Dense Lymphoplasmacytic Infiltrate Research Articles

Primary gastrointestinal clear cell sarcoma: report of 2 cases, one case associated with IgG4-related sclerosing disease, and review of literature

Clear cell sarcoma (CCS) is a distinctive soft tissue sarcoma that shows melanocytic differentiation. Primary gastrointestinal (GI) CCSs have been rarely reported, but to our knowledge, no association between GI CCSs and immunoglobulin G4 (IgG4)-related sclerosing disease has been described in the literature. We experienced 2 cases of CCS that arose in the small intestine and metastasized to the liver. Histologic features and immunophenotype were typical of CCS. One of them showed a unique peritumoral sclerosing inflammatory reaction, which was highly reminiscent of IgG4-related sclerosing inflammatory disease. Dense lymphoplasmacytic infiltration with extensive sclerosis and obliterative phlebitis was observed in the immediate vicinity of the primary and metastatic tumors, but not in the distant areas from the tumor. The average number of IgG4-positive plasma cells was more than 50 per high-power field. We report 2 cases of primary GI CCS with one case showing a unique peritumoral IgG4-related lymphoplasmacytic sclerosing inflammation.

Lung Involvement in IgG4-related Lymphoplasmacytic Vasculitis and Interstitial Fibrosis

There have been a few reports on lung diseases associated with an increased number of infiltrating IgG4-positive plasma cells or lung involvement of IgG4-related sclerosing disease, although their characteristic histologic features have not been well described. Herein, we present 3 cases of interstitial lung disease with common histology and abundant IgG4-positive cell infiltration. Patient 1, a 65-year-old man, was incidentally noted to have a nodular lesion in the left hilar region. In patient 2, a 78-year-old man with dyspnea on effort, computed tomography revealed multifocal consolidation adjacent to the pleura in both lower lobes. Patient 3, a 74-year-old man, underwent lung biopsy for right-sided pleural effusion of unknown etiology. The histologic findings of the 3 individuals were characterized by expansion of the interstitium by dense lymphoplasmacytic infiltrate with prominent vascular involvement, which was indistinguishable from grade 1 lesion of lymphomatoid granulomatosis (LYG-G1). In situ hybridization for Epstein-Barr virus-encoded small RNA (EBER) revealed few or no EBER-positive lymphocytes. Vascular involvement showed subendothelial lymphoplasmacytic infiltrate, including numerous IgG4-positive plasma cells. The percentages of IgG4-positive to IgG-positive plasma cells were 85%, 47%, 46%, respectively. Similar vascular lesions have been described in previous reports of lung complications in IgG4-related sclerosing diseases. Some of these lesions were diagnosed as LYG-G1 without EBER-positive cells. In conclusion, LYG-G1-like lesion characterized by lymphoplasmacytic vasculitis might be a characteristic feature of IgG4-related lung disease.

The Pathology of Diverticulitis

Diverticulosis of the left colon is an acquired condition that is associated with aging. The diverticula arise at the points of penetration of the circular layer of the muscularis propria by the blood vessels supplying the submucosa and mucosa. They are outpouchings of mucosa invested by wisps of muscularis mucosae, which are believed to result from elevated intraluminal pressure in the left colon, associated with degenerative changes in the collagen and elastin content of the colonic wall. Pathologically, diverticulitis occurs when the mucosa of diverticula becomes inflamed. This may result from obstruction of the diverticulum, for example, by inspissated feces or a fecolith, leading to bacterial overgrowth, gas and toxin production, and mucosal injury. The flat mucosa of the colon between the orifices of the diverticula is also commonly inflamed, with changes of varying severity indistinguishable from those of ulcerative colitis or Crohn's disease. Such mucosal changes include a dense lymphoplasmacytic infiltrate, mucin depletion, cryptitis, crypt abscesses, architectural distortion, gland dropout, Paneth cell metaplasia, and ulceration. Complications of diverticulitis include bleeding (the diverticula are in intimate contact with the penetrating blood vessels which may become eroded), ulceration, abscess formation, penetration, perforation, fistulas, stricture formation, and pylephlebitis.

A 32‐year‐old woman with arthralgias and severe hypotension

A 32‐year‐old woman with arthralgias and severe hypotension

Granulomatous Pneumonia, Lymphadenopathy, and Hepatopathy in an Adult Horse with Repeated Injection of BCG

R. van den Boom, E.J.B. Veldhuis Kroeze, W.R. Klein, D.J. Houwers, A.G.M. van der Zanden, and M.M. Sloet van Oldruitenborgh-Oosterbaan

Pyelonephritis Presenting with Severe Acute Renal Failure

We describe an unusual case of an 8-yr-old child presenting with low grade fever and acute renal failure. Investigations showed blood urea 246 mg/dl, serum creatinine 6.4 mg/dl, microscopic hematuria and 2+ proteinuria. Renal biopsy was done in view of rapidly worsening kidney function and showed dense lymphoplasmacytic infiltrate and neutrophils with focal areas of interstitial necrosis, confirming acute pyelonephritis. Ultrasonography and MRI demonstrated multiple renal abscesses. He was managed with antimicrobial therapy and hemodialysis.

Autoimmune pancreatitis: negotiating the labyrinth of terminology, diagnosis and differential diagnosis

Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that typically affects adults with a male predilection. Jaundice, weight loss, anorexia and abdominal pain are the most common presenting symptoms. Serum IgG and IgG4 are frequently elevated. Imaging studies show diffuse enlargement of the pancreas with diffuse or segmental narrowing of the main pancreatic duct. When pancreatic involvement is focal, it can mimic adenocarcinoma on imaging. Histologically, the disease is characterized by a duct-centric fibroinflammatory process, dense lymphoplasmacytic infiltrates and phlebitis. High numbers of IgG4-positive plasma cells are frequently present. The absence of duct dilatation, pseudocyst, fat necrosis or calcification aids in the distinction from alcoholic pancreatitis. AIP can involve other sites in the pancreaticobilairy tree and is frequently associated with other autoimmune and fibrosclerosing diseases. This has led to the concept that AIP is the pancreatic manifestation of systemic IgG4-related immunological disease. The prognosis is generally favourable with an excellent response to steroids.

Lymphoepithelioma‐like carcinoma arising in the scar from a previously excised basal cell carcinoma

We report a case of a primary lymphoepithelioma-like carcinoma of the skin (LELCS) associated with scar from a previous excision of basal cell carcinoma. The patient was a 68-year-old female with a 3.0 mm skin-colored pearly papule on her forehead that developed over 2-3 months. The patient had a history of a basal cell carcinoma in the same location, which was completely excised 1 year earlier. A biopsy and subsequent excision of the tumor were performed. The tumor consisted of small islands of large pleomorphic mitotically active epithelioid cells surrounded by a very dense lymphoplasmacytic infiltrate. The tumor was associated with dermal scar. There was no connection of tumor with the unremarkable epidermis. Immunohistochemical examination showed that the epithelioid tumor cells were positive for pan-cytokeratin and epithelial membrane antigen, supporting the morphologic impression of LELCS. The lesion was negative for Epstein-Barr virus. Retrospective review of the original excision specimen confirmed the diagnosis of an ordinary basal cell carcinoma. Forty-five cases of LELCS have been reported to date. We report the first case of LELCS to arise in the scar from an excision of a cutaneous malignancy.

Update on the diagnosis and treatment of autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is the pancreatic manifestation of a systemic fibroinflammatory disease (IgG4-related systemic disease) in which affected organs demonstrate dense lymphoplasmacytic infiltration with abundant IgG4-positive cells. The diagnosis of AIP and its differentiation from pancreatic cancer, its main differential diagnosis, remains a clinical challenge. The five cardinal features of AIP are characteristic histology, imaging, and serology; other organ involvement; and response to steroid therapy. Recent advances in our understanding of these features have resulted in enhanced recognition and diagnosis of this benign disease. This in turn has resulted in the avoidance of unnecessary surgical procedures for suspected malignancy. This article reviews recent updates in the diagnosis and treatment of autoimmune pancreatitis.

Lymphoepithelioma‐like cholangiocarcinoma not associated with EBV

Reported herein is an unusual case of intrahepatic cholangiocarcinoma with lymphoepithelioma-like appearance in a 64-year-old man who was found to have an intrahepatic mass without cirrhosis. The tumor had two distinct histological patterns with dense lymphoplasmacytic infiltrate. The first was similar to nasopharyngeal undifferentiated carcinoma; the second pattern was a well-differentiated adenocarcinoma. Transition between the two components was observed in the same duct. Immunohistochemistry indicated that the tumor was immunoreactive with AE1/AE3 and cytokeratin (CK) 7, but negative for CEA and CK20. Stromal inflammatory infiltrate primarily consisted of plasma cells and lymphocytes. Immunohistochemical examination and in situ hybridization for EBV showed no integration of the virus in the tumor cells. Intrahepatic lymphoepithelioma-like carcinoma is rare, and most are associated with EBV. Only three cases were not associated with EBV. The authors would like to add one more example of the tumors not associated with EBV.

Pseudotumors due to IgG4 Immune-Complex Tubulointerstitial Nephritis Associated With Autoimmune Pancreatocentric Disease

Autoimmune pancreatitis (AIP) is a mass-forming chronic fibroinflammatory condition centered on the pancreatobiliary system and characterized by predominant immunoglobulin G4 (IgG4)-positive plasma cells. Recent reports have brought to light the multiorgan involvement of this disease. We describe a series of 5 cases of tubulointerstitial nephritis (TIN) associated with AIP and characterize the clinical, pathologic, ultrastructural, and immunopathologic features of TIN. The specimens consisted of 4 biopsies and 1 nephrectomy. The average patient age was 64 years (range 45 to 78) and the male to female ratio was 4:1. All had histologic and/or clinical and radiographic evidence of AIP, mass-forming sclerosing cholangitis, or both. The clinical impression in 4 patients was a renal mass or vasculitis. Two patients had renal insufficiency. Histologic preparations revealed a dense tubulointerstitial lymphoplasmacytic infiltrate. Eosinophils were often numerous. Tubulitis and tubular injury were present, along with tubular atrophy with focally thickened tubular basement membranes (TBMs). The histologic appearance ranged from a cellular, inflammatory pattern without tubular atrophy to a striking expansive interstitial fibrosis with tubular destruction. The nephrectomy specimen demonstrated a masslike nodular pattern of inflammation with normal renal tissue elsewhere. Glomeruli were uninvolved. By immunohistochemistry or immunofluorescence, numerous plasma cells in the infiltrate were positive for IgG4. TBM granular IgG deposits, predominantly of the IgG4 subclass, were detected in 4 of 5 cases by either immunofluorescence or immunohistochemistry. By electron microscopy, corresponding amorphous electron-dense deposits were present in the TBM in these cases. This type of TIN, typically characterized by a masslike lesion consisting of a lymphoplasmacytic infiltrate with eosinophils and prominent IgG4-positive plasma cells and immune-complex deposits in the TBM, may be part of a systemic IgG4-related disease, which we term "IgG4-associated immune complex Multiorgan Autoimmune Disease" (IMAD).

Tubulointerstitial nephritis associated with IgG4-related systemic disease

We report three patients with tubulointerstitial nephritis (TIN) with high serum IgG4 concentrations. None of the patients had notable pancreatic lesions when the TIN developed, although one had a history of autoimmune pancreatitis (AIP). Nevertheless, the clinicopathological findings were quite similar to those of AIP. They were all middle-aged to elderly men. Sialadenitis and lymphadenopathy were often evident. Serum total IgG and IgG4 concentrations were elevated and hypocomplementemia was observed. Although antinuclear antibodies were positive, anti-Ro and anti-La antibodies were negative. Renal biopsy showed dense lymphoplasmacytic infiltration with fibrosis in the renal interstitium, and the infiltrated plasma cells had strong immunoreactivity for IgG4. Furthermore, lymphoplasmacytic infiltration and abundant IgG4-positive plasma cells were observed in the salivary glands of a patient. Steroid therapy was effective for TIN in all three patients. The present findings support the recently proposed concept of IgG4-related systemic disease, and suggest that IgG4 is associated not only with AIP but also with other systemic lymphoplasmacytic diseases, including TIN. The conditions responsible for the pathogenesis of TIN need to be considered, irrespective of the presence of AIP.

Renal Lesions in IgG4-Related Systemic Disease

Recently, a new concept of IgG4-related systemic disease including autoimmune pancreatitis, characterized by a high serum IgG4 level and tissue infiltration by IgG4-positive plasma cells, has been proposed. Our aim was to investigate the renal involvement in this condition. We investigated the results of laboratory and imaging studies of the kidneys in 7 patients with IgG4-related systemic disease, and examined the renal histology in four of them. All patients showed elevated serum IgG4 levels, and 4 had autoimmune pancreatitis. The other three patients showed involvement of various extrapancreatic organs (lymphadenopathy, sialadenitis or renal insufficiency), and abundant IgG4-positive plasma cell infiltration was confirmed in their affected tissues. Six of the 7 patients showed some renal abnormalities. In one patient, hydronephrosis was observed accompanied by retroperitoneal fibrosis. Another patient showed multiple low-density areas in both kidneys by computed tomography, and gallium citrate scintigraphy showed gallium-67 accumulation in both kidneys, although renal function was normal. Four patients had tubulointerstitial nephritis. In two of them, the tubulointerstitial nephritis was diffuse. In one patient, marked diffuse but patchily distributed lymphoplasmacytic infiltration of the renal interstitium was observed. In another patient, computed tomography showed a tumor-like low-density mass; open biopsy of the mass showed aggregates of lymphocytes and plasma cells in the renal interstitium. Renal parenchymal lesions in IgG4-related systemic disease are due to dense lymphoplasmacytic infiltration of the renal interstitium, and the lesions vary from diffuse tubulointerstitial nephritis to tumor-like masses according to the distribution patterns of the infiltrating cells.

Autoimmune Pancreatitis: A Systemic Immune Complex Mediated Disease

Autoimmune pancreatitis (AIP) is a mass forming inflammatory pancreatobiliary-centric disease. Recent reports of multiorgan inflammatory mass forming lesions with increased numbers of IgG4 positive plasma cells suggest that AIP may have a systemic component. In this study, we explore the systemic nature of AIP, investigate the relevance of subtyping AIP, perform a systematic study of tissue IgG4 immunoperoxidase, and ultrastructurally evaluate the presence of immune complexes. Our study group consisted of 36 patients with AIP, 21 of whom underwent a Whipple procedure. On the basis of the pattern of inflammation, pancreatic involvement was subtyped as ductocentric (AIP-D) or lobulocentric (AIP-L). Extrapancreatic lesions included bile duct (n=3), salivary glands (n=3), lung (n=2), gallbladder (n=11), and kidney (n=4). Clinical and radiologic data was recorded. Immunohistochemistry for IgG4 was performed on both pancreatic and extrapancreatic tissues and the numbers of IgG4 positive plasma cells were semiquantitatively scored. A control cohort composed of pancreatic adenocarcinoma (n=19) and chronic pancreatitis-not otherwise specified (NOS) (n=14) was also evaluated. Eleven pancreatic specimens, including 2 cases of chronic pancreatitis-NOS and 4 kidneys were evaluated ultrastructurally. The pancreas, bile duct, gall bladder, salivary gland, kidney, and lung lesions were characterized by dense lymphoplasmacytic infiltrates with reactive fibroblasts and venulitis. IgG4 positive plasma cells were identified in all pancreatic and extrapancreatic lesions. The AIP cases showed significantly more pancreatic IgG4 positive plasma cells than chronic pancreatitis-NOS or adenocarcinoma (P=0.001). However, IgG4 positive cells were identified in 57.1% of chronic pancreatitis-NOS and 47.4% of ductal adenocarcinoma. Fifteen of 21 resected cases were classified as AIP-D, and 6 as AIP-L, the latter notably showing significantly more IgG4 positive plasma cells than the former (P=0.02). Additionally, clinical and radiologic differences emerged between the 2 groups. Ultrastructurally, electron dense deposits of immune complexes were identified in the basement membranes of 7 of the 9 AIP cases and in 3 of the 4 renal biopsies evaluated. AIP represents the pancreatic manifestation of a systemic autoimmune disease. Clinical and immunologic findings justify the recognition of pancreatic lobulocentric and ductocentric subtypes. Documentation of increased numbers of tissue IgG4 positive plasma cells, although not an entirely specific marker for AIP, may provide ancillary evidence for the diagnosis of a IgG4-related systemic disease.

Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease.

Autoimmune pancreatitis (AIP) is a peculiar type of pancreatitis of presumed autoimmune etiology. Many new clinical aspects of AIP have been clarified during the past 10 years, and AIP has become a distinct entity recognized worldwide. However, its precise pathogenesis or pathophysiology remains unclear. As AIP dramatically responds to steroid therapy, accurate diagnosis of AIP is necessary to avoid unnecessary surgery. Characteristic dense lymphoplasmacytic infiltration and fibrosis in the pancreas may prove to be the gold standard for diagnosis of AIP. However, since it is difficult to obtain sufficient pancreatic tissue, AIP should be diagnosed currently based on the characteristic radiological findings (irregular narrowing of the main pancreatic duct and enlargement of the pancreas) in combination with serological findings (elevation of serum γ-globulin, IgG, or IgG4, along with the presence of autoantibodies), clinical findings (elderly male preponderance, fluctuating obstructive jaundice without pain, occasional extrapancreatic lesions, and favorable response to steroid therapy), and histopathological findings (dense infiltration of IgG4-positive plasma cells and T lymphocytes with fibrosis and obliterative phlebitis in various organs). It is apparent that elevation of serum IgG4 levels and infiltration of abundant IgG4-positive plasma cells into various organs are rather specific to AIP patients. We propose a new clinicopathological entity, “IgG4-related sclerosing disease” and suggest that AIP is a pancreatic lesion reflecting this systemic disease.

The Usefulness of Biopsying the Major Duodenal Papilla to Diagnose Autoimmune Pancreatitis: A Prospective Study Using IgG4-Immunostaining

Background and Aim: Autoimmune pancreatitis (AIP) is characterized by irregular narrowing of the main pancreatic duct, enlargement of the pancreas, increased levels of serum IgG4, and dense lymphoplasmacytic infiltration with fibrosis. In segmental mass-forming cases, the differentiation between AIP and pancreatic carcinoma remains difficult. We previously reported that IgG4-positive plasma cells abundantly infiltrated the various organs, as well as the pancreas, of a patient with AIP, and that an abundant infiltration of IgG4-positve plasma cells was not observed in the organs of patients with pancreatic carcinoma or chronic alcoholic pancreatitis.

Lymphoepithelioma-Like Carcinoma of the Skin in a Tunisian Patient

Lymphoepithelioma-like carcinoma of the skin (LELCs) is a rare cutaneous neoplasm with histologic features resembling lymphoepitheliomatous tumors of the nasopharynx. The association of lymphoepitheliomas with Epstein-Barr Virus (EBV) at some extracutaneous sites is well documented. In contrast, the presence of EBV in LELCs has never been shown in either Caucasians or Asian patients. We present the first case of LELCs in a Tunisian patient, a 78-year-old woman who presented with a nodule of the right cheek of 2 months' duration. The patient underwent surgical excision and there was no evidence of local recurrence 6 months later. Histologically, the entire dermis was occupied by lobules composed of atypical epithelial cells surrounded by a dense lymphoplasmacytic infiltrate. Immunohistochemical examination showed that the epithelial tumor cells were positive for cytokeratin and epithelial membrane antigen. In situ hybridization investigations for the presence of EBV-encoded RNA showed negative results. Our findings suggest that LELCs is not related to EBV among North African patients.

Can histopathology be the “Gold Standard” for diagnosing autoimmune pancreatitis?

Can histopathology be the “Gold Standard” for diagnosing autoimmune pancreatitis?

Autoimmune Pancreatitis With Hepatic Inflammatory Pseudotumor

We report a case of autoimmune pancreatitis (AIP) with hepatic inflammatory pseudotumor (IP). The patient was clinically diagnosed as having multiple metastatic tumors originated from cholangiocellular carcinoma as well as autoimmune pancreatitis and underwent left lobectomy of the liver. Histological examination showed a diffuse or dense lymphoplasmacytic infiltration with obliterating phlebitis but an absence of neoplastic proliferation both in the liver tumor and in the biopsy specimen of the pancreas. Abundant IgG4-positive plasma cells were seen in the lesions. This is the first case report that shows a simultaneous occurrence of hepatic IP and AIP, suggesting that these lesions appeared on the background of the recently proposed entity of IgG4-related systemic disease.

IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung

The association between IgG4 dysregulation and inflammatory pseudotumor (IPT) was first reported in sclerosing pancreatitis. Recently, we described IPTs of the liver and breast, into both of which many IgG4-positive plasma cells had infiltrated. In this study, we examined the clinical and histological features of 9 cases of IPT (histologically corresponding to plasma cell granuloma) of the lung with an emphasis on IgG4-positive plasma cell infiltration. The lesions were characterized histologically by dense lymphoplasmacytic infiltrates intermixed with fibrosis and, in some cases, prominent eosinophilic infiltration, irregular narrowing of bronchioles entrapped in nodules, and an interstitial pneumonia pattern at the boundaries of nodules. Obliterative phlebitis was easily found in all cases, and 5 lesions also had obliterative arteritis. Immunostaining revealed many IgG4-positive plasma cells diffusely distributed within nodules, and the ratios of IgG4-positive to other plasma cells were extraordinarily high. Of the 9 patients, 8 underwent surgical treatment and in 1 patient, lesion was diagnosed on transbronchial biopsy and effectively treated with corticosteroid. Two cases were associated with chronic sclerosing sialadenitis or lymphadenopathy, in which many IgG4-positive plasma cells were also identified by immunostaining. The clinicopathologic similarities between IPT of the lung and sclerosing pancreatitis suggest that IgG4-related immunopathologic processes might be involved in the pathogenesis of the pulmonary lesions.