and immunoelectrophoresis or immunofixation—allowing quantification of the paraprotein concentration as well as the identity of the Ig type
Immunoglobulin profile	IgA, IgG and IgM quantification
FeLV antigen and FIV antibody	Confirm positive test results with a second assay
Microbiology—blood and/or other cultures	Where intercurrent infection is clinically suspected in these immunosuppressed patients
Blood viscosity	Can be considered for monitoring (e.g., in patients undergoing plasmapheresis)
Urinalysis	Microscopy (white blood cell count), bacterial culture
Urine Ig light chains	Urine protein electrophoresis or immunofixation
Urine protein : creatinine ratio	A high UPC combined with evidence of urine Ig light chains is highly suggestive of renal amyloidosis
Survey skeletal radiographs	Lytic lesions, osteoporosis, compression fractures, osteosclerotic lesions
Survey abdominal radiographs	Organ enlargement/masses
Abdominal ultrasonography	Enlargement/distortion of normal organ architecture (in particular of the liver/spleen) or the presence of masses
Magnetic resonance imaging	MRI is recommended (over computed tomography) in suspected myeloma patients with normal conventional radiography findings, as well as in patients with an apparently solitary plasmacytoma (of bone or extramedullary)90
Coagulation profiles prior to biopsy	Thrombocytopathia and altered coagulation times as a result of hyperglobulinemia
Cytology	Bone marrow aspirate, fine-needle aspirates of abnormal organs, masses on the liver or spleen; B cell immunomorphology
Histopathology	Bone marrow core, tissue biopsy of abnormal organs/masses; B cell immunomorphology, amyloid
Immunohistochemistry or immunocytochemistry	Indication of clonality; expression of a single light or heavy chain type
Polymerase chain reaction	Indication of clonality151

FeLV, feline leukemia virus; FIP, feline infectious peritonitis; FIV, feline immunodeficiency virus; Ig, immunoglobulin; UPC, urine protein:creatinine ratio; MRI, magnetic resonance imaging

Clinical Pathology of Gammopathies

Hyperglobulinemias (or gammopathies) can broadly be divided into polyclonal and monoclonal protein increases. Polyclonal globulin increases are associated with reactive or inflammatory plasma cell disorders and these patients are generally not considered to have a MRD. Monoclonal proteins (also known as M-proteins or myeloma proteins and a subset of the paraproteins) are Igs typically of normal structure and charge but present in excessive quantity, and they are a hallmark of MRD.⁸⁵ Standard high-resolution agarose gel SPE has been reported to identify a monoclonal protein in 82% of human patients with MM.⁸⁶ However, low levels of monoclonal protein can be concealed within the beta or gamma regions of a routine SPE trace. Over time electrophoretic tests have improved (e.g., capillary zone electrophoresis). Furthermore, a combination of tests are used to increase the diagnostic accuracy for PCD.⁸⁷ Serum protein electrophoresis will detect monoclonal levels as low as 500 mg/L, immunofixation as low as 150 mg/L, but the latest nephelometric immunoassays for serum immunoglobulin free light chains (SFLC) are capable of detecting less than 1 mg/L. Quantification of SFLC is now recommended in all human MRD patients for the purposes of diagnosis, prognosis, and monitoring.⁸⁸ Note that even where standard electrophoresis methodologies do detect a quantitative abnormality, they cannot always reliably identify a monoclonal protein and differentiate it from, for example, a restricted oligoclonal gammopathy. Therefore, immunofixation electrophoresis is used as the confirmatory gold standard test for the presence of a monoclonal protein and to distinguish its heavy and light chain type. A 24-hour urine collection for urine protein electrophoresis, protein quantification, and immunofixation are additional tests frequently used in the investigation of monoclonal gammopathies in humans.⁸⁹

Although most cases of hyperglobulinemia can be commonly assigned to either a poly- or a monoclonal gammopathy, it is not universally dichotomous. Human patients with biclonal and triclonal gammopathies have been described, most with a confirmed lymphoproliferative neoplasm, but some were of undetermined significance, and others had nonhematological diseases.90, 91

In the cat, cases of hyperglobulinemia are typically further assessed by standard agarose gel electrophoresis. Use of capillary zone electrophoresis and immunoelectrophoresis (but not immunofixation) have recently been described in feline MRD.18, 21

Most cases of feline hyperglobulinemia have a polyclonal gammopathy. The underlying cause of a polyclonal gammopathy is a diverse range of disorders with a reactive or inflammatory plasma cell component.⁹³

Monoclonal gammopathies in cats are most commonly associated MRD and/or lymphoma.1, 19, 26, 36, 48 Monoclonal gammopathies have been reported in rare cases of FIP, lymphocytic-plasmacytic stomatitis, and anaplasmosis.19, 40, 92, 93, 94 However, the stringency of diagnosis in these latter reports is relatively uncertain (where described, it is based on histopathology or hematopathology only and no further confirmatory tests). Furthermore, there is a possibility of ascertainment bias and coincidental association.⁹⁵ Note that biclonal paraproteinemias have been reported in feline MRD.1, 12, 38

The evolved complexity, precision of analysis, and interpretation of gammopathies seen in human patients have not been available in the cat. Some reports in the feline literature of monoclonal and biclonal gammopathies in association with MRD may be incorrect in the absence of immunofixation electrophoresis and confirmation of a clonal MRD within the tissue of interest. Furthermore, there are four cases reported in the feline literature to have MRD on the basis of routine histopathology, with no demonstration of tissue clonality but instead having a polyclonal gammopathy.26, 58, 62 They may be cases of MRD intercurrent with another disease process inducing the polyclonal gammopathy, but it is more probable that they are misdiagnoses, reflecting reactive or inflammatory plasma cell lesions. They are not considered further in this review.

Pathology of Plasma Cells and Plasma Cell Disorders

Cellular Morphology

The key morphological features of a mature plasma cell (also known as a terminally differentiated plasma cell, Marschalko cell, or plasmacyte) are as follows: intensely basophilic cytoplasm due to the high ribonucleoprotein content, an acroplasm (or pale perinuclear “hof”, a focal area of clearing) representing a prominent Golgi apparatus, an eccentric nuclear position, and “cartwheel” chromatin arrangement. Variations in plasma cell morphology have been clearly defined in humans. Plasmacytoid is a descriptor for (1) any nonspecific variation of mature plasma cell characteristics, and (2) plasma cell type appearance of cells of non-B cell origin. Lympho-plasmacytoid cells have a mixed lymphocyte and mature plasma cell appearance with typically less basophilic cytoplasm. Flame cells and/or thesaurocytes have red to violaceous coloration of the cytoplasm attributed to the accumulation of high carbohydrate content Ig within the endoplasmic reticulum cisternae.⁹⁶ Mott cells contain multiple cytoplasmic Russell bodies (Ig inclusions).⁹⁷ Proplasmacytes are larger than mature plasma cells with greater anisocytosis, asynchronous nuclear and cytoplasmic maturation, and indistinct or small nucleoli.⁹⁸ Plasmablasts are larger than mature plasma cells with greater anisocytosis, a narrow rim of cytoplasm, less distinct or inapparent perinuclear hof, high N : C ratio, a large and immature round to ovoid eccentric nucleus with anisokaryosis, and one or more prominent nucleoli.⁹⁸ Binucleate, trinucleate, and multinucleate giant myeloma cells may also be observed.⁹⁹

In the feline MRD literature, many histopathologic and cytopathologic reports of feline MRD simply describe the neoplasia as comprising of plasma cells. Other reports have provided greater detail and virtually all of the morphological descriptors used in human myeloma have been used in the cat including mature (Marschalko-type) plasma cells,⁶⁴ plasmacytoid,14, 25, 39 lympho-plasmacytoid,23, 50, 59 flame cells,⁴⁸ Russell bodies,⁶⁴ Mott cells,⁵³ proplasmacytes,⁶⁴ plasmablasts,⁶⁴ and giant multinucleated myeloma cells.78, 94 Cytopathological and histopathological examples of these cells may be seen at the Veterinary Myeloma Website.¹⁰⁰

Achieving a Pathological Diagnosis in Myeloma-Related Disorders

Taken in isolation, the examination of a single plasmacytoid cell or even groups of plasma cells does not allow the cytopathologist or histopathologist to define that these cells are myeloma cells (that is to say, neoplastically transformed). Progressive morphologic changes within plasma cells (with ultimately the development of plasmablastic features) have clearly been correlated with accumulating cytogenetic aberrations and progressive clinical disease.101, 102 Yet these morphologic changes do not take place uniformly. Diverse populations of plasma cell morphology may be seen within a single biopsy. Therefore, a provisional diagnosis of a MRD is achieved through synthesis of multiple observations including lesional and perilesional tissue and cellular changes, density of plasma cells, as well as the above plasma cell morphological features and the relative proportions between these cells. In soft tissues, the presence of mass-related changes allows greater confidence in the provisional diagnosis. Within bone marrow, although near complete effacement of the marrow cavity by plasma cells is occasionally observed, it is more common to see varying degrees of plasma cell density and a cut off of 10% or greater infiltration is required for diagnosis.¹⁰³

The demonstration of monoclonality in the tissue of interest remains the gold standard for the pathological component of diagnosis of this hematopoietic neoplasia (e.g., patients can have concurrent MGUS and an unrelated round cell tumor misinterpreted as a MRD). The demonstration of polyclonality within the tissue of interest implies a reactive or inflammatory plasma cell population. Clonality may be investigated via a number of techniques. Immunohistochemistry and immunocytochemistry allow the surrogate demonstration of clonality when expression of a single Ig light chain only is revealed, and this is the most common technique in veterinary medicine. Alternative techniques include flow cytometry, molecular biological tests such as polymerase chain reaction and Southern blot, and an array of cytogenetic and epigenetic tests.89, 104, 105, 106, 107, 108 In practical terms, the confirmed presence of IA can also be used as a surrogate marker of clonality, but there should be an awareness that in rare patients there may be discordant results.109, 110

In some of the published feline MRD series, there have been arguably insufficiently stringent inclusion criteria, with some individual patients diagnosed with MRD on the basis of histopathology alone, with no serum or urine protein electrophoresis carried out, and no other assessment of clonality.26, 36, 48 In the practice of veterinary medicine, there is often a pragmatic clinical supposition of a MRD if routine hematoxylin and eosin (H&E) stained pathology or cytopathology provide a morphological diagnosis consistent with a MRD and this is combined with an indirect indication of clonality (i.e., the detection of a monoclonal protein in serum or urine). However, the importance of clonal confirmation in the tissue of interest in cases of feline MRD has been reported. In one study, 34 histopathological samples with an original diagnosis of MRD made by a diversity of board-certified pathologists in various institutions and laboratories were subjected to review by an independent panel of board-certified pathologists who examined H&E stained sections along with additional histochemical and immunohistochemical stained sections. Only 56% (n = 19) of the cases were eventually shown to be clonal MRD by light chain restriction.⁶⁴ Some of the excluded feline cases were not of B cell origin despite a plasmacytoid appearance (instead proving to be histiocytic neoplasms or mast cell tumors). Cellular morphology is linked to function, and other non-B lymphoid cells that have high demand for protein production (e.g., not Ig) may have a plasmacytoid appearance. Further examples include plasmacytoid dendritic cells, histiocytes, salivary gland duct luminal cells, and myoepithelial cells.110, 111, 112, 113, 114

Pathological Classification and Grading

In human patients, there is no internationally accepted standard for the morphologic categorization of MRD, but a key feature of most reported systems is the division into well-differentiated, intermediate-grade, or poorly differentiated tumors, depending on the proportions of cell types from mature plasma cells to poorly differentiated plasmablastic cells. Tumor grading has prognostic significance.115, 116 There is generally good agreement between cytologic and histologic categorization of tumors.64, 98

Only two case series with clonally confirmed MRD have presented tumor morphologic classification systems in the cat.41, 64 In the largest case series of feline MRD thus far, tumors were classified as well-differentiated (less than 15% plasmablasts, with the remainder being mature myeloma cells, proplasmacytes, or lymphocytes), intermediate-grade (15% to 49% plasmablasts), or poorly differentiated (greater than 50% plasmablasts). A correlation between morphology and survival was proved with statistical significance. Cats with well-differentiated tumors had increased median survival time relative to those with poorly differentiated tumors (254 versus 14 days [Figure 55-1 ]).⁶⁴

Figure 55-1.

Kaplan-Meier survival curves for poorly differentiated myeloma-related disorders (MRD) versus well-differentiated MRD.⁶⁴

(Redrawn from Mellor PJ, Haugland S, Smith KC, Powell RM, Archer J, Scase TJ, et al. Histopathologic, immunohistochemical, and cytologic analysis of feline myeloma-related disorders: further evidence for primary extramedullary development in the cat. Vet Pathol Online. 2008;45(2):159–73.)

Pathology of Protein Deposition Diseases—Amyloidosis and Monoclonal Immunoglobulin Deposition Disease

Amyloidosis is a subset of the protein conformation diseases that share a common pathophysiological mechanism, proteotoxicity. This occurs through both the direct cellular toxic effect of amyloid precursors, as well as damage to organ structure and function via massive deposition of amyloid fibrils in extracellular spaces. Biopsies must show amyloid deposition confirmed by Congo-red staining and apple-green birefringence under polarizing light microscopy. The amyloid must then be typed, which historically has been achieved through histochemical assessment or immunohistochemistry, although more recently it has been supplanted by laser microdissection with mass spectrometry (LMD/MS).¹¹⁷ Typing allows precise categorization of the amyloid. Numerous amyloidogenic proteins have been discovered, but only a single group is relevant to the MRD—the IA.¹¹⁸ Historically, IA diseases have largely been considered separately from MRD. Even in recent times, IA is described by some authors as a nonproliferative and nonneoplastic PCD.¹¹⁹ However, current work confirms shared aspects of pathogenesis in terms of the underlying cytogenetic aberrations, as well as outcomes in subsets of human patients, with the suggestion that IA be considered as low-proliferative, neoplastic MRD.120, 121

In feline PCD, amyloidosis confirmed by light microscopy has been reported, but confirmation of amyloid type (to Ig) has been inconsistent. Both systemic and local forms of IA have been suspected in the cat.46, 48, 70, 71, 79, 81, 94 Precise amyloid typing in cats (including immunohistochemistry and LMD/MS) can be conducted with assistance from human medical laboratories (Paul Mellor, unpublished observations).

Monoclonal immunoglobulin deposition diseases (MIDD) are rare in humans. They are characterized by the deposition of monoclonal Ig molecules in basement membranes and in contrast to amyloidosis, the deposits are nonfibrillar and Congo-red negative.¹²² Noncongophilic Ig deposition has been described in the cat, but MIDD has not yet been described in the feline literature.⁷⁶

Feline Plasma Cell Disorder—Existing Diagnoses in the Published Literature

The existing feline literature outlines a diversity of PCD presentations. Plasma cell disorders are described with sometimes confusing terminology and diagnostic criteria, and where this is relevant it is highlighted later. Table 55-2 outlines a range of existing diagnoses and diagnostic criteria for PCD in cats.

Table 55-2.

Traditional Diagnostic Scheme for Plasma Cell Disorders, with Alternate Diagnostic Names and Summarized Diagnostic Criteria

Principal Name (Alternate Names in Italics)	Diagnostic Criteria Typically Applied in Cats
Plasma cell disorders
Plasma cell pododermatitis (Plasmacytic pododermatitis)	Clinical signs with histopathology/cytology, +/− polyclonal gammopathy; note demonstration of polyclonality within the tissue is desirable for academic confirmation
Nasal plasma cell dermatitis	As above
Plasma cell stomatitis-pharyngitis (Plasma cell stomatitis, lympho-plasmacytic stomatitis)	As above
Monoclonal gammopathy of undetermined significance (monoclonal gammopathy of unknown/uncertain significance, monoclonal gammopathy unassociated/unattributed, paraproteinemia, monoclonal gammopathy, benign monoclonal gammopathy, monoclonal hypergammaglobulinemia)	SPE monoclonal protein without initial evidence of clinical signs, nor hematologic or biochemical abnormalities, nor radiographic evidence for bone lytic lesions, and <10% marrow plasma cell content48
Preneoplasmic plasma cell disorder
Smoldering myeloma (Indolent myeloma, asymptomatic myeloma)	Not formally described in feline literature; however, at least one reported feline case would be consistent with the description48
Malignant plasma cell disorders—Myeloma-related disorders
Multiple myeloma (Plasma cell sarcoma, plasma cell tumor, plasma cell myeloma, reticulum cell myeloma, Kahler's disease, myelomatosis)	Variable criteria used historically; typical example—at least two of the following criteria: (1) monoclonal gammopathy, (2) radiographic evidence of osteolysis, (3) Bence Jones proteinuria, (4) >5% marrow plasma cells26
Symptomatic multiple myeloma	Not reported in the feline literature
Nonsecretory & oligo-secretory myeloma	Not adequately reported in the feline literature
Solitary extramedullary plasmacytoma (soft tissue plasmacytoma, nonosseous plasmacytoma, cutaneous, noncutaneous)	Variable criteria used historically; typical example—neoplastic plasma cell formation in soft tissue without primary evidence of bone marrow involvement1
Multiple solitary extramedullary plasmacytoma	Strict criteria are undefined in the feline literature
Solitary plasmacytoma of bone	Inadequately stringent diagnostic criteria in the feline literature44
Multiple solitary plasmacytoma of bone	Not reported in the feline literature
Immunoglobulin M macroglobulinemia (Waldenström's macroglobulinemia, lymphoplasmacytic lymphoma, immunocytoma)	Strict criteria are undefined in the feline literature59
Immunoglobulin secreting lymphoma	Based on morphological description (histopathology/cytopathology) only
Osteosclerotic myeloma (POEMS syndrome, multicentric Castleman disease, Crowe-Fukase syndrome, Takatsuki syndrome)	Not reported in the feline literature
Plasma cell leukemia (Myeloma with leukemic overspill)	Variable criteria used historically; typical example—peripheral blood plasma cells >20% or >2 × 109 cells/L49
Low proliferative clonal plasma cell disorders as protein deposition diseases
Immunoglobulin amyloidosis	Inadequately stringent diagnostic criteria in the feline literature

POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; SPE, serum protein electrophoresis.

Polyclonal Plasma Cell Disorders

Reactive plasmacytosis and a plethora of inflammatory diseases contain lesser or greater numbers of polyclonal plasma or plasmacytoid cells, particularly in the feline species. Plasma cell pododermatitis, nasal plasma cell dermatitis, and plasma cell stomatitis-pharyngitis are inflammatory plasma cell disorders in the cat.123, 124, 125, 126, 127 Some cats present with a combination of the aforementioned disorders.128, 129 An accompanying polyclonal gammopathy has been reported in some cases across all three disorders.¹³⁰ No infectious etiology has been demonstrated and an immune-mediated pathogenesis is suspected.¹³¹ Only in two cats have possible connections to a MRD been construed. In a single report of feline stomatitis, a monoclonal protein was demonstrated in serum and urine. However, the validity of this report is questionable with no proof or disproof of clonality within the tissue biopsy, and no exclusion of intercurrent MRD in alternate locations.⁹³ In the second case, a cat with pododermatitis was reported to have subsequently developed systemic amyloidosis. There was no typing of the amyloidosis (to confirm Ig origin) and no exclusion of intercurrent MRD in alternate locations.¹²³

Plasma cell granulomas (more commonly known as inflammatory pseudotumor in the cat or inflammatory myofibroblastic tumor) contain polyclonal plasma cells but are clinically and pathologically readily distinguishable from other PCDs and MRDs.132, 133

Monoclonal Plasma Cell Disorders

Monoclonal Gammopathy of Undetermined Significance, Benign Monoclonal Gammopathy, and Smoldering Myeloma

Monoclonal gammoptahy of undetermined significance describes the finding of a serum monoclonal protein without clinical or investigational evidence for myeloma (see Table 55-2 for diagnostic criteria). The proportion of healthy people with MGUS increases with age. In long-term follow-up studies of MGUS in humans, approximately 75% of patients do not evolve into classical MM.8, 134 These patients can be described as having had a benign monoclonal gammopathy at point of death only and where death was due to nonmyeloma-related causes. However, despite the fact that most MGUS patients do not within their lifespan develop overt symptoms of myeloma, most or all are expected to have a clonal plasma cell disorder. In cytogenetic studies alone, plasma cell clone(s) have been demonstrated in 77% of human patients with MGUS.¹³⁵ All human myeloma patients are believed to progress from MGUS, through smoldering myeloma (asymptomatic myeloma), and to myeloma (see Table 55-2 for diagnostic criteria).

Monoclonal gammopathy of undetermined significance was first reported in a cat in 1977, although the stringency of exclusion of MRD is not known as details of the clinical investigations are lacking in this earlier paper.⁴⁰ Feline MGUS has been reported in a 4-year-old cat with monoclonal gammopathy, with no evidence of clinical signs, nor other abnormalities (hematologic, biochemical, radiographic evidence for lytic lesions, ultrasonographic evidence for lesions, light chain proteinuria) and less than 10% marrow plasma cell content. This cat developed myeloma at 9 years of age.⁴⁸ The details of progression are not documented in the report, but the expectation is that this cat will have evolved from MGUS though to smoldering myeloma and ultimately myeloma.

Multiple Myeloma

Classical cases of MM have been described in the cat, with marked bone marrow plasma cell infiltration, radiographic evidence for bone lysis, and a monoclonal protein detectable in serum and/or urine.1, 26, 28, 29, 32, 40, 48, 54 Diagnostic criteria are given in Table 55-2. However, there has been some confusion in earlier literature regarding the diagnostic criteria of MM in cats. For example, cats have been reported as having MM despite pathological evidence of the absence of bone marrow infiltration, and instead having extramedullary involvement.36, 46 In general, across the feline literature, given the historical diagnostic criteria, there will likely have been a tendency to a reporting bias towards MM cases that involved radiographic bone lesions. Examining the literature prior to 2005, 75 cases of all types of MRD had been described, of which 36 provided clinical details of investigations (mainly in the form of case reports or small case series). Of these, 22 cases were explicitly described as MM, of which only 6 (27%) had radiographically evident bone lesions—a notably low proportion in comparison to humans—in whom 80% of MM cases have radiographically detectable osteolysis.¹³⁶ Then in 2005, two larger clinical case series of MM were published. In one series from a single institution, 58.3% of MM cases had radiographically evident bone lesions.⁴⁸ In another series from a single veterinary practice with an orthopedic bias, the proportion was 71.4%.²⁶ However, in 2006, in a multi-departmental, multicenter clinical case series, the authors proposed that feline MRD cases infrequently (8%) present with radiographic bone lesions, with some additional statistical support for this hypothesis.¹ The conclusions that can be drawn are limited by the retrospective nature of all of these studies, the failure to obtain complete skeletal survey radiographs in all cases, and the imperfect comparisons made. However, given the pre-existing literature and the authors' findings, it is probable that fewer feline MRD cases have classical radiographically detectable osteolysis compared to human patients.

Extramedullary Plasmacytoma

Soft tissue involvement can arise by metastatic extension from intramedullary myeloma via the hematogenous route, by direct extension from skeletal disease (arising from a focal marrow lesion broaching cortical bone with adjacent soft tissue infiltration), and by infiltration of traumatized areas (including sites of subcutaneous injection, intravenous catheter placement, surgery, and pathological fracture).137, 138, 139 However, a primary (true) EMP is a monoclonal plasma cell neoplasm that arises de novo in soft tissue without evidence for concurrent bone marrow involvement (see Table 55-2). There is evidence that extramedullary tissue may be a more common primary site of myeloma cell development than the intramedullary compartment in the cat.1, 64

There have been pathological reports of cutaneous masses in feline MRD,14, 39, 41 but relatively few with accompanying comprehensive clinical investigations that allow a diagnosis of cutaneous extramedullary plasmacytoma (CEMP—see Table 55-2). Some feline CEMPs have been apparently solitary masses, not associated with systemic signs or hyperglobulinemia and where surgical excision resulted in prolonged survival.¹ This is similar to the biologic behavior typically shown in other species, where CEMPs are usually nonsecretory, have a benign course, and surgical excision is curative.79, 140 Rarely, CEMPs show a malignant course with progression to myeloma in either humans or the dog.79, 141 By contrast, a number of feline MRD reports exist where cats with cutaneous plasma cell neoplasms exhibited systemic signs, had a demonstrable monoclonal protein, were affected by multi-organ plasma cell infiltration, and experienced rapid tumor development.1, 15, 19, 27, 49

Noncutaneous extramedullary plasmacytoma (NCEMP) appears to be common in the cat, comprising 50% of those MRD cases that had both bone marrow and abdominal organ sampling carried out in one series.¹ Occasional feline NCEMP reports have described isolated tumors showing localized signs, without evidence for systemic involvement or hyperglobulinemia (e.g., within the uveal tract or sinonasal cavities).35, 45, 53 However, the majority of feline NCEMP feline cases have had signs of systemic illness, an accompanying monoclonal protein, and later metastatic or multisite development.1, 27, 42, 48, 56, 61 Typically, the liver and/or spleen were infiltrated. Other locations have included the kidneys, gastrointestinal tract, lymph nodes, stomach, epidura, orbit, and retroperitoneal space. In the largest clinical series of confirmed feline MRD, the hypothesis that cats with MRD commonly present with extramedullary involvement in contrast to human patients with MRD was demonstrated (67% versus 5% respectively, p < 0.001).¹

Nonsecretory Myeloma

A single cat with a pathological diagnosis of uveal and mandibular lymph node plasma cell neoplasia along with immunohistochemically confirmed cellular cytoplasmic IgG expression, did not have a monoclonal gammopathy as assessed by serum protein electrophoresis alone, but further serum or urine studies for a monoclonal protein were not carried out.⁴⁵ More stringent diagnostic criteria are necessary for a tentative diagnosis of nonsecretory myeloma (see Table 55-2). Less than 3% of human patients diagnosed with a MRD are described as having nonsecretory myeloma.¹⁴² Immunohistochemical studies demonstrate the presence of cytoplasmic monoclonal proteins within the plasma cells of most of these patients, (e.g., Ig synthesis is intact).¹⁴³ In humans, true nonsecretory myeloma patients have no detectable monoclonal protein in serum or urine by any of the aforementioned methods (including SFLC).103, 144

Solitary Plasmacytoma of Bone

Solitary plasmacytoma of bone (SPB) patients present with a single lesion of monoclonal plasma cells in bone but with no evidence of myeloma cells elsewhere. Typically, these patients present with localized signs (e.g., bone pain in association with the lesion), although some patients will have a painless bony deformity, neurological signs in association with compression, or lesion(s) discovered as an incidental finding during radiographic surveys for other purposes. Solitary plasmacytoma of bone is a rare MRD. Clinical evolution from SPB to MM is recognized, although a key feature of SBP patients is the slow natural time course of disease progression. As diagnostic testing methodology has advanced, the diagnostic criteria for SPB have changed. For example, many more SPB patients have been discovered with monoclonal proteins with the advent of more sensitive techniques for assessment. Patients thought to be affected with SPB have instead been reclassified as MM through magnetic resonance imaging (MRI) discovery of additional bone lesions not apparent on standard skeletal radiographic survey.¹⁴⁵ Current diagnostic criteria for SBP are given in Table 55-2. Two feline cases of SBP have been reported.⁴⁴ Both cats presented with single spinal lesions causing neurological signs. Both were treated, and prolonged remissions for several years were achieved with radiotherapy in one case and chemotherapy in the other.

Immunoglobulin M Macroglobulinemia

In humans, Waldenström macroglobulinemia is the most common subset of the comparatively rare IgM macroglobulinemias. It has rarely been reported in cats.40, 60 A feline case providing greater investigational detail including postmortem findings, was found to have IgM-secreting lympho-plasmacytoid cells in the liver only and no evidence of bone marrow infiltration.⁵⁹

Immunoglobulin-Secreting Lymphoma

Some patients present with either risk factors for the development of, or actual clinical signs of MRD dysfunction (e.g., gammopathy or amyloidosis), but they lack typical plasma cell or plasmacytoid cell characteristics (as assessed by routine cytopathology, histopathology, immunocyto- or immunohistochemistry, flow cytometry, etc.) instead being classified as lymphoma.

Several feline cases have been described in the literature as having Ig-secreting lymphoma (but with limited pathological descriptions ranging from lymphoid cells to lymphoplasmacytic cells).19, 33, 34, 40, 50, 146

Plasma Cell Leukemia

Plasma cell leukemia (PCL) is a rare and aggressive MRD characterized by the presence of circulating plasma cells (see Table 55-2). Note that nonneoplastic conditions, such as severe sepsis, can occasionally result in transient elevations of circulating plasma cells.¹⁴⁷ Therefore, demonstration of monoclonality is required as per other MRDs (e.g., by flow cytometry, immunocytochemistry, cell block preparations for immunohistochemistry, or molecular techniques). It is classified as either primary PCL when it presents “de novo” in patients with no previous history of MRD or as secondary when it is observed as a leukemic transformation of a pre-existing progressive MRD. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings.¹⁴⁷ Plasma cell leukemia has been reported in three cats, of which two case reports provide good clinical description of secondary PCL.49, 55

A Suggested Reclassification of Plasma Cell Disorder

From the earlier sections, it can be seen that the PCDs form a complex set of disorders. Indeed in humans, there are additional disorders involving plasma cell pathology and gammopathies that have yet to be described in the feline literature. In the past two decades, there has been a move to classify human patients into a new category: “Symptomatic Multiple Myeloma.” This new diagnosis accommodates patients with either intramedullary or extramedullary disease, or both (see Table 55-2). Symptomatic multiple myeloma also accords significance to whether patients are displaying signs of myeloma-related end organ damage. There may be value in recategorizing MRDs in veterinary medicine, employing a system that potentially facilitates greater consistency in diagnostic investigation and classification. The proposed system retains a central role for pathological diagnosis, but with an altered, more patient-centric focus explicitly incorporating a broader range of myeloma-related clinical problems. A system that incorporates other lymphoproliferative disorders into MRD when they have protein-related functional disorders (e.g., lymphoma patients producing a monoclonal protein, or patients with IA or MIDD). Ultimately, this system is a combined diagnosis and risk stratification system. This last point in particular is of assistance when there are indistinct boundaries between traditional MRD diagnostic categories which may be observed in patients of any species. Patients may be asymptomatic with low cellular proliferation (benign monoclonal gammopathy at time of death), clinically affected with low cellular proliferation (immunoglobulin amyloidosis), or clinically affected with high cellular proliferation (multiple myeloma). Furthermore, clonal plasma cells can show widely varying biological behavior within the same patient over the course of a lifetime.

In the proposed new system, a plasma cell disorder may be subcategorized as a myeloma-related disorder typically by combining (i) cytopathology or histopathology with (ii) a demonstration of clonality in the tissue of interest and (iii) evidence of clinical problems attributable to the MRD. Therefore, the distinguishing feature of a MRD is a judgment regarding the transition to neoplastic behavior (Table 55-3 ) that results in accompanying local or systemic clinically relevant problems. A tentative diagnosis of “suspected MRD” can be achieved in the absence of cellular evidence of plasma cell infiltration or IA through confident demonstration of a serum and/or urine monoclonal protein (preferably by immunofixation) and with no alternate diagnosis for the monoclonal protein evident. Suspected MRD is a preneoplastic categorization in a proportion of patients. Examples include MGUS and smoldering myeloma. In the event of patient death due to unrelated causes, these conditions may never have progressed to displaying neoplastic behavior (in terms of evident pathological damage or clinical relevant problems attributable to a MRD). Nevertheless they are clonal disorders, and the rationale for the ongoing monitoring of these patients is contingent upon the known risk of the development of overt neoplasia.

Table 55-3.

Mellor's Classification Scheme for Myeloma-Related Disorders

Area	Pathology	Protein—Serum/Urine Monoclonal	Problems—MRD Attributable	Mellor's Classification Based on Location and Rate of Progression Risk	Traditional Example(s)
Single site	Amyloid positive and predominant pathology, typically with minimal plasma cell content	Usually negative, but low positive possible	None	Solitary MRD—slow rate of progression risk	Primary cutaneous immunoglobulin amyloidosis
Single site	Plasma cells (WD or Int) and/or amyloid positive (local single site only); no MIDD	Negative, low positive or positive	None	Solitary MRD—moderate rate of progression risk	CEMP or NCEMP or IgM macroglobulinaemia or SBP or amyloidoma
Single site	Plasma cells (WD or Int) and/or amyloid positive (local single site only); no MIDD	As above	Yes (but no vital organ failure)	Solitary MRD—high rate of progression risk	As above
Single site	As above but plasma cells PD or WD or Int grade if accompanied by vital organ failure (see signs)	As above	Yes (up to and including vital organ failure)	Solitary MRD—very high rate of progression risk	As above
No clearly defined lesion	Marrow negative; no soft tissue lesion. No amyloid; no MIDD	Low positive or positive	None	Multifocal suspected MRD—slow rate of progression risk	MGUS
Lesion(s) may/may not be clearly defined	Marrow negative; or marrow positive, but no other organs, or soft tissue infiltration is uncertain (e.g., liver with sinusoidal plasma cells); no amyloid; no MIDD	Positive with recent evidence for accelerating levels	None	Multifocal suspected MRD—moderate rate of progression risk	Smoldering myeloma
Two or more lesions	Plasma cells (WD or Int) at ≥2 marrow sites, ≥2 soft tissue sites, or marrow plus soft tissue site(s) and/or amyloid positive (internal organ(s)) and/or MIDD-positive	Usually positive (but can be negative in nonsecretory myeloma, amyloidosis and MIDD cases)	Yes (but no vital organ failure)	Multifocal MRD—high rate of progression risk	MM, EMP, combined intra- & extramedullary myeloma, IgM macroglobulinaemia, systemic Ig amyloidosis, MIDD
Two or more lesions	As earlier but plasma cells PD, WD, or Int grade if accompanied by vital organ failure (see signs)	As above	Yes (up to and including vital organ failure)	Multifocal MRD—very high rate of progression risk	As above
Blood	Blood positive for plasma cells or other Ig secreting leukemic cells (≥5%)	Usually positive	Yes (up to and including vital organ failure)	Multifocal MRD—very high rate of progression risk	Plasma cell leukaemia and Ig secreting leukaemias (primary or secondary)
Two or more lesions	Amyloid positive and predominant pathology, typically with minimal plasma cell content; bone marrow usually negative, but can be positive (any grade)	Usually positive	Yes—including vital organ failure	Multifocal MRD—very high rate of progression risk	Systemic Ig amyloidosis
Two or more lesions	Monoclonal Ig deposition—usually both kidneys—but with minimal intralesional plasma cell content; other organs can be affected by Ig deposition; plasma cell infiltration of bone marrow and/or soft tissues can be positive or negative (and any grade)	Usually positive	Yes—including vital organ failure	Multifocal MRD—very high rate of progression risk	MIDD

This is a novel combined diagnostic and staging scheme based around “APPP” (Area, Pathology, Protein, Problems), allowing patients to be broadly stratified according to their “rate of progression risk”. This new system is designed to facilitate greater consistency in diagnostic investigation, clarify classification, and assist in therapeutic decision making.

Notes:

In the pathology column; WD = well-differentiated grade, Int = intermediate grade, PD = poorly differentiated grade tumours. Marrow negative implies <10% plasma cells in bone marrow, where (a) marrow has been successfully sampled at preferably two separate anatomic sites and (b) preferably at least one aspirate and one trephine biopsies have been obtained. Marrow positive implies ≥10% plasma cells in bone marrow obtained by any sampling technique. Amyloid must be demonstrated to be of immunoglobulin origin. MIDD—deposits must be shown not to be amyloid.

In the protein column: “Usually negative” or “usually positive” refers to the absence or presence of a monoclonal spike by standard protein electrophoresis of serum or urine. “Low positive” refers to the presence of a small monoclonal spike as detected by either examination of the original densitometer trace in standard protein electrophoresis or other more sensitive assessment techniques (see text for details), when the total serum globulin level is only slightly elevated or within normal limits.

In the problems column: refer to text for the description of key MRD attributable problems arising from organ damage or tissue impairment (systemic, multi-focal or local). Vital organ failure (e.g., of the kidneys or liver) may have a chronic or acute-on-chronic presentation. Vital organ failure does not always include simple visceral organ capsular compromise leading to capsular rupture and hemorrhage (e.g., an infiltrated spleen).

CEMP, cutaneous extramedullary plasmacytoma; EMP, extramedullary plasmacytoma; Ig, immunoglobulin; MGUS, monoclonal gammopathy of undetermined significance; MIDD, monoclonal immunoglobulin deposition diseases; MM, multiple myeloma; MRD, myeloma-related disorders; NCEMP, noncutaneous extramedullary plasmacytoma; SBP, solitary plasmacytoma of bone.

In summary, the proposed new system categorizes patients according to whether the disease is apparently solitary or multifocal, examines pathological grade, and describes disease effects of monoclonal protein production and/or deposition, as well as any key clinically relevant problems seen in the patient. This assessment may be summarized to the mnemonic; “APPP” (Area, Pathology, Protein, Problems). From this, patients can be stratified according to their “rate of progression risk”:

Area (or anatomic location) defines the location(s) of affected areas. Either:

• (a)multifocal lesions (a single osteolytic lesion plus a separate bone marrow site [not associated with clinical or imaging evidence of a lesion] showing greater than 10% plasma cell content, ideally in both sites), two or more osteolytic lesions with proof of plasma cell infiltration in at least one lesion, combined intramedullary and extramedullary biopsy confirmed lesions, or two or more biopsy confirmed extramedullary lesions,
• (b)apparently solitary lesion (with qualification as to the imaging and/or other investigational techniques used to assess the absence of lesions), or
• (c)no definite lesion (e.g., no imaging evidence for lesions and marrow with less than 10% plasma cell content with qualification as to the technique used such as two-site aspiration and trephine).

Pathology assesses cellular pathology and where appropriate, assigns a pathological grade: (a) well differentiated, (b) intermediate, or (c) poorly differentiated (plasmablastic). It may be that a biopsied lesion has low plasma cell content (e.g., in some localized amyloid lesions or MGUS) or very minimal plasma cell content (systemic amyloidosis).

Protein production or deposition include: (a) monoclonal protein (serum or urine) and Ig type, (b) IA, (c) MIDD, or (d) monoclonal protein not detected (with qualification as to the technique used to assess for monoclonal protein).

Key MRD attributable problems arise from related organ damage or tissue impairment. These may comprise the following:

• (a)Key systemic or multifocal problems. While other pathogenetic mechanisms of disease may be present, the systemic problems should be principally attributable to myeloma or IA and include, but are not limited to: renal failure, HVS, coagulopathy, anemia, and hypercalcemia. Multifocal organ problems include multiple osteolytic lesions or multifocal soft tissue organ disruption or impairment.
• (b)Key localized problems such as solitary osteolysis, solitary organ disruption, or focal compressive signs resulting in organ damage or impairment.
• (c)No key problems. The patient is either apparently asymptomatic or has limited clinical signs (not including the key local or systemic MRD attributable problems earlier).

The final consideration is an overall “rate of progression risk” based on the earlier and natural behavior of the MRD allowing a tentative “global” categorization of the risk of progression of morbidity (see Table 55-3). In veterinary medicine this will be a crude stratification estimate, but the system should prove adaptable to additional diagnostic and stratification criteria over time (e.g., “APPPO”, where the inclusion of “O” for “other” allows consideration of independent prognostic features such as serum albumin, beta-2 microglobulin, cytogenetics, etc., as used in humans).¹⁴⁸ Case examples of the diagnostic approach are given in Table 55-4 . By stratifying patients in this way—according to the evolutionary stage of their disease—this new system should prove useful in aiding clinical decision making with respect to therapy (see Table 55-3).

Table 55-4.

Case Examples of the Working Diagnostic Approach to Patients with MRD as Categorized by APPP Methodology and Mellor's Classification

Example 1
	Area	Pathology	Protein—Serum/Urine Monoclonal	Problems—MRD Attributable
Notes:	Single skin lesion	Cutaneous plasma cell lesion—well-differentiated grade; contains intralesional amyloid	Low positive	None
Qualifications	Complete skeletal survey radiography negative, abdominal sonography negative	Immunohistochemistry confirms clonality (IgG, lambda) Amyloid Ig confirmed by LMD/MS Bone marrow negative on two-site assessment using both trephine and aspirate; liver Tru-Cut biopsy negative for amyloid	SPE only UPE negative	No relevant clinical signs; no key hematologic or serum biochemical problems
Classification (Mellor's and Traditional)		Apparently solitary MRD—moderate rate of progression risk, (CEMP with intralesional amyloid)
Example 2
	Area	Pathology	Protein—Serum/Urine Monoclonal	Problems—MRD Attributable
Notes:	1)Suspected splenomegaly 2)Osteolysis	1)Splenic aspirate cytology—plasma cell lesion—well-differentiated grade 2)Bone marrow sample—borderline (around 8%-10% plasma cell content)	Monoclonal protein	Yes
Qualifications	Clinical exam, sonography and radiography- suspected moderate splenomegaly. Complete skeletal survey radiography—single vertebral osteolytic lesion. MRI spine—multiple vertebral osteolytic lesions	Immunocytochemistry confirms splenic aspirate clonality Bone marrow Vertebral osteolytic lesions—suboptimal sample acquisition, borderline positive for plasma cell content; difficult locations—so not repeated Humerus (nonlesioned site)—aspirate & trephine. Borderline positive	SPE and UPE positive	Anemia. Probable spinal pain with multiple osteolytic lesions
Classification (Mellor's and Traditional)		Probable*multifocal MRD—high rate of progression risk, (probable combined intramedullary and extramedullary myeloma)

In the first example, the patient presents with a skin mass; in the second the patient presents with an abdominal mass and is subsequently discovered to have osteolysis at imaging.

APPP, Area, Pathology, Protein, Problems; CEMP, cutaneous extramedullary plasmacytoma; IgG, immunoglobulin G; LMD/MS, laser microdissection with mass spectrometry; MRD, myeloma-related disorders; MRI, magnetic resonance imaging; SPE, serum protein electrophoresis; UPE, urine protein electrophoresis.

^*Probable—on the basis that pathology was confirmed at a single site only, but there is a high risk of multisite involvement given the imaging lesions.

Treatment and Outcome

Treatment of polyclonal PCDs is not reported here. There is a paucity of systematic data regarding the treatment of feline MRDs. Treatment of suspected and confirmed MRD is dictated by the risk stratification suggested earlier.

Solitary Lesions

From the earlier sections concerning diagnostics, it should be clear that apparently solitary lesions should be examined skeptically and with a sound knowledge of the diversity of diagnostic presentations available in MRDs, and a planned, sensible sufficiency of investigative tests. In general, many solitary lesions can be controlled with local therapy (with exceptions—seen further in this section and in Table 55-3). However, all owners should be informed that in general, there remain levels of risk of progression of disease following local therapy for a solitary MRD lesion.

In cases where the rate of progression risk is slow (see Table 55-3), such as localized amyloidosis, excisional biopsy is indicated. This can result in long-term remission or cure.³⁵

In cases where the rate of progression risk is moderate (see Table 55-3), such as solitary EMP, surgical excision may be considered for the purposes of diagnostic confirmation and therapy where appropriate. Statistically significant survival benefit for selected cats receiving surgery has been demonstrated when compared to cats that received no therapy or glucocorticoids alone.1, 64 A variety of surgical therapies including cutaneous mass excision, splenectomy, and enucleation have been reported across the feline literature, and generally positive responses have been documented in appropriately selected cases. For example, in a typical clinical decision-making process, a solitary plasmacytoma of the spleen might be suspected on the basis of a discovered serum/urine monoclonal protein along with sonographic evidence for splenic structural changes, cytopathological indications of well differentiated plasma cells, and no radiographic evidence for bone lesions (based on a complete skeletal survey). Further testing could include additional splenic aspirates for immunocytochemistry or flow cytometry or polymerase chain reaction for antigen receptor rearrangements as well as further imaging (e.g., MRI or fluorodeoxyglucose positron emission tomography scans and concurrent bone marrow aspirate and trephine). If there are no further involved sites identified, then splenectomy would follow. This paradigm follows the current best evidence in human patients—that truly localized EMP at accessible sites should be completely surgically excised.⁷⁹ However, in areas of poor surgical access (e.g., the upper respiratory or digestive tract), radiotherapy alone is the treatment of choice.⁷⁹ Solitary visceral organs that are diffusely infiltrated and cannot be safely excised or irradiated (e.g., hepatic plasmacytoma with diffuse hepatic infiltration) may be treated with chemotherapy as per other myeloma cases (see Multifocal Lesions).

Solitary plasmacytoma of bone (confirmed) is classified as moderate for rate of progression risk. It may also be optimally treated by local megavoltage radiotherapy.⁴⁴

Solitary MRD in the high-risk progression category (e.g., EMP with a pathology grade of a poorly differentiated tumor—see Table 55-3), should be approached with caution with regard to local therapy alone. There should be suspicion of the possibility of undiagnosed lesions and/or more rapid transition to multifocal myeloma. Risks of local therapy should be considered with respect to the potential morbidity to the patient versus any potential therapeutic gain.

Multifocal Lesions

Monoclonal gammopathy of undetermined significance is an example of an assumed multifocal, suspected MRD with risk of slow progression, and where monitoring alone is appropriate. Extrapolating from current data in humans, smoldering myeloma should be monitored only, although further trials for early stage therapies are underway.¹⁴⁹ In multifocal disease where the rate of progression risk is high (see Table 55-3), systemic chemotherapy is appropriate. Where the rate of progression risk is classed as “very high” and the MRD is accompanied by organ failure, then chemotherapeutic options and dosages should be considered carefully.

In the feline literature, many individual reports describe the usage of a wide range of options from no therapy to the use of steroids alone, or more commonly, combination chemotherapy protocols including melphalan and prednisolone (the most commonly used combination); COP (cyclophosphamide, vincristine, prednisolone); or permutations that have included dexamethasone, chlorambucil, lomustine, and L-asparaginase. Across the literature, generally positive responses to chemotherapy have been documented. However, caution must be employed in the usage of melphalan in cats. A typical historical regime has been the administration of a 2 mg tablet every four days (equating to approximately 8 mg/m² for a 4 kg [9 lb] cat). However, myelosuppression may be cumulative, and in some individuals this has resulted in severe illness accompanied by marked neutropenia. Recompounding of chemotherapeutics is recommended to allow for accurate dosing. Both a qualitative description and a statistical assessment of the effect of treatment on survival have been published in only one series of feline MRD, which showed significant survival benefit in those cats receiving combination chemotherapy versus cats that received no therapy or glucocorticoids alone.1, 64 Novel therapies such as low dose dexamethasone alone, thalidomide and derivatives, and other newer generation antimyeloma drugs might be appropriate to try in appropriately selected cats with relapse, but there is no data at this time.

There is a lack of data on the treatment of confirmed cases of feline systemic IA. In humans, therapy directed against the plasma cell clone as per treatments employed for myeloma has resulted in improved outcomes for patients with systemic IA.¹⁵⁰

Adjunctive and Supportive Therapies

Myeloma-related disorder complications including hypercalcemia, renal failure, anemia, bone lysis, bone pain, pathological fractures or bone collapse, hyperviscosity syndrome, coagulopathy, thromboembolic disease, and infections may be managed with an array of adjunct therapies. There is a paucity of data in feline MRD. Reports have described the use of plasmapheresis to alleviate congestive heart failure resultant from HVS in three cats.¹³ The use of bisphosphonates to control hypercalcemia or bone-related signs has not been described in the cat, but could be appropriate in selected cases. Effective management of bleeding, embolic disease, and infections has not been described in detail in the cat, but awareness should facilitate treatment.

Monitoring

In the slow to moderate progression of suspected MRDs (MGUS and smoldering myeloma), owners should be appraised of the clinical signs of myeloma, extramedullary plasmacytoma, or amyloidosis that may develop over time. Laboratory testing of total globulin, and/or quantification of serum, and/or urine monoclonal protein should be considered at 3- to 6-month intervals, or more frequently if there is suspicion of more rapidly progressing disease. New bone lesions or visceral organomegaly can occasionally develop in the absence of a rising monoclonal protein, so in the event of appropriate clinical suspicion, further imaging may be conducted. Further assessments (e.g., serum biochemistry or hematopathology) are useful in the detection of impending organ failure or increasing peripheral blood plasma cell content with respect to the development of secondary leukemia.

In patients with a secretory MRD that are undergoing combination chemotherapy, some improvement in clinical signs can often be expected within days and usually by 2 to 4 weeks. In one study, of feline MRD patients responding to chemotherapy, half achieved normoglobulinemia within this time period.¹

Prognosis

The outlook with regard to the initial response to combination chemotherapy in feline MRD is good. In one study, 85% responded (reduced clinical signs and concomitant decreases in serum globulin levels).¹ A return to good quality of life can be expected in most of these patients.

The long-term prognosis is however invariably grave. Cats that received no treatment or glucocorticoids alone had a median survival time (MST) of less than 1.5 months. This was statistically worse than for cats receiving combination chemotherapy (MST 9.4 months). The subgroup of responders to chemotherapy (those that improved clinically and had reduced globulinemia) had a median survival of 12.4 months.