Gastrointestinal manifestations of extramedullary plasmacytoma: a narrative review and illustrative case reports

Abstract

Introduction

Solitary extramedullary plasmacytoma are rare, solid-mass tumours which appear immunophenotypically similar to multiple myeloma. The diagnosis and management of gastrointestinal plasmacytoma is complex and requires multidisciplinary input. This study presents a narrative review of intra-abdominal extramedullary plasmacytoma, illustrated with two case studies.

Methods

The PubMed database was searched without date restrictions for reports of intra-abdominal extramedullary plasmacytoma to synthesise a narrative review. Electronic records were reviewed at a high-volume, quaternary soft-tissue sarcoma centre to identify patients with histopathologically confirmed extramedullary plasmacytoma affecting the gastrointestinal tract.

Results

Gastrointestinal extramedullary plasmacytomas can present with mass effect or organ-specific dysfunction. Techniques for tissue diagnosis of extramedullary plasmacytoma vary dependent on location, with a formal diagnosis often being made from a resected specimen. Management can include surgery, radiotherapy, systemic chemotherapy or a combination. No high-quality evidence base exists to guide treatment. Two case studies of operated gastrointestinal extramedullary plasmacytoma are presented at different phases of disease progression, with a resultant impact on survival.

Conclusion

Intra-abdominal extramedullary plasmacytoma is a rare and heterogeneous condition that lacks consensus guidelines for diagnosis and management. Collaboration between international specialist centres will create better quality evidence for treatment of this cohort.

Introduction

Plasma-cell neoplasms are characterised by the dysregulated proliferation of mature B-cells, producing immunoglobulins by clonal expansion. These neoplasms can present as single (solitary plasmacytoma), or multiple (multiple myeloma) lesions. The vast majority of solitary plasmacytoma occur intraosseously. Single, solid-mass tumours occurring as solitary extramedullary plasmacytomas, outside the bone marrow, are a rare and heterogenous group.

Extramedullary plasmacytomas are most commonly found in the upper respiratory tract and nasopharynx, while only about 4% are of primary gastrointestinal origin.¹ The median age of presentation is 55 years, some 10 years earlier than multiple myeloma, with a male preponderance. They have a broad phenotype, causing differing degrees of mass effect and organ dysfunction, depending on their anatomical location. While appearing immunophenotypically similar to multiple myeloma, tissue diagnosis in vivo can be challenging in an intra-abdominal location and diagnosis and treatment planning requires multidisciplinary planning from surgeons, haematologists, oncologists, radiologists and pathologists. Here, we present a narrative review of the diagnosis and management of intra-abdominal extramedullary plasmacytoma, illustrated with two operated cases from a large, quaternary soft-tissue sarcoma centre in the UK.

Methods

The PubMed database was searched using the terms ‘extramedullary’ AND ‘plasmacytoma’, without date restrictions. Studies including patients with solitary or multiple intra-abdominal extramedullary plasmacytoma were included. A search of ‘related articles’ was also conducted to identify papers not captured by these search terms. Non-English language papers were excluded. The last search date was 28 February 2017. Data extraction was undertaken by two independent assessors. Details of disease, author, country, anatomical location, presentation, method of diagnosis investigation, treatment and outcomes were included in synthesis.

Electronic records were reviewed at a high-volume, quaternary soft-tissue sarcoma centre to identify eligible patients. Patients with suspected intra-abdominal extramedullary plasmacytoma were screened for inclusion, based on imaging reports and clinical letters (1997–2017). Patients with histopathologically confirmed extramedullary plasmacytoma were included as case studies.

Narrative review

Presentation

Intra-abdominal extramedullary plasmacytoma usually has an indolent life course and manifests by mass effect on surrounding viscera. This can present as abdominal pain,^2,3 intestinal obstruction^4,5 or hydronephrosis.⁶ Intraluminal disease can also present with symptoms mimicking other common gastrointestinal malignancies, such as microcytic anaemia, melaena,⁷ haematochezia,⁸ intussusception,⁹ localised perforation¹⁰ or tenesmus.¹¹ Table 1 details described presentations of intra-abdominal extramedullary plasmacytoma in the literature.

Table 1.

Published case reports of intra-abdominal extramedullary plasmacytoma.

Study	Country	Patient		Anatomical location	Presentation	Therapy
		Age (years)	Sex			Operative	Non-operative
Upper gastrointestinal tract
Park et al., 201427	South Korea	70	male	Stomach	Indigestion	Endoscopic submucosal resection	Thalidomide, dexamethasone
Zhao et al., 201428	China	79	male	Stomach	Epigastric pain	Total gastrectomy, subtotal pancreatectomy, splenectomy	None
Han et al., 201429	South Korea	62	male	Stomach	Periumbilical pain	Gastric bypass (palliative)	None
Fukuhara et al., 201630	Japan	36	male	Stomach	Dyspnoea, fatigue	Total gastrectomy, extended lymphadenectomy	Bortezomib, cyclophosphamide, dexamethasone
Ammar et al., 201025	USA	69	female	Duodenum	Fatigue, melaena	Percutaneous trans-hepatic biliary drainage	Extracorporeal radiotherapy
Ariyarathenam et al., 20139	UK	58	male	Ileum	Intussusception, small bowel obstruction	Segmental small bowel resection	None
Gabriel et al., 201410	USA	62	male	Ileum, caecum	Melaena	Endoscopic submucosal resection (failed), right hemicolectomy	None
Lower gastrointestinal tract
Gupta et al., 200731	India	42	male	Colon (multiple sites)	Subacute obstruction, diarrhoea, cachexia	Subtotal colectomy	Adjuvant chemotherapy
Doki et al., 200832	Japan	64	male	Ascending colon	Abdominal pain, mass	Right hemicolectomy	Salvage chemotherapy (recurrence)
Lee et al., 201333	South Korea	45	male	Descending colon	Lower abdominal pain, diarrhoea, weight loss	Laparoscopic extended left hemicolectomy	None
Zihni et al., 201334	Turkey	54	male	Descending colon	Abdominal pain, mass, cachexia	Left hemicolectomy, small bowel resection	None
Islam et al., 201035	USA	52	male	Sigmoid colon	Haematemesis	Sigmoid colectomy, proctectomy, partial cystectomy	Chemotherapy
Gohil et al., 201511	India	55	male	Rectum	Perianal pain, altered bowel habits	Abdominoperineal resection	Adjuvant radiotherapy
Hepatobiliary or pancreatic
Demirhan et al., 199736	Turkey	22	female	Liver	Abdominal pain, hepatomegaly	None	Chemotherapy
Roh et al., 201437	South Korea	58	female	Pancreas	Incidental finding (CT)	None	Radiotherapy, bortezomib, mephalan, prednisolone
Urological or gynaecological
Feldman et al., 201538	USA	84	female	Ovarian	Cachexia, change in bowel habit, mass	Bilateral salpingo-oophorectomy, radical para-aortic lymphadenectomy	None
Mondal et al., 20152	India	47	female	Ovarian	Lower abdominal pain	Hysterectomy, bilateral salpingo-oophorectomy	None
Rogers et al., 200439	USA	75	female	Adrenal	Incidental finding (CT)	Laparoscopic adrenalectomy	Adjuvant radiotherapy
Cao et al., 20153	China	34	female	Adrenal	Intermittent right flank pain	Laparoscopic adrenalectomy	Anti-retroviral therapy (concurrent HIV diagnosis)
Mei et al., 201740	China	14	female	Kidney	Abdominal pain, mass	Radical nephrectomy	None
Klein et al., 201041	Germany	82	female	Ureter	Haematuria	Radical nephroutetectomy	None

Disease progression

The majority of extramedullary plasmacytomas progress to multiple myeloma (upwards of 70% in population-based registries),¹² with a median time of progression of around 19 months, although a wide range is described (7–293 months). Progression to multiple myeloma may be dependent on specific chemokine receptor expression profiles of the malignant plasma cells, as well as dysfunctional cellular adhesion molecules.¹³ Predictors of progression to multiple myeloma include the Bartl’s histological grade, size and MIB1 proliferation index, with greater than 10% demonstrating significance.^14,15 Extramedullary plasmacytoma can therefore also present with symptoms of progression to multiple myeloma and disseminated disease, such as weight loss or cachexia, bony pain from intramedullary disease, renal failure, anaemia or neurological symptomology. The five-year local overall survival rates are generally favourable, reportedly between 78.4% and 87.4% for extramedullary plasmacytoma, although significantly lower survival rates have been reported in the cohort with intra-abdominal disease. In addition, local recurrence, relapse or progression to a plasma-cell myeloma can occur late (5–10 years post-resection), so continuing surveillance of patients with extramedullary plasmacytoma is often recommended.¹⁶

Investigation

Primary identification of an extramedullary plasmacytoma mass lesion can occur through any type of axial imaging or direct visualisation (e.g. laparoscopy, endoscopy). Plain computed tomography (CT) reveals a solitary, well-defined mass, typically associated with areas of variable splenic necrosis and cystic degeneration.¹⁷ Contrast-enhanced scans reveal enhancement in the cystic wall and any internal septa and solid portions. 18F-fluorodeoxyglucose positron emission tomography (PET) can be used to detect regions of disease activity, differentiate extramedullary plasmacytoma from multiple myeloma,¹⁸ as well as helping to monitor treatment response.

Methods for formal tissue diagnosis of extramedullary plasmacytoma depend on its anatomical location. Endoscopic ultrasound-fine needle aspiration has, for example, been performed for diagnosis of extramedullary plasmacytoma within the pancreas,¹⁹ liver²⁰ and gallbladder.²¹ Gastroscopic biopsy has been performed for gastric extramedullary plasmacytoma.¹⁶ Minimally invasive techniques for biopsy can be challenging within the abdomen, due to risk of visceral injury, so resectional surgery or open/laparoscopic biopsy are often required to formalise a tissue diagnosis. More experimental diagnostic tests for extramedullary plasmacytoma that have been profiled include circulating plasma cell load²² and narrow band imaging endoscopy.²³

Differential diagnosis of gastrointestinal extramedullary plasmacytoma includes adenocarcinoma, gastrointestinal stromal tumour, lymphoma (of various lineages) and multiple myeloma.²⁴ Histological diagnosis of extramedullary plasmacytoma requires the presence of clonal plasma cells. Immunohistochemical markers include CD38, CD138 and CD79a, and monoclonal cytoplasmic kappa or lambda light chain expression. Immunophenotypically, this very closely mirrors multiple myeloma,but can be differentiated by its extramedullary pattern of disease.

Treatment

There are no consensus guidelines for the management of intra-abdominal extramedullary plasmacytoma. Treatment planning can be based upon institutional or surgeon experience, with only small-volume case series available within the literature. Treatment strategies described for intra-abdominal extramedullary plasmacytoma are detailed in Table 1. These have included resectional surgery, radiotherapy, systemic chemotherapy or a combination of these. Discussion at a multidisciplinary meeting with input from surgeons, haematology, oncology, pathology and radiology is key to optimising patient outcomes. Systemic chemotherapy regimens often mimic those used in multiple myeloma, using agents such as thalidomide, bortezomib and high-dose steroid therapy. Varying radiotherapy regimens have been described; for example targeted radiotherapy, 40–50 Gy over a four-week period.²⁵

Evidence from a larger case series by Li et al. (n = 38) suggests a potential for improved five-year local progression-free survival with radiotherapy alone, rather than surgery and radiotherapy. However, this series grouped extramedullary plasmacytoma presenting at a range of anatomical sites (including head and neck, pulmonary and abdominal primaries) and failed to consider differences in tumour biology in different tissue types.²⁶

Case study 1

Patient 1 was a white woman who presented at 72 years of age with persistent change in bowel habit, iron deficiency anaemia and weight loss. She had a past medical history of non-alcoholic steatohepatitis and gastroesophageal reflux disease secondary to hiatus hernia. After outpatient review, she underwent urgent cross-sectional imaging, which revealed a solitary tumour affecting the terminal ileum and caecum (Fig 1). She underwent expedited laparoscopic right hemicolectomy to excise the primary focus. Histopathology confirmed the diagnosis of extramedullary plasmacytoma (Fig 2). A blood film, bone marrow biopsy and skeletal survey did not reveal any evidence of multiple myeloma.

Figure 1.

Axial computed tomography of a solitary extramedullary plasmacytoma effecting the terminal ileum and caecum (case study 1)

Figure 2.

Immunohistochemistry slide of an extramedullary plasmacytoma (case study 1)

In her fifth postoperative year, she was detected to have an enlarged right axillary lymph node during surveillance by clinical oncology. Her systemic examination was unremarkable, with no signs of hepatosplenomegaly or other enlarged lymph nodes. Unfortunately, a biopsy of the axillary lymph node showed features of anaplastic plasmacytoma. Blood and bone marrow profiles were repeated, which did not detect progression to multiple myeloma. There was very little infiltrative marrow disease and her paraprotein level was undetectable.

She was started on systemic thalidomide and prednisolone therapy but, despite this, her disease progressed. She was palliated for treatment-refractory multiple plasmacytoma and died in her sixth postoperative year.

Case study 2

Patient 2 was an East Asian man who presented 69 years with cachexia, abdominal pain and an abdominal mass. Initial oral and intravenous dual-phase CT revealed a large small-bowel mass with a concurrent mass lesion within his adjacent psoas muscle. A whole-body PET-CT revealed psoas infiltration associated with a large mesenteric mass and small bowel uptake. He underwent small-bowel resection with excision of a mesenteric pedicle (Fig 3). Histopathology confirmed a diagnosis of extramedullary plasmacytoma with multiple foci. Unfortunately, R0 resection was not possible and this patient died of progressive physiological decline as his disease progressed, within the first 60 days postoperatively.

Figure 3.

Positron emission tomography–computed tomography findings, with increased uptake into a small bowel/mesenteric focus of extramedullary plasmacytoma, in both coronal and axial planes (case study 2)

Conclusion

Intra-abdominal extramedullary plasmacytoma is a rare and heterogeneous condition that typically presents with a mass lesion or features of organ-specific dysfunction. Definitive tissue diagnosis is often made after surgical resection or excision biopsy. While some treatment strategies employed in multiple myeloma may be harnessed in extramedullary plasmacytoma, a tailored approach to its management based on size, organ system effected and disease stage may be favourable. Collaboration between international specialist centres should be harnessed to create registries and to produce better quality evidence for treatment paradigms in this cohort.