Woody Hard Swelling Over Submandibular Region with Multicentric Lymphadenopathy

Dear Editor, Multicentric Castleman’s disease (MCD) is a rare and often misdiagnosed disorder which requires a keen dermatological acumen to recognise the varied skin manifestations, ranging from papules to nodules, which can mimic other dermatoses. A 37-year-old female presented with a painful, erythematous to brownish swelling on the right submandibular region for the past 10 months. The swelling was insidious in onset, progressively enlarging in size, and was woody-hard at the time of presentation. This was also accompanied by difficulty in chewing food; however, there was a lack of dysphagia, dyspnoea, or hoarseness of voice. There was a history of malaise, loss of appetite, and undocumented weight loss described as loosening of clothes by the patient. She also complained of multiple episodes of fever, with a daily peak of 101°F–103°F for the past 2 months, not associated with chills and rigors. On cutaneous examination, there was a solitary, non-tender, well to ill-defined, 8 cm × 4 cm woody- hard swelling on the right submandibular area, fixed to the overlying skin [Figure 1]. There was also the presence of multiple enlarged, non-tender, mobile lymph nodes in the right posterior cervical, left anterior cervical, left axillary, and inguinal groups, the largest measuring 3 cm × 2 cm.Figure 1: Index case showing solitary, non-tender, well to ill-defined, 8 × 4 cm woody hard swelling on the right submandibular area, fixed to the overlying skinRoutine investigations revealed severe anemia (hemoglobin- 6.4 gm/dL), polyclonal hypergammaglobulinemia (raised IgG/A/M), raised IgG4 levels (3463 mg/L), raised C-reactive protein (CRP) (118.24 mg/dL), and raised erythrocyte sedimentation rate (55 mm/h). A thorough screening was done to rule out all infections, including negative serologies for hepatitis B, hepatitis C, HIV, negative staining for acid-fast bacilli, Fite stain, Giemsa and PAS stain on skin biopsy sample; rK39 antigen was also negative. rK39 antigen testing was done to rule out visceral leishmaniasis in our patient, given the history of having unexplained fever, severe anaemia, hepatosplenomegaly in the past, and generalised lymphadenopathy. Culture for fungal and mycobacterial profile from tissue biopsy was negative. Ultrasonography of the abdomen revealed bilateral hydronephrosis with dilation of renal calyces due to pelviureteric junction obstruction. Histopathological examination of the skin revealed diffuse pan-dermal dense inflammation rich in plasma cells. Nodular lymphoid aggregates admixed with histiocytes were seen. CD3 and CD20 highlighted reactive T and B cells, CD163 and CD68 highlighted reactive histiocytes, and CD1a and S100 were negative. IgG4 stain showed an increase in IgG4-positive plasma cells. There was no evidence of storiform fibrosis or obliterative venulitis [Figure 2].Figure 2: (a) Histopathological examination of the skin revealed diffuse pan-dermal dense inflammation rich in plasma cells (H and E, ×4); (b) Nodular lymphoid aggregates admixed with histiocytes were seen (H and E, ×200). (c) IHC showing reactivity to CD163 and (d) CD68 highlighting reactive histiocytes, CD1a and S100 were negative. IgG4 stain showed an increase in IgG4-positive plasma cells. There was no evidence of storiform fibrosis or obliterative venulitisOverall, features were suggestive of Castleman’s disease (plasma cell variant). Contrast-enhanced magnetic resonance imaging of paranasal sinuses with brain screening showed mucosal thickening and enhancement involving the walls of the left maxillary sinus. There was the presence of subcutaneous tissue thickening and heterogeneous enhancement in the right submandibular region. Contrast-enhanced computed tomography (CT) chest showed multiple sub-centimetric enlarged lymph nodes in pre-carinal, subcarinal, paratracheal, and para-aortic regions, the largest measuring ~10.2 mm. Multifocal nodular areas of consolidation were seen in the lungs with surrounding ill-defined nodules. Positron emission tomography (PET)-CT confirmed the above findings. PET-guided fine needle aspiration smears from the left upper lobe of the lung were moderately cellular and showed polymorphs, macrophages, respiratory epithelial cells, lymphocytes, and occasional plasma cells. Following investigations, the patient’s condition was optimized and she was started on oral prednisolone (1mg/kg), after which she significantly improved in one month. Urology consultation for hydronephrosis was sought, and double-J stenting was performed. Our patient is under regular follow-up while still being in remission. MCD is a rare and complex lymphoproliferative disorder, characterised by lymph node enlargement throughout the body. Given the high incidence of lymphadenopathy, IgG4+ plasma cell-enriched tissue infiltrates, and higher serum IgG4 levels observed in both disorders, as was also seen in our patient; MCD and IgG4-related disease (IgG4-RD) exhibit significant overlap.[1,2] IgG4-RD usually affects middle-aged to elderly males, and its histological findings are distinct, which include storiform fibrosis and obliterative venulitis, neither of which was seen in our patient. It seldom shows the hyper-interleukin-6 systemic inflammatory symptoms of MCD, like fever and high CRP. Inflammatory mass lesions caused by the histiocytic illnesses such as Erdheim-Chester disease and Rosai-Dorfman-Destombes disease might resemble IgG4-RD or MCD. In the context of Erdheim-Chester disease, patients typically have retroperitoneal fibrosis, which may raise the suspicion of MCD or IgG4-RD; however, more than 95% of patients have skeletal involvement. The histology of Erdheim-Chester disease reveals an invasion of CD68+ S100- CD1a- histiocytes, frequently accompanied by foamy histiocytes, which was absent in the present case. Histopathological evaluation of Rosai-Dorfman-Destombes disease can, however, show infiltrates of IgG4+ plasma cells. Skin involvement in MCD can be categorised based on pathomechanisms: cytokine-related (vasculitis-like lesion, cherry angioma, hyperpigmentation), immune complex-related (paraneoplastic pemphigus, xanthogranulomas), and non-specific (pruritus).[3] Rarer cutaneous manifestations include plane xanthomas[4] and localised plaques on the scalp.[5] Further molecular and immunological studies are warranted to unravel the intricate interplay of factors leading to dermatological involvement. Given the heterogeneous nature of MCD, collaboration with hematologists and oncologists is crucial for a comprehensive approach to diagnosis and management. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.