Clinical correlates of granulomas in muscle

We evaluated the clinical and myopathological features of all patients with granulomas in muscle biopsy specimens identified over a 5-year period (1992-1996) at the Washington University Medical Center. Ten patients were found to have granulomas in their muscle biopsy specimens. Of these, eight patients had myopathic changes. Seven had dysphagia as a major functional difficulty during the course of their disease. None had elevated levels of serum creatine kinase (CK). Four of the patients with myopathy had systemic sarcoidosis and relatively severe proximal weakness with functional disability. Treatment with corticosteroids was followed by marked improvement in strength and functional disability. The four other patients with myopathy had no systemic signs of sarcoidosis. Weakness was especially prominent distally in three of these patients. The two patients in this group treated with corticosteroids did not improve. The final two patients, who had granulomas in muscle but no myopathic changes, had clinical syndromes of mononeuritis multiplex and eosinophilic fasciitis (Shulman syndrome). We conclude that granulomatous myopathy, in the presence or absence of systemic sarcoidosis, is commonly associated with dysphagia (87%) and a normal serum CK. Clinical features in patients with sarcoidosis included severe proximal weakness with functional disability that often responded to corticosteroid treatment. Granulomatous myopathy without systemic sarcoidosis was associated with milder, but more predominantly distal weakness.     

Spinal cord compression by catheter granulomas in high-dose intrathecal morphine therapy: case report

OBJECTIVE AND IMPORTANCE: The use of chronic intrathecal morphine for the treatment of intractable, nonmalignant pain is becoming more prevalent. A rare but devastating complication of this therapy is the development of spinal cord compression secondary to the formation of intrathecal granulomas. CLINICAL PRESENTATION: We report three cases of intrathecal granuloma formation in the thoracic subarachnoid space, associated with intrathecal morphine pumps. These three patients were receiving high doses of morphine to control their pain (25 mg/d, 28 mg/d, and 45 mg/d, respectively) when they presented with signs and symptoms of thoracic spinal cord compression. Myelography and postmyelographic computed tomography of the spine revealed masses causing spinal cord compression. INTERVENTION: Two patients underwent thoracic laminectomies for resection of these masses, and the other patient had the intrathecal catheter removed. A pathological examination revealed sterile granulomas in the resected masses. CONCLUSION: Intrathecal granulomas are likely to occur with increasing frequency as the use of chronic intrathecal morphine delivery increases in patients with nonmalignant pain. The cause of intrathecal granulomas is unknown, although it is likely that morphine plays a major role in their formation. We think that those patients receiving high doses of morphine are at greater risk for developing this complication.     

Malignant lymphoma obscured by concomitant extensive epithelioid granulomas: report of three cases with similar clinicopathologic features

Three similar cases are described of an unusual combination of malignant lymphoma and extensive non-necrotic granulomas. The three patients presented with prominent splenomegaly without peripheral lymphadenopathy. They had normal or moderately elevated lymphocyte counts, abnormal lymphoid cells in the peripheral blood and bone marrow, and abnormalities of serum immunoglobulins. The lymphoid tumor was difficult to recognize but it was best identified in abdominal lymph nodes, it was composed of small atypical lymphocytes proliferating in a vaguely nodular pattern. The presence of multiple epithelioid granulomas obscured the neoplastic proliferation in the spleens and misled or delayed the final interpretation of the malignant disease. Abdominal lymph nodes and liver also contained granulomas although to a lesser extent. Studies of the lymphocyte surface characteristics in one patient suggested that the neoplasm derived from a monoclonal proliferation of B cells. The relationship between the exuberant epithelioid granulomas and the underlying neoplastic lymphoid proliferation is not clear. Regardless of whether it represents a distinct clinicopathological entity, recognition of this remarkable association has important practical implications since the lesions may be erroneously interpreted by the pathologist.     

Endothelins: mechanisms of action and prospects of research

Fibrin ring granulomas of the bone marrow are described in two organ transplant patients (one renal, one cardiac) with disseminated cytomegalovirus infection. Infection was documented by viral cultures and seroconversion, and in both cases typical cytomegalic cells were identified in proximity to the fibrin ring granulomas. These represent the first case reports of bone marrow fibrin ring granulomas associated with cytomegalovirus.     

Pulmonary manifestations in cerebrotendinous xanthomatosis

We investigated five cases with cerebrotendinous xanthomatosis (CTX) with particular reference to biochemical and pathological pulmonary disorders. To date, few reports discuss the pathophysiology of pulmonary disorders of CTX patients. This study is the first investigation of such pulmonary disorders. All 5 patients had no pulmonary symptoms and no disturbances on radiological studies and pulmonary function tests. However, in bronchoalveolar lavage (BAL) fluids, many cells with cruciform reflexes, which is characteristic of intracellular sterol accumulation, were found under phase contrast microscopy. Biochemically, cholestanol was found to be increased in the BAL fluid as well as in serum. Pathological findings of transbronchial lung biopsy (TBLB) samples disclosed foamy macrophages and small granulomas in alveolar septa. In conclusion, the lung was apparently involved in CTX, and the lesions were characterized with the accumulation of foamy and giant cells with a high concentration of cholestanol, which likely results in the formation of foreign body granulomas.     

Biomechanics of A-to-T flap design

We present two types of "new" foreign body granulomas caused by the injectable aesthetic microimplants Bioplastique and Artecoll. We report the clinical and histopathologic findings in five patients who had undergone treatment of mainly facial contour abnormalities with one of these implants. All patients were women, and the mean age was 45 years (age range 24-72 years). Two patients presented after treatment with Bioplastique; in three patients, augmentation was achieved by using Artecoll. Unsatisfactory cosmetic effects led to excision of the implants in four patients; in one patient, parts of the implant were excised during another cosmetic intervention. Subsequent histopathologic examination showed features of foreign body granulomas with distinctive cystic spaces. The clue to the diagnosis is the particular configuration of these cystic spaces and the characteristic shape of the foreign bodies. Bioplastique granuloma presents with irregularly shaped cystic spaces of varying size containing jagged, translucent, nonbirefringent foreign bodies whereas Artecoll granuloma shows numerous round vacuoles nearly identical in size and shape enclosing round and sharply circumscribed, translucent, nonbirefringent foreign bodies. These specific histopathologic findings unequivocally allow the correct diagnosis in spite of sparse clinical information.     

Granulomatous glomerulonephritis in intravenous drug users: a report of three cases in oxycodone addicts

Various well-documented renal lesions are associated with intravenous drug use; however, intraglomerular mesangial granulomas have not been previously described. We report three patients who developed an unusual granulomatous glomerulonephritis and interstitial nephritis after intravenous injection of oxycodone, derived from suppositories. Granulomas were seen in an intraglomerular mesangial and also interstitial location. In both sites, the granulomas were associated with filamentous material, presumably derived from a component of the suppositories. This material was periodic acid-Schiff-positive, but negative with Congo red and silver stains. Ultrastructurally, the filamentous material was seen within the mesangial granulomas and also in a subendothelial location, suggesting derivation from the circulation with subsequent transport across the basement membrane and accumulation in the mesangium, where a granulomatous reaction was elicited. All patients developed a degree of renal failure; two of the patients require hemodialysis 20 and 30 months after presentation.     

Vocal process granuloma

Vocal process granuloma or contact ulcer is uncommon disease in which there is chronic irritation and granulation tissue formation at the posterior third of the vocal folds. Thirteen patients (11 men and two women) with vocal process granuloma were enrolled in this study; cases of intubation granuloma were excluded. The most frequent complaints were throat irritation, frequent throat clearing and voice change. Forty-seven percent of patients had a recurrence two to four months after surgery. Computed tomography (CT) of the larynx in four patients showed arytenoid sclerosis on the involved side and disclosed moderate enhancement of the vocal fold granuloma after contrast injection in one. Three patients had hyperacidity and four had hyperfunctioning granulomas: two used their voices excessively and the other two had bilateral sulcus vocalis. To our knowledge this is the first report of sulcus vocalis with vocal process granuloma, and of enhanced vocal process granuloma.     

Cytokine patterns in tuberculous and sarcoid granulomas: correlations with histopathologic features of the granulomatous response

Cytokines play an important role in granuloma formation, but the extent that cytokine profiles are similar in different granulomatous diseases and whether differences in the histopathologic features of the granulomatous response results from differences in cytokine production have not been evaluated. To investigate these questions, we used RT-PCR to quantify the expression of mRNAs coding for 16 cytokines in granulomatous lymph nodes from patients with tuberculosis and sarcoidosis and from control tissues, and we sought correlations between the level of expression of these cytokines and the histopathologic features of the granulomas. Expression of mRNAs coding for a number of cytokines (IL-1beta, IFN-gamma, TNF-alpha, granulocyte-macrophage (GM)-CSF, IL-12 (p40), and lymphotoxin-beta) was increased in tuberculous and sarcoid granulomas compared with that of control tissues. All sarcoid granulomas were shown to express a Th1 pattern of cytokine mRNAs, while tuberculous lymph nodes expressed either a Th1 or a Th0 profile. GM-CSF and lymphotoxin-beta mRNAs were more abundant in sarcoid than in tuberculous granulomas, whereas IL-8 mRNA was strongly expressed only in tuberculous lymph nodes. Strong expression of GM-CSF, TNF-alpha, and IL-8 by granulomas was shown to be correlated, respectively, with the presence of florid granulomatous lesions, the absence of central necrosis, and the presence of neutrophil infiltration. These results demonstrate that the formation of tuberculous and sarcoid granulomas in humans is associated with the expression of characteristic cytokine profiles and indicate that the expression of certain cytokines is associated with the development of specific pathologic features in the resulting granulomas.     

Consanguineous marriages among parents of patients with Down syndrome

A middle-aged woman with common variable immunodeficiency noted a papular skin eruption that simulated Gottron's sign of dermatomyositis on the dorsal hands. Examination of a skin biopsy specimen demonstrated noninfectious granulomatous inflammation. The patient was subsequently found to have visceral granulomas when examined using laparotomy. Noninfectious granulomas of the viscera and integument have been previously reported in patients with several immunodeficiency syndromes, including common variable immunodeficiency.     

Central nervous system aspergillosis in two young adults

Unusual and unique features were present in the cases of two patients with central nervous system aspergillosis: One had a previously unreported complication of aspergillosis, extracranial internal carotid artery thrombosis documented by angiography, and in the other patient, cerebral granulomas developed from Aspergillus fumigatus in association with intravenous narcotic abuse. The latter etiologic mechanism was suggested once before. Neither of these patients showed other underlying disease. A detailed neuropathologic examination correlated the salient clinical findings with formation of aspergillosis cerebral granulomata, basilar meningitis, and arterial occlusion. Diagnostic and therapeutic methods in this disease are limited.     

Cutaneous sarcoid-like granulomas in primary immunodeficiency disorders

We report the occurrence of cutaneous sarcoid-like granulomas in one patient with common variable immunodeficiency and another with 'thymoma and hypogammaglobulinaemia'. To our knowledge, this is the first time that such skin lesions have been described in patients with primary immunodeficiency. These granulomas may be attributed to a combination of interleukin-2 deficiency and a profound CD4 lymphopenia. The lesions are similar to the non-infectious 'papular eruption' associated with human immunodeficiency virus infection, and might reflect a common pathogenic mechanism.     

Pancytopenia in children with brucellosis: clinical manifestations and bone marrow findings

Among 276 paediatric cases of brucellosis seen over a 7-year period, 16 patients (5.8%) with pancytopenia were identified. The most frequent presentations were fever, malaise, anorexia, weight loss, arthralgia, and hepatosplenomegaly. Fourteen patients (87.5%) had positive blood and/or bone marrow cultures for Brucella melitensis. Bone marrow aspiration specimens showed hypercellularity in 14 patients and normocellularity in 2. Histiocytes, eosinophils and plasma cells were increased in every marrow aspirate, and haemophagocytosis was observed in 14 patients (87.5%). Non-caseating granulomas were present in the bone marrow biopsy of 11 patients (68.8%). The pancytopenia was transient, and resolved on treatment of the Brucella infection.     

DNA replication is completed in Saccharomyces cerevisiae cells that lack functional Cdc14, a dual-specificity protein phosphatase

A 35-year-old man affected with pulmonary sarcoidosis had a 12-year history of fatigue and pain in the limbs, with normal neurological examination, except for diffusely absent deep tendon reflexes. Muscle biopsy samples showed multiple noncaseating granulomas, most prominent around the intramuscular nerves, with predominance of CD4+ cells. Intramuscular nerve bundles surrounded by granulomas were immunolabelled with laminin alpha1, alpha2, beta1 and gamma1 chain, and collagen IV. Sural nerve biopsy samples were normal. This patient showed a unique histopathological pattern of sarcoid neuromyopathy characterized by distribution of granulomas or infiltrating cells around intramuscular nerve fibers. The clinical picture, restricted to nonspecific symptoms of fatigue and myalgia, and loss of deep tendon reflexes, correlated well with the selective localization of sarcoid lesions in contiguity with the intramuscular nerves. To our knowledge, this peculiar clinico-pathological correlation has not been reported previously.     

CNS cryptococcosis in AIDS: spectrum of MR findings

Cryptococcus is a ubiquitous saprophytic fungus that may become pathogenic, particularly in immunosuppressed patients. In the CNS of AIDS patients, the incidence of this fungal infection is 5% of all the opportunistic infections. In this study, we review the MR findings in nine AIDS patients affected by CNS cryptococcosis. All MR studies were performed before and after intravenous administration of a single dose of gadopentetate dimeglumine and again after an additional dose. Autopsy was performed in one case. Magnetic resonance imaging revealed evidence of meningitis or meningoencephalitis, dilated Virchow-Robin spaces, cyst-like structures (gelatinous pseudocysts), and granulomas (cryptococcomas) of the choroid plexuses. The last two findings (pseudocysts and choroidal ependymal granulomas) are relatively specific for cryptococcosis.     

Granulomatous hepatitis in three children due to cat-scratch disease without peripheral adenopathy. An unrecognized cause of fever of unknown origin

OBJECTIVE: To report the clinical experience of three patients with fever of unknown origin ultimately diagnosed as having cat-scratch granulomatous hepatitis in the absence of peripheral adenopathy. DESIGN: Case-control study. SETTING: Referral center at university-based referral practice. PATIENTS: Three children with fever of unknown origin. Follow-up following presentation was 6 months for each patient. MEASUREMENT AND RESULTS: All three patients with fever of unknown origin were diagnosed radiographically to have multiple hepatic defects. The defects were shown histologically to be granulomatous. Two of the three patients had Warthin-Starry staining bacilli in the granulomas consistent with a diagnosis of Afipia felis. All three had positive cat-scratch skin test results. CONCLUSIONS: Cat-scratch disease in the absence of peripheral adenopathy is a heretofore unrecognized cause of fever of undetermined origin and may account for a small, but significant, percentage of children presenting with it.     

Haematopoietic capacity of colony-forming cells mobilized in hepatic inflammatory reactions as compared to that of normal bone marrow cells

Chronic inflammatory periovular granulomatous reactions elicited in liver by schistosomal infection are a site of active myelopoiesis. We quantified the colony-forming cells (CFCs) in granulomas and found that the whole liver contains a number of CFCs roughly equivalent to 50% of a femur. Clonogenic analysis showed the presence of committed as well as pluripotent and totipotent CFCs. Long-term Dexter-type cultures showed that the granuloma-derived totipotent CFCs do not have self-renewal capacity. Hence, they did not correspond functionally to haematopoietic stem cells, despite the fact that the stroma established by adherent cells harvested from granulomas had the capacity to sustain long-term proliferation of bone-marrow-derived haematopoietic stem cells. We conclude that myelopoietic cytokines produced by inflammatory reactions in schistosomiasis elicit mobilization of bone marrow CFCs into the circulation, which can settle in hepatic granulomas. This environment may induce their proliferation and differentiation, but not their self-renewal, sustaining temporary production of myeloid cell lineages which nevertheless depends upon cell renewal from the bone marrow pool of haematopoietic precursors.     

Invasive breast carcinoma with granulomatous stromal response

An unusual case of invasive ductal carcinoma of the breast associated with epitheloid granulomas is reported. Multinucleated giant Langhans'-type giant cells were found in the epitheloid granulomas in breast carcinoma, but there were not present in the breast tissue and axillary lymph nodes. Congo-red deposits were found haphazardly in the stroma between tumor cells and granulomas. Numerous mast cells were found surrounding granulomas. The patient lacked any clinical evidence of the systemic granulomatous disease. The presence of epitheloid granulomas, amyloid deposits and numerous mast cells in invasive breast carcinoma could be related to a host immune response towards the tumor.     

Differential cellular response within the rabbit tendon unit following tendon injury

Since 1975, 340 patients were treated by tracheal sleeve resection for tracheal or subglottic laryngeal iatrogenic stenoses in our unit. Preoperative iterative Nd YAG laser sessions have usually been performed, without success. The length of the sleeve specimen was an average of 3 1/4 cm. Twelve patients died on the post operative course (3.5%), 3 more patients died later after failure of the procedure (0.9%) and nineteen had recurrent stenoses treated with use of a tracheostomy tube, a permanent Montgomery tube, or an endotracheal stent (5.6%). Three hundred and six patients are definitely cured (90%), at the first attempt for 265 patients, after a laser session for granulomas for 20 patients, after a second tracheal resection for 6 patients and after a temporary Montgomery tube for 15 patients. Providing there is a good selection of the patients, tracheal sleeve resection is the best treatment for iatrogenic stenosis.     

Bartonella henselae infection in immunocompetent patients: cat scratch disease

BACKGROUND: Cat scratch disease, whose etiologic agent is Bartonella henselae, is a benign disease in immunocompetent subjects, characterized by lymphadenopathy of prolonged course and occasional involvement of other organs such as liver, spleen, central nervous system, eye and lung. In immunocompromised patients, the infection is bacteremic and disseminated. AIM: To report Chilean cases of cat scratch disease. PATIENTS AND METHODS: Ten children (seven male, aged between 6 and 13 years old) with histologically or serologically confirmed cat scratch disease are reported. RESULTS: Lymphadenopathy location was pre auricular in four cases, axillary in two, inguinal in two and epitrochlear in two. Three children had fever over 39 degrees C and two had a parinaud syndrome. Nine children had a history of cat scratch and one of a cat byte. Six had an erythrocyte sedimentation rate over 40. Lymph node ultrasound examination was a useful diagnostic tool. Two patients had splenic granulomas. Lymph node biopsies were obtained in four cases, showing a suppurative granulomatous lymphadenitis in all and a positive Warthin-Starry stain in two. Serology, done in patients without histological confirmation was positive with titles ranging from 1:64 to 1:8192. All patients had a satisfactory outcome with regression of lymphadenopathy. CONCLUSIONS: Infections by Bartonella hemselae occur in the Chilean population and must be considered in the differential diagnosis of regional lymph node enlargement.