Signature of Castleman disease in gastrointestinal mucosal biopsies and resected specimen: report of four cases and literature review

To the Editor,

Castleman disease (CD), also known as giant lymph node hyperplasia, is a rare non-clonal lymphoproliferative disorder that includes both solitary/unicentric (UCD) and multisystemic/multicentric (MCD) subtypes; the latter incorporating idiopathic (iMCD), human herpes virus 8 (HHV8)-associated, and POEMS (polyneuropathy, endocrinopathy, organomegaly, monoclonal paraprotein, and skin changes) syndrome-associated variants. In 2010, a Japanese group further stratified HHV8-negative MCD into iMCDnos (not otherwise specified) and TAFRO syndrome [thrombocytopenia (T), anasarca (A), myelofibrosis/fever (F), renal dysfunction/reticulin fibrosis (R) and organomegaly (O)]. While UCD presents as a mass-like lesion at organ-specific anatomical sites (both nodal and extranodal), clinical presentation of MCD variant may range from: significant B symptoms, mimicking a lymphoproliferative malignancy, to inflammatory serositis, body cavity effusion secondary to vascular leak syndrome; organomegaly, hypergammaglobulinemia, organ dysfunction; or as a part of POEMS syndrome. The pathophysiology of MCD is complex and poorly understood, and this is postulated to be IL-6 mediated where HHV8 might play a pathogenic role.

Extranodal manifestations of CD are not uncommon with sporadic reports describing dominant cutaneous, leptomeningeal, gastrointestinal (GI), and retroperitoneal involvement, which may pose great diagnostic challenges to the surgical pathologist. Dominant GI manifestations in CD that require evaluation by endoscopic and/or colonoscopic mucosal biopsy are rarely reported in the literature. We aimed to describe the clinical, endoscopic/colonoscopic, and mucosal biopsy findings of four cases of extranodal CD that presented with dominant GI manifestations with a brief review of published reports in the literature. To the best of our knowledge, this is the first report to describe GI mucosal biopsy findings in a series of cases of CD with lymph node biopsy correlation wherever available.

The clinical presentation, endoscopy and/or colonoscopic findings, and mucosal biopsy histomorphological changes in the four cases are presented in Table 1. These cases occurred in adult males aged 29–62 years with prominent B symptoms in the form of fever and weight loss occurring in three (Cases 1, 3, 4) and persistent diarrhoea mimicking malabsorption syndrome in two (Cases 1, 4). One had associated features suggestive of POEMS syndrome in the form of distal asymmetric polyneuropathy involving the lower extremities associated with cutaneous hyperpigmentation (Case 1). Case 2 underwent segmental ileal resection and anastomosis secondary to subacute intestinal obstruction and ileocecal (IC) valve involvement, clinically mimicking Crohn disease, tuberculosis, or malignancy. He also received a 6-month course of anti-tubercular therapy without any relief. Significant abdominal lymphadenopathy with B symptoms associated with diffuse abdominal pain mimicking lymphoma or tuberculosis dominated the clinical presentation in Case 3. Endoscopic and colonoscopic findings revealed variable features ranging from multifocal erythema, erosion, ulceration, nodularity, and reduced mucosal folds involving the first and second parts of the duodenum to the deformed IC valve.

Histomorphological abnormalities in Cases 1, 3, and 4 were confined mostly to the duodenum and terminal ileum, which were characterised by blunted villous architecture, presence of benign looking lymphoid follicles within the lamina propria, plasmacytosis, and focal atrophy of the mucosal glands. Few of these lymphoid follicles showed penetrating hyalinised blood vessels, hyalinised/atrophied GC with onion skinning of the mantle zone, twinning of the germinal centre (GC), reminiscent of regressingly transformed nodal GC, and presence of perifollicular radiating blood vessels (Fig. 1, Fig. 2). The resected ileal specimen from Case 2 showed surface ulceration and transmural involvement with the presence of numerous lymphoid follicles, giving the appearance of a ‘string of beads’, and a few showing penetrating and radial blood vessels (Fig. 3). Cervical and inguinal lymph node biopsies in Case 1, mesenteric lymph node biopsies in Case 2, and right inguinal lymph node biopsy in Case 3 revealed histomorphological features consistent with the diagnosis of hyaline-vascular type CD. Clinically palpable or radiologically evident deep lymphadenopathy was noted in Case 4. Haematological evaluation revealed normocytic to macrocytic anaemia, normal leukocyte count, and high normal platelet count in Cases 1, 2, and 3, but pancytopenia in Case 4. Bone marrow aspiration and trephine biopsies (performed in Cases 1, 3, and 4) showed maintained trilineage haematopoiesis and patchy gelatinous marrow transformation (GMT)-like changes secondary to significant weight loss, megaloblast-like erythroid nuclear changes, and mild plasmacytosis (8%, 10%, and 10%, respectively; clonal in Case 1 as part of POEMS syndrome). There was no evidence of lymphoid follicles in any of the bone marrow biopsy specimens. Serum interleukin 6 and HHV8 testing were not performed in any of the cases due to lack of facility at our centre.

Two cases (Cases 1 and 4) received bortezomib and dexamethasone-based therapy which resulted in dramatic improvement in their diarrhoea-related symptoms with gain of weight; one case (Case 3) was referred to a higher centre for further management and subsequently lost to follow-up, and the case with segmental resection is currently symptom free at 60 months of follow-up.

We describe the GI mucosal biopsy findings in four cases of multicentric CD with dominant GI manifestations, and with lymph node biopsy correlation in three of them. Two patients had associated features suggestive of POEMS syndrome. Histomorphological features of the mucosal biopsy were reminiscent of nodal CD. Transmural CD-like lymphoid follicles mimicking Crohn disease or tuberculosis, and presenting with intestinal obstruction requiring resection and anastomosis were noted in one case, which created a diagnostic dilemma.

A literature review (1989–2021) on GI involvement in CD (both luminal and abluminal) found 10 such cases.^{,  ,  ,  ,  ,  ,}  These occurred in four males and six females (age range: 13–69 years) involving the stomach (n=4), small intestine (n=3), rectum (n=2), and oesophagus (n=1) with diverse clinical manifestations. Significant B symptoms in the form of fever, weight loss, raised erythrocyte sedimentation rate (ESR), and hypergammaglobulinaemia were noted in three cases, repeated uncontrolled haematemesis due to gastric lesion dominated in one, systemic lupus-like anticoagulant was associated with one case of gastric CD in a 13-year-old female, one case had co-existent rectal involvement in MCD in association with gastric adenocarcinoma, thrombocytosis, paraproteinaemia, demyelinating peripheral neuropathy, Raynaud phenomenon and myocardial infarction as a complication of thrombocytosis in POEMS syndrome occurred in one case, whereas refractory fatal diarrhoea secondary to POEMS-associated amyloidosis occurred in one patient. Mucosal biopsy histomorphological features were not described in any of the cases other than that described by Moss and colleagues who reported jejunal lymphangiectasia on mucosal biopsy secondary to lymphatic obstruction by mesenteric and para-aortic lymphadenopathy in MCD. The remainder of cases presented with abdominal discomfort/pain with mechanical obstruction secondary to tumour-like lesions involving the wall of the gut as a part of unicentric (hyaline-vascular) CD, which was amenable to surgical resection and anastomosis with a favourable outcome.

Unicentric and multicentric CD are distinct entities that require different therapeutic approaches. Surgical resection is standard and curative in unicentric CD. The management of iMCD is challenging and depends on disease severity. Recent guidelines have suggested risk stratification by monitoring serum IL-6 levels. The preferred treatment for non-severe iMCD is anti-IL-6 monoclonal antibodies (mAb), such as siltuximab, whereas for some patients with limited symptoms, a short course of rituximab with or without adjuvant corticosteroids is an alternative. For patients with mild symptomatology, a limited course of rituximab is an option. Patients who do not respond to anti–IL-6 mAb therapy should be considered for rituximab-based therapy, steroids, and immunomodulatory/immunosuppressive agents (thalidomide, cyclosporine A, sirolimus, anakinra, or bortezomib). We do speculate from our experience that mucosal CD may respond well to bortezomib and dexamethasone-based regimen which needs to be reaffirmed by future case studies.

Rare dominant GI manifestations in CD may pose diagnostic challenges, and this may require thorough correlation with clinicohaematological, biochemical, and radiological features to determine the correct diagnosis for appropriate management. Considering the inclusion of CD under the category of ‘tumour-like lesions with B-cell predominance’ in the upcoming World Health Organization (WHO)-HAEM5, awareness of varied presentations of this entity is required among pathologists and clinicians.