Rare Case of a Patient Presenting with Parathyroid Hormone-related Peptide Mediated Hypercalcemia and Igg Heavy Chain Disease: Case Report and Review of Literature

IgG Heavy Chain Disease (γHCD) is a rare plasma cell disorder. Hypercalcemia related to plasma cell dyscrasias is related to non-PTHrP related mechanisms. Here we describe the first case of a patient with γHCD and PTHrP related hypercalcemia. Methods: Patient case derived from chart review from 2011 to 2015. Literature review performed searching PubMed 1968-current. Results: The patient was diagnosed with hypercalcemia with elevated PTHrP and exclusion of other etiolo-gies of hypercalcemia. She was diagnosed with (γHCD) by M-spike 0.64 g/dL, IFE showing a broad band of IgG heavy chain, without associated light chains and severe depression of the non-mono-clonal IgG. Serum immunoglobulins demonstrated elevated IgG (2110 mg/dL), normal IgA (46 mg/dL) and decreased IgM (<21 mg/dL). Bone marrow biopsy showed 5% PCs, non-clonal by kap-pa/lambda, but exclusive for IgG by IHC, without any staining for IgA or IgM. The patient was started on therapy with improved hypercalcemia and PTHrP levels. Conclusions: This is the first reported case of γHCD presenting with PTHrP related hypercalcemia. Given that skeletal involvement is uncommon in γHCD, hypercalcemia secondary to γHCD may at times be a PTHrP driven phenomenon and we recommend that this test be ordered in such cases.


Background
IgG Heavy Chain Disease (γHCD) is a rare and often lymphoplasmacytic neoplasm that produces an abnormally truncated gamma heavy chain protein that lacks associated light chains [1].It is a heterogeneous entity that occurs within a wide spectrum of lymphoproliferative disorders.Consequently, γHCD displays a wide range of clinicopathologic characteristics.Here we describe a unique case of a patient diagnosed with Hodgkin's lymphoma and diagnosed several years later with γHCD who presents with PTHrP related hypercalcemia.

Methods
A retrospective chart review of one patient from 2011 to 2015 including detailed clinical history, laboratory data, imaging, pathology and treatment response was performed.PubMed, EMBASE and the Cochrane Library databases were searched for English language abstracts that included mesh terms "IgG Heavy Chain Disease" or "franklin disease" from 1968-current.79 abstracts were retrieved.38/79 abstracts were available for review of clinicopathologic information.

Results
This is a case of a 60-year-old woman diagnosed in 1992 with stage IIA Hodgkin's lymphoma, treated with total nodal radiation with recurrence in 1997 then treated with 6 cycles of ABVD achieving complete remission.On March 2011 the patient was then found to have hypercalcemia (11.0 mg/dL) and renal failure (1.29 mg/dL).Workup for the hypercalcemia revealed suppressed PTH (<3 pg/ml), elevated ionized calcium (6.1 mg/dL) elevated parathyroid related peptide (38 pg/ml), normal vitamin D and ACE levels.Complete blood count was normal.Serum protein electrophoresis (SPEP) showed M-spike of 0.9 g/dL.Immunofixation electrophoresis (IFE) demonstrated an IgG monoclonal immunoglobulin without a corresponding light chain (Figure 1).Free serum kappa and lamda light chains were within normal limits.Serum IgG was elevated (4678 mg/dL) with normal IgA (127 mg/dL), and low IgM (39 mg/dL).Beta-2 microglobulin was elevated (14.3 mg/L) also.The patient was seen by hematology for monoclonal gammopathy and hypercalcemia.Since the most common mechanism of hypercalcemia for multiple myeloma is bone turnover driven and not PTHrP related a solid tumor work up was done including CT chest/abdomen/pelvis, bone scan, bone survey, mammography, pelvis ultrasound which were all negative.Bone marrow biopsy was performed in November 2011 showing 10% plasma cells (PC) by CD138, non-clonal by kappa/lambda staining.Despite zolendonic acid therapy and IV fluids for hypercalcemia, her renal function and hypercalcemia continued to worsen for the next couple of months.A kidney biopsy was performed in April, 2012 and revealed acute and chronic tubulointerstitial nephritis with secondary glomerulosclerosis, mild interstitial fibrosis and tubular atrophy suggestive of sarcoidosis so the patient was placed on a course of prednisone with transient improvement in calcium and renal function but patient lost to follow up.
She presented in emergency room in April 2013 with altered mental status.She was found to have hypercalcemia (12.0 mg/dL), renal failure (1.55 mg/dL).SPEP revealed M-spike 0.64 g/dl.IFE displayed a broad band of IgG heavy chain, without associated light chains and severe depression of the non-monoclonal IgG.Serum immunoglobulins demonstrated similar results with elevated IgG (2110 mg/dL), normal IgA (46 mg/dL) and decreased IgM (<21 mg/dL).Bone marrow biopsy showed 5% PCs (Figure 2), CD 138 positive by IHC (Figure 3), non-clonal by kappa/lambda-but exclusive for IgG by IHC, without any staining for IgA or IgM (Figure 4).Cytogenetics were normal.Based on the constellation of findings and similarity to prior workup the patient was diagnosed with IgG heavy chain disease.She received 5 cycles of cytoxan, dexamethasone, bortezomib.PTHrP declined along with her IgG level and M-spike.Due to compliance issues, therapy was changed in multiple occasions receiving Revlimid, Carfilzomib, Bendmustine with different responses as showed in Table 1.    1 CyBORd: velcade-cytoxan-dexametasone.Discontinued due to noncompliance. 2 Revlimid discontinued due to patient noncompliance. 3 Received 6 months of Carfizomib and then discontinued on 12/2014 due to side effects. 4Bendamustine stopped per patient request on March 2015.Not further treatment.

Pathologic Characteristics
Pathologic diagnosis of γHCD represents a challenge for many reasons.First γHCD may be underdiagnosed and classified elsewhere since it arises in the setting of many lymphoproliferative disorders with specific WHO criteria.Also, γHCD is a rare entity with less than 200 reports in the literature and the majority of cases was diagnosed and classified using outdated classification schemes [1].Last, the WHO 2008 classification is conflicted as γHCD is classified as both a variant of LPL and as a distinct disorder [27].

Histopathology Findings
γHCD has no specific histological pattern [4] and there is a great diversity with lymphoplasmacytic proliferation being most common [4].However, γHCD has been described in association with a plasmacytic process (as in our patient), CLL [4].Furthermore γHCD has been reported to arise in the setting of non-Hodgkin lymphoma of various morphologic types, Hodgkin lymphoma, amyloidosis, myelodysplastic syndrome [4] [29] [30].

Clinical Outcomes
Given γHCD is a heterogeneous entity and its clinical course is expected to be quite variable as well.The clinical course can vary from an asymptomatic stable process to an aggressive rapidly progressive malignancy [4].In some cases γHCD protein is the only abnormality and no treatment is necessary [4].In fact, spontaneous disappearance of the γHCD protein has been documented in several instances [28] [36].For example, one patient with γHCD was observed and had stable disease after 134 months follow up [1].When an underlying malignancy exists, therapy should be directed at the underlying hematologic malignancy and pathologic findings.A wide variety of chemotherapies with or without rituximab have been used successfully including rituximab monotherapy with resolution of adenopathy at 22 month follow up [1], fludarabine and rituximab resulting in partial response (PR) with one cycle [35], second line fludarabine with complete remission (CR) [37], fludarabine, mitoxantrone, dexamethasone (FND) with PR [9], melphalan and prednisone resulting in PR [14], rituximab, etoposide, cyclophosphamide, prednisone, procarbazine resulting in PR [10], sustained CR 20 years with chlorambucil prednisone [9], cyclophosphamide, vincristine, prednisone with PR [9], bortezomib and prednisone with CR [1].
Even autologous stem cell transplant with high dose melphalan has been reported where the patient achieved stable disease after 26 months [38].In one series where 16/23 patients were treated (14 chemotherapy, 1 splenectomy, 1 thyroidectomy) 6 had CR, 10 had SD.Of the 7 untreated patients 4 had SD, 3 patients died of disease within 15 months.The median survival in this series was 7.4 years [9].

Conclusion
This case highlights the challenge of correctly recognizing and diagnosing γHCD which is due to its highly heterogeneous clinicopathologic presentation most common being a lymphoproliferative disorder, autoimmune disease or both.It represents a diagnostic challenge since it arises in the setting of many lymphoproliferative disorders, and the WHO 2008 classification is conflicted as γHCD is classified as both a variant of LPL and a distinct disorder [27].Another critical point related to this case is that kappa/lambda staining, the primary mechanism of determining plasma cell clonality, is not useful in exclusively heavy chain disease and can, in such cases, obscure the diagnosis of this malignancy.This is the first reported case of IgG heavy chain disease presenting with PTHrP related hypercalcemia further added to the diagnostic challenge because PTHrp related hypercalcemia is more common in solid tumors and uncommon in hematologic malignancies.Given that skeletal involvement is uncommon in γHCD, hypercalcemia secondary to γHCD may at times be a PTHrP driven phenomenon; we will recommend that this test be ordered in such cases.Because γHCD is a heterogeneous entity, the choice of therapy should target the underlying entity and pathologic findings.In our case, the etiology of the γHCD is a plasma cell clone and this is what we target with therapy, with good clinical effect.

Figure 1 .
Figure 1.SPEP demonstrating M-spike.The blue trace shows a normal SPEP pattern.

Figure 4 .
Figure 4. (a) 200×, few plasma cells positive for kappa light chain by immunohistochemistry.(b) 200×, few plasma cells positive for lambda light chain by immunohistochemistry. (c) 200×, majority of the plasma cells show positive staining for IgG by immunohistochemistry.(d) 200×, plasma cells are negative for IgM by immunohistochemistry.

Table 1 .
Treatments and responses.