Antonovych recognized the presence of monoclonal light chains associated with glomerular lesions in patients with myeloma [18]. Light chain deposition disease (LCDD) was first recognized as a specific entity in 1976 by Randall and associates [19], who reported two patients with renal failure and clinical manifestations involving multiple organ systems. In both cases, autopsies were performed and they showed that deposition of monoclonal light chains occurred in many organs, to highlight which the term systemic LCDD was coined. Light chain deposits were confirmed in the kidneys, liver, pancreas, heart, central and peripheral nervous system, skin, muscle, thyroid, and gastrointestinal tract. Extrarenal deposits appear to be less common in HCDD, but they have been reported in the heart [20], synovial tissues [20, 21], skin [22], striated muscles [22], thyroid [23], pancreas [23], and the liver [23].

In spite of the clear systemic nature of this disorder, most of the studies that followed focused on the recognition of this disease and understanding of its pathogenesis as a renal disorder. In the kidney, all three renal compartments have been demonstrated to be involved in most (but not all) cases. It has been shown that the glomerulopathic light chains associated with LCDD interact with a purported receptor on mesangial cells eliciting a cascade of pathological alterations anchored by the activation of transforming growth factor-β and resulting in increased matrix, rich in tenascin.

HCDD was first recognized in 1993 by Aucouturier et al. [23]. HCDD is a disease characterized by deletions in the heavy chains. A deletion in the constant domain of the γ gamma (IgG) heavy chain—CH1—predominates in these patients, but there are published cases with deletions in the hinge and CH2 domains of the heavy chains involved. In HC disease, the variable domain is also partially or completely deleted and this may be a factor in promoting tissue precipitation. Structural studies of HCDD have shown physicochemical abnormalities with unusual amino acid substitutions in the VH region which generally alter charge and hydrophobicity. The deletion in the heavy chains is likely to be necessary for abnormal light chains to be able to be secreted from the neoplastic plasma cells. Normal heavy chains must associate posttranslationally with heavy chain binding protein (BiP) in the endoplasmic reticulum [24], later assembling with heavy chains and eventually delivered to the Golgi complex where additional packaging and processing occur. When a mutant heavy chain lacks one of the key domains (especially CH1), it fails to properly associate with the BiP and may be prematurely secreted into the circulation.

The morphologic characteristics of HCDD are similar to those of LCDD. Light and electron microscopic features are identical. Research in HCDD has been rather limited and certainly the in vitro mesangial cell-oriented studies that have been conducted in LCDD to understand pathogenesis and progressive development of this disease have not taken place. However, it is assumed that HCDD shares rather similar pathogenetic pathways (as those shown to occur in LCDD).

This chapter focuses on the systemic manifestations of LCDD (with only a short but necessary incursion into kidneys) in an effort to increase exposure of this entity to surgical pathologists and, hopefully, maximize its detection.

In the advanced stage of LHCDD, a nodular glomerulopathy (Fig. 10.1a) that mimics the classical lesion that has been described in diabetic nephropathy—nodular glomerulosclerosis with so-called Kimmelstiel-Wilson nodules—is identified in the kidneys [25–28]. However, a number of other morphologic manifestations are seen prior to this more classically recognized pattern and may be the source of diagnostic confusion [27, 28]. Immunofluorescence and electron microscopy are of crucial value to identify these variants. The reader is referred to a number of excellent publications which describe this disease as a renal disorder in detail, emphasizing its pathogenesis, clinical presentation, treatment, and prognosis [2–7, 25–28]. The criteria for diagnosis in tissues other than in kidneys have emanated from the renal studies.

Isolated reports of the involvement of various organs have been published in the literature. However, these reports have generally been descriptive and have emphasized diagnostic criteria and suggested workup for appropriate diagnosis. The most complete reports are those emanating from autopsies with ample sampling to study the extent of multiorgan involvement [19]. It is very likely that systemic deposits in LHCDD are not detected or even misdiagnosed in surgical material. The question remains as to how aggressive clinicians are in documenting extrarenal disease in these patients and, therefore, this figure may not be at all accurate.

Liver and cardiac involvement is most common and has been documented to occur in approximately 25 % of patients with LCDD or LHCDD [29] but appears to occur less commonly in patients with HCDD.

Mild hepatic dysfunction is commonly noted. Liver deposits are often found in the hepatic sinusoids (Figs. 10.4a, b and 10.5a) and basement membranes of biliary ducts without associated parenchymal alterations [30]. In fact, liver deposits of monoclonal light chains are found in virtually every patient with LCDD whose liver is examined [31–33]. The material may be deposited in a similar fashion as amyloid. Amyloid seems to involve blood vessel walls with much greater frequency than LHCDD, and this can be used to favor one entity over the other. Nevertheless, It remains essential to rule OUT amyloidosis using the appropriate stains such as Congo red and Thioflavin T and/or ultrastructural criteria (Fig. 10.5a). Immunohistochemical stains can be used to demonstrate the presence of monoclonal light chains (Fig. 10.4b) in eosinophilic material filling sinusoids. Immunogold labeling at the ultrastructural level can confirm monoclonality (Fig. 10.5b, c). In a few instances, there may be destruction of the liver parenchyma creating an appearance reminiscent of peliosis hepatis [34].

Clinically, hepatomegaly is usually seen and alterations of liver function may be rather mild. Some patients present with altered liver enzymes and a liver biopsy is performed to diagnose the liver ailment. In a few cases, portal hypertension or hepatic failure has been reported.

Cardiac involvement in LHCDD is life-threatening and tends to occur commonly in the advanced stages of the disease process. The incidence of cardiac manifestation is difficult to be determined and varies from approximately 19–80 % depending on the series [3, 6]. Congestive heart failure is frequently seen in these patients resulting in severe cardiac failure in the advanced stages of the disease [35]. Cardiomegaly is a common finding in patients with cardiac involvement. Conduction disturbances with arrhythmias represent a common clinical presentation [36]. Varying degrees of restrictive cardiac failure may also be detected depending on the amount of light/heavy chain parenchymal deposition. Echocardiography and catheterization studies have demonstrated diastolic dysfunction and reduction in myocardial compliance similar to cases with cardiac amyloidosis. Deposition of light chains in cardiac vessels and perivascular areas is always identified in autopsies of patients with LHCDD [34], but can also be seen in biopsy specimens from patients with these conditions (Fig. 10.2a, b).

Peripheral neuropathy related to LHCDD has been documented in approximately 20 % of the reported cases. Light chain deposits may be in the endoneurium. In cases of LCDD, peripheral nerve involvement has been reported occasionally with patients presenting clinically with a polyneuropathy.

Deposits of light chains in the choroid plexus represent a common finding in these patients. A couple of case reports of LCDD restricted to the brain appeared in 2006 and 2007 by Fisher et al. and Popovic et al., respectively [37, 38]. The concept that has prevailed is that the blood–brain barrier protected the central nervous system from the circulating and sometimes misfolded monoclonal light chains, preventing both AL amyloidosis and pristine light chains from reaching and producing pathologic changes in the brain. Thus, it is not difficult to understand why the periventricular white matter is the most common site for the deposits of these monoclonal proteins, either in LCDD or amyloidosis.

Deposition of light chains in the lungs of patients with LCDD has been documented in case reports and small series [39–49]. The first case report was published in 1988 [39]. Less than 30 cases of LCDD involving the lungs have been reported. The major clinical manifestation is dyspnea on exertion. The clinical and immunopathologic findings have been summarized in one of the publications referenced [40].

While in most cases the lesions are in the pulmonary parenchyma itself, cases with endobronchial lesions have also been documented. Two different histologic patterns have been reported: diffuse and nodular, similar to what has been observed in AL amyloidosis with pulmonary involvement [41–47]. The diffuse form appears to have a more ominous prognosis than the nodular form. Approximately 50 % of patients with the nodular form will have an identifiable lymphoproliferative disorder at the time of diagnosis, and also evidence of renal involvement, generally in the form of renal failure. One case was associated with extensive cystic changes in the pulmonary parenchyma [43].

The light chain deposits are usually punctate and electron dense, but may also infrequently acquire a needle-shaped electron-dense crystalline appearance [40]. Interstitial fibrosis generally accompanies and surrounds the light chain deposits.

The differential diagnosis of light chain deposition in the lung includes several conditions. One of the most common manifestations of LCDD in the lung is the presence of amyloid-like nodules which fail to stain with Congo red and Thioflavin T, thus essentially ruling out amyloidosis. In cases with nodules, hyalinizing and infectious granulomata and old sarcoid nodules are conditions that should be considered as part of the differential diagnosis [40, 45].

It appears that pulmonary nodules similar to those seen in LCDD can be found in a small subset of patients as a manifestation of localized LCDD without systemic involvement [46–48]. Three patients with nodules mimicking amyloidosis were found without demonstrable systemic LCDD [45]. Three additional similar patients have been reported in the literature by Morinaga, Piard, and Stokes, respectively [47–49]. Interestingly, one of these patients showed a combination of amyloid and light chain deposits with both lambda and kappa light chain specificity, respectively [49]. However, such conclusion (the absence of a systemic process) can only be definitely confirmed after a careful and extensive diagnostic workup is performed and at least several years of follow-up, as local manifestations may precede overt generalized disease quite sometime. Nevertheless, there is no doubt that in some of these cases, localized monoclonal light chain production by a clone of plasma cells located at the site where the paraprotein deposits are present is responsible for the disease process (extramedullary plasmacytomas). The diffuse form must be distinguished from interstitial fibrosis and dense scars, as the light chains elicit much fibrosis and can be easily missed.

Diarrhea is often a complaint of patients with LCDD affecting the gastrointestinal (GI) tract. However, findings in the GI tract appear to be infrequent and only approximately 20 % of the cases reported address gastrointestinal symptoms (present or absent), while less than 10 % of the patients afflicted with these disorders manifest clinical and/or pathological gastrointestinal manifestations [6]. This data suggests that only approximately 10 % of patients with LCDD have symptomatic gastrointestinal light chain deposition [6]. The light chain deposits are typically found in the vasculature and surrounding areas [3] (Fig. 10.6).

Heavy chain disease can be an enteric disease and it is in the majority of the cases of alpha-heavy chain disease. The usual clinical presentation is diarrhea and abdominal pain, vomiting, weight loss, and evidence of malabsorption. Morphologic studies usually reveal an infiltrative plasmacytic or lymphoplasmacytic disorder localized to the GI tract, in some cases involving the lamina propria of the whole length of the small intestine and often associated with variable villous atrophy. However, there is no data documenting heavy chain deposits in the GI tract of patients with HCDD.