Department of Human Oncology, University of Wisconsin School of Medicine, Madison, Wisconsin

Sarah A. Thurman, MD

Department of Radiation Oncology, Beth Israel-Deaconess Medical Center, Boston, Massachusetts

Steven P. Howard, MD, PhD

Department of Human Oncology, University of Wisconsin School of Medicine, Madison, Wisconsin

The presence of five discrete synchronous or metachronous primary neoplasms in a single patient is an extremely rare event. This is a report of a patient with a malignant (invasive) thymoma and four other independent primary neoplasms including: gliosarcoma, papillary thyroid cancer, meningioma and metastatic adenocarcinoma of the colon, found synchronously at autopsy. Thymoma patients appear to have an inherent predisposition towards developing additional neoplasms. Other than the thymoma, the presented patient had no obvious risk factors for neoplasia. This case provides evidence for an unusual syndrome of thymoma and multiple primary neoplasms. Further research is required to elucidate the mechanism of this association. Meanwhile, heightened awareness of this association may allow earlier detection and treatment of additional cancers in patients with a history of thymoma.

The development of five primary tumors in a single patient is extremely uncommon. Finding the five neoplasms synchronously is an extraordinarily rare event. Although cases of five or more synchronous primary tumors have been reported, these cases typically include multiple discrete tumors within the same or contralateral-paired organ. A patient who died of gliosarcoma and was found to synchronously have a total of five independent primary neoplasms including gliosarcoma, papillary thyroid cancer, meningioma, adenocarcinoma of the colon with hepatic metastases, and thymoma, is presented. Gliosarcoma itself is a highly aggressive, rarely encountered tumor of the central nervous system. Synchronous association of this unusual neoplasm with four other distinct neoplasms is exceptional, and to our knowledge, not previously reported. Such a peculiar array of multiple primary tumors appearing synchronously seems unlikely to be merely coincidental, but is suggestive of carcinogen exposure, or perhaps a sort of a “cancer syndrome.” This particular patient was without a history of carcinogen exposure, a prior personal history of cancer, or a familial predisposition. The presence of the thymoma is intriguing. A report from the Johns Hopkins Hospital¹ found additional neoplasms in 31% of thymoma patients at some time during their follow-up. Other large series^2–8 have similarly observed thymomas to be associated with additional non-thymic neoplasms with incidence rates ranging from 8% to 21%. Other than the thymoma, the patient had no obvious risk factors for neoplasia, providing further evidence for this unusual syndrome of thymoma and multiple primary malignancies.

A female, 85 years of age, in good general health, presented to a local emergency department with an acute onset of left hemi-paresis. The patient was clinically diagnosed with an acute right cerebral hemispheric stroke. After being stabilized, the patient was transferred to Johns Hopkins Hospital for further management. Brain magnetic resonance imaging (MRI) identified a 3 x 2-cm right parietal lesion and a 1.5-cm right frontal lesion, both causing mass effect. Although the findings were compatible with hemorrhagic metastases, the differential diagnosis also included separate primary brain tumors. Radiographic studies including chest x-ray, bilateral mammogram, abdomen and pelvis were unremarkable. The carcinoembryonic antigen (CEA) was elevated to a level of 23 ng/ml. Other labs including thyroid function tests were within normal limits except for a slightly elevated alkaline phosphatase. Both the patient and her family decided to not pursue further work-up at that time. The patient was in stable condition and discharged home.

The patient’s past medical history was notable for hypertension, mild dementia, depression, anemia, glaucoma and congestive heart failure. The patient had an aortic graft in the past, as well as a hysterectomy. There was no history of prior malignancy or family history of cancer. There was no record of carcinogen exposure.

The patient was readmitted two months later because of progressive left-sided hemi-paresis and mental status changes. Repeat brain MRI showed a large right hemispheric cystic tumor measuring 5.4 x 4 x 3 cm with massive peritumoral edema and mass effect, causing midline shift and subfalcine herniation. Given steady decline in performance status, the patient’s family chose to only pursue supportive treatment. The patient was placed in hospice and died two months later.

Autopsy revealed 5 discrete primary tumors. The cause of death was attributed to a primary brain tumor, which was diagnosed as gliosarcoma by light microscopy and immunohistochemical staining. The patient was also noted to have a 2-cm, high-grade, poorly differentiated adenocarcinoma of the cecum invading through the muscularis and into the surrounding fat. Multiple liver metastases were found and attributed to the cecal primary. The third primary was a follicular variant of papillary thyroid carcinoma of the inferior right thyroid lobe measuring 1 x 1 x 1 cm. The fourth primary tumor was a right frontal lobe meningioma measuring 1.5 x 1 x 1 cm. The fifth and final primary was a malignant (invasive) thymoma, measuring 3 x 2 x 2 cm and extending into the anterior pericardial fat.

Multiple Neoplasms

Occult thyroid carcinomas found at autopsy are not rare. Autopsy series have revealed incidental thyroid cancers in about 10% of cases.^9,10 Incidental meningiomas are also found in autopsy series at slightly over 1%.¹ The probability of finding both in the same patient is simply the product of these two prevalences (0.1%). The likelihood of also simultaneously discovering a gliosarcoma, metastatic colorectal adenocarcinoma and invasive thymoma in the same patient is exceedingly small. A review of 140,000 cancer patients identified only one patient (0.0007%) with 5 discrete primary malignancies.¹² Rohde and Jakse¹³ reviewed the literature on multiple primary malignant neoplasms and found 16 patients with 5 or more distinct primary tumors. Excluding cases in which separate tumors were reported in the same organ or in the contralateral-paired organ, only 10 patients with 5 or more discrete primary neoplasms, including their own case were identified. However, in 7 of these cases, the neoplasms developed metachronously, in contrast to the synchronous appearance in our case. The extreme rarity of the current case is suggestive of an underlying mechanism, rather than a mere chance association.

Etiology of Multiple Neoplasms

Gliosarcoma is considered a rare variant of glioblastoma multiforme, constituting 1.8% to 2.4% of glioblastoma cases in large series.^14,15 It has been reported in association with prior exposure to ionizing radiation.^16,17 Meningiomas^18–20 and thyroid cancers^21–23 likewise have been linked with radiation exposure. In addition to radiation, chemotherapy is well-known to be associated with secondary malignancies in cancer patients.^24–27 The presented patient never received any radiotherapy or chemotherapy for symptomatic gliosarcoma or any of the tumors; thus, iatrogenic carcinogenesis can not explain the remarkable constellation of neoplasms.

Additional cancers are known to develop at a higher rate in people with a prior personal history of cancer. Patients with primary head and neck cancers occasionally develop additional tumors, presumably due to a history of heavy smoking and/or alcohol consumption, resulting in a “field cancerization” effect, predisposing the entire upper aerodigestive tract to additional cancers.^28,29 The additional neoplasms in these cases are typically squamous cell carcinomas restricted to the upper aerodigestive system. The elevated risk of second cancers in patients with a personal history of cancer cannot always be explained by exogenous carcinogen exposure. Developmental and genetic factors play a role in some patients. Patients with ovarian and breast cancers are at higher risk for development of cancer in the contralateral paired organ, perhaps because of an endogenous hormonal imbalance and/or a genetic predisposition. While patients with Hodgkin’s disease occasionally develop second malignancies after cytotoxic therapies, a baseline analysis revealed abnormalities in sister chromatid exchange in some patients, which was independently predictive of the development of a second cancer.³⁰ These abnormalities were identified before any treatment was administered. Treatment itself was not found to be an independent risk for second cancers, supporting the notion of an inherent predisposition to neoplasia in patients with Hodgkin’s disease. Well-studied inherited mutations such as p53 (Li-Fraumeni syndrome),³¹ mismatch-repair genes in Lynch syndromes³² and Rb protein (p105-RB), in retinoblastoma,³³ predispose individuals and their families to a variety of multiple malignancies. This patient did not have a history of smoking, alcohol abuse, carcinogen exposure, or a personal or family history of cancer. However, the patient did have a thymoma.

Thymoma and Additional Neoplasms

Several series have confirmed an increased incidence of thymoma and additional neoplasms (table 1), with prevalence rates as high as 31%.¹ The discovery of multiple synchronous neoplasms along with thymoma has also been reported in the veterinary literature. In a study of 23 dogs with thymoma, additional neoplasms were concurrently found among 5 dogs (22%), paralleling the human observations.³⁴ In people, thymoma has been found to be associated with additional malignant neoplasms of various sorts, most notably colorectal adenocarcinoma and thyroid cancer.^1,8 At the Mayo Clinic, Souadjian et al.⁶ found that 21% of 146 thymoma patients developed second malignancies. This was compared and contrasted with an 8% second malignancy rate among 177 patients with parathyroid tumors. Their review of the literature⁷ revealed a reported second malignancy incidence of 17% among patients surviving beyond 5 years after diagnosis of thymoma. The true incidence of additional malignancies was higher, as cases with simultaneously diagnosed lymphoma or leukemia were excluded to avoid potential confusion between thymoma and secondary lymphocytic infiltration of the thymus. Interestingly, this population (thymoma plus leukemia or lymphoma) accounted for a high proportion (10%) of the 588 evaluable patients, a finding observed by others.^35,36 In Taiwan, Pan et al.⁵ also found an increased risk of second malignancies among thymoma patients. In their study, the second malignancy incidence rate among thymoma patients was significantly higher compared to a matched cohort of patients with nasopharyngeal carcinoma (8% vs. 2%). The largest single series reporting thymoma and additional neoplasms was conducted by Lewis et al.⁴ who reviewed the Mayo Clinic experience and revealed a second malignancy rate of 17% (48 of 283), corroborating the prior work of Souadjian et al.^6,7 A recent review⁵ confirmed a 17% (152 of 909) incidence of second malignancies in patients with thymoma with colorectal carcinomas representing the most common site. The current review resulted in an identical 17% figure (table 1).

Treatment-Induced Malignancies

As the early reports did not specify treatment for the thymomas, the possibility of treatment-induced neoplasia remained. Welsh et al.¹ showed that the high incidence of additional neoplasms in thymoma patients cannot be attributed to adjuvant radiotherapy or chemotherapy and appears to be an intrinsic association. Of 142 thymoma patients, 46 received radiation or chemotherapy. Among these 46 patients, 16 (35%) developed second neoplasms. This did not differ significantly from the prevalence of second neoplasms in those who did not receive radiation or chemotherapy (25%), or the thymoma population as a whole (28%). Conversely, of the 38 patients with additional neoplasms, only 16 received radiation or chemotherapy, while 22 did not. Among patients who received radiotherapy and developed additional neoplasms, the second tumors usually developed outside the radiation fields, a finding confirmed by others,⁵ which strongly argues against a link to the radiotherapy. Finally, as in the present case, the other tumors were often diagnosed shortly after, synchronously, or even before the thymoma, again not consistent with treatment-induced neoplasia. Thus, radiation or chemotherapy apparently does not account for the high rate of additional neoplasms in thymoma patients.

Because of the integral role of the thymus in immunity, one may speculate that surgical removal of the thymus may be predisposing thymoma patients to additional malignancies. However, Bulkley et al.³⁷ observed no increase in malignancies among patients who underwent thymic resection for myasthenia gravis, except when the myasthenia gravis was accompanied by thymoma.⁸ Similarly, Masaoka et al.³⁸ analyzed 390 patients with myasthenia gravis who had undergone thymic resections and found no increase in the extrathymic malignancy rate among those without an associated thymoma. In contrast, patients with thymoma and myasthenia gravis who underwent thymic resection had an observed-to-expected malignancy ratio of 3:42. Pan et al.⁵ also found a higher rate of additional tumors in patients undergoing thymectomy for thymoma (8%) compared to patients who had thymectomy for myasthenia gravis alone (2%). Thus surgical resection of the thymus for myasthenia gravis apparently does not increase the chances of developing cancer.

Associated Paraneoplastic Disorders

The paraneoplastic conditions typically linked with thymoma such as myasthenia gravis, red cell aplasia and hypogammaglobulinemia represent immunological disorders and thus could conceivably be related to the higher rates of cancer either intrinsically, or because of immunosuppressive therapy for the autoimmune disorder. The presented patient did not have any obvious thymoma-associated paraneoplastic immunological phenomenona. Wilkins et al.⁸ and others,¹ found that the presence or absence of paraneoplastic immunological disorders did not appear to influence the development of further neoplasms. Of 67 patients with immunological disorders, only 24% developed additional tumors–no greater than in the total thymoma population studied (38 of 135 [28%]) or in the thymoma patients without associated disorders (21 of 68 [31%]). Thus, the presence of (or treatment for) such thymoma-associated conditions cannot entirely explain the high malignancy rate.

Multiple Malignancies Associated with Thymoma

The finding of multiple malignancies in human patients^1,5,39 and in dogs³⁴ with thymoma supports the concept of an inherent, rather than coincidental link between thymoma and cancer. This strong oncogenic tendency among patients with thymoma is illustrated by a review by Freidman et al.³⁹ in which a third discrete malignancy developed in 33% of patients with a history of thymoma and a hematologic neoplasm. Very similar findings were reported from Johns Hopkins,¹ where 58 additional neoplasms were found in 44 thymoma patients. A total of 14 patients (31%) were found to have 3 or more discrete primary tumors either synchronously, or metachronously during follow-up. Our present case with 5 synchronous distinct primary neoplasms provides an extreme example of this susceptibility.

Pathogenesis

A precise pathogenic mechanism linking thymoma to an increased incidence of cancer remains elusive. Studies have demonstrated histologic differences in thymic tissue from cancer patients compared to normal controls.⁴⁰ Although this may implicate thymic function in some way; it is unclear if this is a cause or effect relationship. The authors postulated that development of thymoma implies a defect in thymic epithelium that hinders T-cell development, leading to immune defects and a higher incidence of cancer. Some thymoma patients reportedly have peripheral T-cell lymphocytosis, which may reflect a perturbation of systemic immunoregulation that accompanies thymic neoplasia.⁴¹ Such immune dysfunction could theoretically lead to a breakdown in immune surveillance allowing uncontrolled proliferation of neoplasms, which would otherwise be kept in check. Skinnider et al.³⁶ have suggested that decreased natural killer cell function resulting from increased suppressor T-cell activity could be causally linked to the increased incidence of cancer in patients with thymoma. Freidman et al.³⁹ proposed that the thymoma epithelium may continuously stimulate T-lymphocytes, which in turn predisposes to neoplasia. While this may account for cases of hematologic malignancies, it does not adequately explain the various solid tumors encountered, nor does it explain the tumors observed before or synchronously with the thymoma.

Although cytogenetic abnormalities have been reported in thymoma,^44,45 presently no molecular or cytogenetic mechanisms adequately explain the tendency of thymoma patients to acquire additional neoplasms. Interestingly, patients with Hodgkin’s disease also have a high incidence of second malignancies.^25,27 While it is assumed that this high incidence of additional malignancies is due to radiation or chemotherapy, baseline cytogenetic studies of patients with Hodgkin’s disease before treatment have identified abnormalities in sister chromatid exchange as an independent risk factor for second primary cancers.³⁰ Occasionally, Hodgkin’s disease occurs synchronously with other neoplasms, suggesting that like thymoma, some of these patients have an intrinsic predisposition towards additional cancers.⁴² Curiously, as this case, a patient with Hodgkin’s disease as one of 5 distinct malignant neoplasms has been reported,¹³ as has a patient with gliosarcoma developing after Hodgkin’s disease.⁴³

The presence of 5 or more distinct metachronous primary neoplasms in a single patient is a very rare event. The detection of 5 or more primary neoplasms simultaneously in a single patient is extraordinary. There is now convincing evidence of a syndrome associating thymoma with additional cancers. Most cases of second malignancies appear metachronously, with an overall prevalence of 17%. Adenocarcinomas of the gastrointestinal tract appear most frequently but a wide array of different histologies has been observed. The precise pathogenic mechanism remains unclear. We suspect that the presented patient’s thymoma was related to the multiple neoplasms by either inducing a proclivity towards neoplasia or serving as a marker for an inherent propensity for neoplasia. Although medical texts routinely describe the classic associations of thymoma with myasthenia gravis, pure red cell aplasia, and hypogammaglobulinemia, there is also an important association between thymoma and malignant neoplasms. The existence of this syndrome is illustrated by this case and is supported by a review of the medical and veterinary literature. For patients with a past history of thymoma, awareness of this association should allow earlier detection and treatment of any future cancers through proper surveillance.

The authors gratefully acknowledge and appreciate the assistance of Anne Kammer of the Johns Hopkins Tumor Registry.  

1.                    Welsh JS, Wilkins KB, Green R, Bulkley G, Askin F, Diener-West M, Howard SP. Association between thymoma and second neoplasms. JAMA 2000;283:1142–1143.[Free Full Text]

2.                    Couture MM, Mountain CF. Thymoma. Semin Surg Oncol 1990;6:110–114.[ISI][Medline]

3.                    Gray GF, Gutowski WT 3rd. Thymoma. A clinicopathologic study of 54 cases. Am J Surg Pathol 1979;3:235–249.[ISI][Medline]

4.                    Lewis JE. Wick MR. Scheithauer BW. Bernatz PE. Taylor WF. Thymoma. A clinicopathologic review. Cancer 1987;60: 2727–2743.[ISI][Medline]

5.                    Pan CC, Chen PC, Wang LS, Chi KH, Chiang H. Thymoma is associated with an increased risk of second malignancy. Cancer 2001;92:2406–2411.[ISI][Medline]

6.  Souadjian JV, Silverstein MN, Titus JL. Thymoma and cancer. Cancer 1968;22:1221–1225.[ISI][Medline]

7.                    Souadjian JV, Enriquez P, Silverstein MN, Pepin JM. The spectrum of diseases associated with thymoma. Coincidence or syndrome? Arch Intern Med 1974;134:374–379.[ISI][Medline]

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Clinical Nuclear Medicine. 21(8):626-628, August 1996.
KINOSHITA, TOSHIBUMI M.D. *; ISHII, KIYOSHI M.D. *; MORI, YOUKO M.D. +; NAGANUMA, HIROSHI M.D. ++

Abstract:
A case of Castleman disease in the anterior cervical region is presented. Ga-67 scintigraphy revealed moderate uptake in the thyroid region. Thyroid scintigraphy demonstrated the presence of an extrinsic thyroid tumor. Contrast-enhanced CT showed dense homogeneous enhancement within the tumor. Radionuclide tracer accumulation on gallium scintigraphy as well as dense contrast enhancement on CT scan may be characteristic of Castleman disease. Castleman disease should be considered in the differential diagnosis when increased tracer activity is noted in an anterior cervical extrathyroid tumor on Ga-67 scintigraphy.

(C) Lippincott-Raven Publishers

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Hospital de Clinicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos 2350/7, Porto Alegre, CP 90.030-003, Brazil

The use of highly active antiretroviral therapy (HAART) was associated with a dramatic improvement in the outcome of patients with human immunodeficiency virus (HIV) infection [1, 2]. In this report, we would like to describe the case of a patient with AIDS-related multicentric Castleman’s disease who has also enjoyed a long-lasting complete clinical and pathological remission following the use of HAART alone.

Castleman’s disease belongs to the group of atypical lymphoid proliferations, which are usually confused with the diagnosis of malignant lymphoma. First described in 1956, the typical patient presents with either localized mediastinal lymphadenopathy or a more aggressive form of the disease characterized by diffuse lymphadenopathy and systemic symptoms [3]. The differential diagnosis of Castleman’s disease should include malignant lymphoma, as well as other causes of lymphoma-like syndromes, such as adverse reactions to drugs, autoimmune disorders and viral or bacterial infections.

Until recently, Castleman’s disease was not considered an AIDS-related event, being managed with local surgery, irradiation and cortisteroids. Cytotoxic therapy was reserved only for highly symptomatic patients with refractory disease. Over the past years, however, a newly described AIDS-related multicentric form of Castleman’s disease (MCD) has been recognized. In this aggressive form of the disease, patients develop progressive lymphadenopathy, B symptoms and usually a fatal course [4].

Our patient was a 46 year-old HIV-positive black man who presented with dyspnea, cough, hemoptysis and severe weight loss. He had fever, bibasilar rales and widespread lymphadenopathy. The blood tests were normal, except for a hemoglobin level of 10.7 g/dl. The chest X-ray showed bilateral reticulonodular infiltrates and the computed tomography (CT) scan revealed multiple mediastinal lymph nodes (Figure 1a). The CD4 count was 54 cells/mm³ and the CD4/CD8 ratio was 0.06. A supraclavicular and submandibular lymph node biopsy confirmed MCD. The additional medical work-up ruled out malignant lymphoma, catch-scratch fever, autoimmune or infectious diseases.

Due to the aggressiveness of the disease, combination chemotherapy was offered to the patient, which he refused due to fear of infectious complications. HAART (lamivudine/zidovudine plus indinavir/ritonavir) alone was started and, surprisingly, the patient showed a rapid clinical improvement, with the disappearance of B symptoms within days. By the end of an 18-month follow-up period, the CT scan showed a complete disappearance of the mediastinal lymph nodes (Figure 1b) and a new lymph node biopsy revealed only reactive changes. The CD4 count was 135 cells/mm³ and the viral load was less than 50 copies/ml. The patient remains completely asymptomatic with no evidence of Castleman’s disease following a 24 month follow-up period on HAART alone.

Our report comes as the first in which a complete histologically-proven response for a prolonged period of follow-up is clearly documented in AIDS-related MCD with the use of HAART alone. There are other reports on the clinical outcome of AIDS-related MCD, using a variety of combined therapeutic approaches including antiviral drugs, interferon-, anti-interleukin-6 and chemotherapeutic agents along with HAART. In general, tumor responses are partial and short-lasting, sometimes at the cost of significant clinical toxicity [5–8]. It should be noted that our patient did not develop a clear neoplastic transformation of the disease into a malignant lymphoma after such a long-term follow-up period. Considering the poor treatment results and high risk of infectious complications following cytotoxic therapy in the AIDS population, we postulate that patients with AIDS-related MCD should be first managed with HAART, leaving more aggressive therapeutic approaches for patients at relapse.

REFERENCES

1. Palella FJ Jr, Delaney KM, Moorman AC et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–860.[Abstract/Free Full Text]

2. Miller V, Staszewski S, Nisius G et al. Risk of new AIDS diseases in people on triple therapy. Lancet 1999; 353: 463–464.[ISI][Medline]

3. Castleman B, Iverson L, Menendez VP. Localized mediastinal lymph-node hyperplasia resembling thymoma. Cancer 1956; 9: 822–830.[CrossRef][ISI][Medline]

4. Oksenhendler E, Duarte M, Soulier J et al. Multicentric Castleman’s disease in HIV infection: a clinical and pathological study of 20 patients. AIDS 1996; 10: 61–67.[ISI][Medline]

5. Lanzafame M, Carretta G, Trevenzoli M et al. Successful treatment of Castleman’s disease with HAART in two HIV-infected patients. J Infect Dis 2000; 40: 90–91.

6. Revuelta MP, Nord JA. Successful treatment of multicentric Castleman’s disease in a patient with human immunodeficiency virus. Clin Infect Dis 1998; 26: 527.[Medline]

7. Scott D, Cabral L, Harrington WJ Jr. Treatment of HIV-associated multicentric Castleman’s disease with oral etoposide. Am J Hematol 2001; 66: 148–150.[Medline]

8. Dupin N, Krivine A, Calvez V et al. No effect of protease inhibitor on clinical and virological evolution of Castleman’s disease in an HIV-1 infected patient. AIDS 1997; 11: 1400–1401.[Medline]

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¹ Department of Radiology, Changi General Hospital, 2 Simei Street 3, Singapore 529889, ² Department of Otolaryngology, Singapore General Hospital, Departments of ³ Diagnostic Imaging, ⁴ Otolaryngology and ⁵ Pathology, KK Women’s and Children’s Hospital, Singapore

Castleman’s disease of the neck is an uncommon benign lymphoproliferative disease that usually presents as homogeneously enhancing enlarged lymph nodes on contrast-enhanced CT scan. We described the appearance of four confirmed cases of Castleman’s disease of the neck on contrast-enhanced CT scan. Three of these presented as a solitary enhancing lymph node and the fourth case presented with multiple bilateral enhancing lymph nodes. A central non-enhancing area was present in two of the three cases that presented as a solitary node. Pathological correlation of one of these cases showed that this was due to a central fibrotic scar. One of the enhancing nodes in the fourth case with multiple and bilateral lympadenopathy also contained a central non-enhancing area. We would like to propose that if a central non-enhancing scar is observed in an enhancing lymph node in the neck on CT scan, Castleman’s disease should be considered as a possible diagnosis.

Castleman’s disease is an uncommon benign lymphoproliferative disorder that is characterized by hypervascular lymphoid hyperplasia [1, 2]. When this condition affects the neck, it usually presents as a solitary neck mass. There are several previous publications on the imaging features of Castleman’s disease of the neck and most of these are single-case reports [1–5]. We would like to describe the appearance of four confirmed cases of Castleman’s disease of the neck on post-contrast CT scan, and to suggest that a central non-enhancing scar, if present, is a useful diagnostic clue of the disease.

Four patients underwent CT scan of the neck as their first line investigation, after presenting with a neck mass. The scan parameters were: 5 mm slice thickness, angle of scan parallel to the hyoid bone, scanning from the level of the external auditory canal to the root of the neck, 20 cm field of view, 135 Kv, 200 mAs and 512 x 512 matrix. All the patients, except in case 2, were given an intravenous bolus dose of 75 ml of non-ionic iodinated contrast agent. The patient in case 2 was given a bolus dose of 50 ml. Scanning for all cases started at 60 s from the onset of contrast injection.

A 33-year-old man presented with a painless, non-tender, mobile, level II lymph node of 1 year’s duration. Endoscopy of the upper aerodigestive tract was normal. CT scan showed an enhancing (136 Hounsfield units) level II lymph node measuring 4.5 cm in the longest diameter on the left side of the neck. A low-attenuation crescentic band was observed in the centre of the mass (Figure 1). The mass was excised and histopathological evaluation revealed Castleman’s disease of the hyaline vascular type

Case 2
A 12-year-old boy presented with a 4 cm non-tender, mobile level III neck lymph node on the left side for a duration of 3 months. Nasopharyngoscopy showed a normal upper aerodigestive tract. CT scan showed a left-sided 4 cm ovoid enhancing (140 Hounsfield units) lymph node at level III. A low-attenuation stellate band was observed in the centre of the mass (Figure 2a). Histology revealed Castleman’s disease of the hyaline vascular type. The gross specimen contained a dense fibrous stroma in a stellate pattern, forming a scar in the centre of the mass (Figure 2b). This correlated very well with the low-attenuation stellate band seen on the CT scan.

Castleman’s disease is an uncommon lymphoproliferative disorder with a characteristic hypervascular lymphoid hyperplasia [1, 2]. First described by Castleman and associates in 1956 [6], it has since come with many synonyms. These include angiofollicular mediastinal lymph node hyperplasia, angiomatous lymphoid hamartoma, lymph nodal hamartoma, follicular lymphoreticuloma and benign giant lymphoma [7]. The many synonyms reflect the uncertainty over its pathogenesis, although most authors would regard Castleman’s disease as a hamartoma or an inflammatory/infective lesion [2, 8].

Histologically, the disease can be divided into two types; the hyaline vascular type and the plasma cell type. The hyaline vascular type makes up about 90% of the cases [1]. Microscopically, the hyaline vascular type is characterized by abnormal small follicles and interfollicular vascularity; consisting of a network of small capillaries with thickened, hyalinized walls radially penetrating the germinal centres from the perifollicular tissue. Follicles characterized by concentric layering of lymphocytes within germinal centres can also be seen. Large fibrotic masses surrounding vessels are often found scattered in the interfollicular areas [7]. The plasma cell type makes up about 10% of the cases [1]. It is characterized microscopically by solid sheets of plasma cells in the interfollicular area. The follicles are usually larger and the prominent interfollicular capillary network characteristic of the hyaline vascular type is usually lacking in the plasma cell type [7].

More than 50% of patients with plasma cell type of Castleman’s disease have systemic manifestations including fever, fatigue, anaemia, hyperglobulinaemia and elevated sedimentation rate. Our patient in case 4 though, did not have any constitutional symptoms. Only about 3% of patients with hyaline vascular type of Castleman’s disease exhibit these features [8]. Most patients with hyaline vascular type of disease are asymptomatic, although they can present with compressive symptoms caused by the mass lesion [1]. Castleman’s disease has no sex predilection and the age of presentation ranged from 8 years to 70 years, although the youngest patient reported was diagnosed at 6 weeks after birth [8].

Surgical excision is the treatment of choice for Castleman’s disease of the neck. There is no reported recurrence for the hyaline vascular type. However, plasma cell type requires closer follow-up after the surgical excision and systemic chemotherapy may be required [8].

Castleman’s disease is usually limited to one site, although a widespread and aggressive form involving lymphadenopathy in several sites with splenomegaly has also been described [9]. The most common site of the localized form is the mediastinum (about 70% of cases). The neck is the next most common [1, 4]. Most of the previously reported cases of Castleman’s disease of the neck were of the hyaline vascular type and these usually present as a solitary mass lesion both on clinical examination and on imaging [1–5, 8]. This was also the observation in our cases, as the patients in case 1 to 3 all presented with solitary neck masses on imaging and were all of the hyaline vascular type. The exception was in case 4 where the patient presented with multiple bilateral lymphadenopathy and the histology was of the plasma cell type. It may be that plasma cell type of Castleman’s disease of the neck has a greater tendency to present as multiple rather than solitary neck masses, although a further study with a larger number of cases would be needed before this impression could be confirmed.

Castleman’s disease of the neck on CT scan has been described as well-circumscribed homogeneous mass lesion with moderate to intense enhancement [1, 3–5, 8]; with the hyaline vascular type having a tendency to enhance more than the plasma cell type, due to the greater vascularity of the former [2, 10]. One case of Castleman’s disease of the neck presenting with ring-enhancement on CT scan has also been described [2]. Unlike pelvic disease where calcification can occur in up to 50% of the cases [10, 11], calcification in the neck disease is uncommon. On MRI of Castleman’s disease of the neck, some authors have described the presence of linear hypointense signals in a stellate or arborizing pattern especially on the T₂ weighted sequences [1, 4, 12]. They attributed these hypointense signals to perivascular lamellar fibrosis or sinus histiocytes and radial fibrosis; and suggested that these hypointense signals could be an important diagnostic clue of Castleman’s disease [1, 4, 12]. In contrast, the appearance of Castleman’s disease of the neck on CT scan has often been described as non-diagnostic [4, 8]. This is because other disease conditions like lymphoma, tuberculosis, metastatic papillary thyroid carcinoma, Kaposi’s sarcoma and Kimura’s disease can also present with enhancing lymph nodes in the neck [13]. Ota and co-authors reported on a case of hyaline vascular Castleman’s disease of the abdomen which had a central stellate fibrotic area within the mass on CT scan [14]. Similar changes have not described before in previous reports of CT appearance of Castleman’s disease of the neck. Crescentic, stellate and rounded areas of non-enhancement were observed in three of our four patients (cases 1, 2 and 4, respectively). Correlation with the gross specimen in case 2 showed that dense fibrous stroma forming a scar was responsible for the appearance, similar to what was reported in Ota’s paper. Although no correlation was made with the gross specimen in cases 1 and 4, we believe that dense fibrous scar could also be responsible for the crescentic and rounded areas of non-enhancement in these two cases, respectively. The absence of a central non-enhancing area in the intraparotid mass of case 3 could possibly be due to an absence of a dense concentration of fibrous tissue. We would therefore like to propose that the presence of a central non-enhancing scar in an enhancing lymph node in the neck on contrast-enhanced CT scan could be an important diagnostic clue of Castleman’s disease.

Received for publication August 20, 2002. Revision received May 9, 2003. Accepted for publication June 23, 2003.

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When her son was born, on Jan. 15, 1996, at 8 pounds, 5 ounces, she knew exactly what she was going to name him: Omoiyanu Ishmael. “It means ‘the miracle child that God hears,’ ” said Ms. Hawkins, sitting up in a hospital bed and inhaling oxygen from a tank in her mother’s co-op apartment in Fort Greene, Brooklyn.

A few minutes later, her 10-year-old miracle, known as Yani, arrived home from Public School 20, the Clinton Hill School. He made a beeline for his mother, embraced her warmly and said with pride, “I got 90 on a test today.”

Ms. Hawkins beamed. “He is my little leader in training,” she said. “He is the smartest.”

Next year, she hopes he will attend Philippa Schuyler Middle School in Brooklyn, a school for the gifted and talented.

The two have lived with Ms. Hawkins’s mother, Lucille Hawkins, 61, in her complex since an electrical fire damaged their apartment on Pacific Street in Brooklyn in August 2005. The co-op has three bedrooms. Also living there is Mrs. Hawkins’s other daughter, Christianna Melissa, 19, whom she adopted at 3 years old.

Mrs. Hawkins, a retired events coordinator for a bank, was also a foster mother for 20 years and adopted a son named Omar, who died of brain cancer when he was 12.

“He died three days before my 30th birthday,” said Ms. Hawkins.

Her eyes welled up, and she wiped away the tears. She said that watching him die — and hoping to be around for her son — has made her fight that much harder to live.

Ms. Hawkins recalled when she first started chemotherapy. “That was the first time I lost my hair,” she said, rolling her eyes and laughing. “I was devastated, oh please. I was bald.”

To be fashionable, she wore fabulous wigs, Ms. Hawkins said. “My mother, she made it funny. She made it not as bad as it could be.”

Ms. Hawkins’s cancer went into remission for most of her 20s, but then returned. She has become weaker and can no longer handle chemotherapy. With care from her mother, her son and two nurses, she takes eight medications a day. She has been using the oxygen since she moved in with her mother after the fire, she said.

“That’s when I started to wear this thing all the time,” she said, lifting a tube going to her nose. “My carbon levels are increasing; my oxygen will decrease if I don’t have this.”

Sitting up in the hospital bed, she pushed a pillow under her right side to cushion an inoperable fluid mass that has grown to the size of a grapefruit. She tires quickly and rarely walks. When she goes out, she uses an old, heavy electric wheelchair.

While the nurses tend to her medical needs, Mattie Williams, a home care attendant, helps with Yani’s care. Ms. Williams’s services are provided by the Brooklyn Bureau of Community Service, one of the seven charitable agencies supported by The New York Times Neediest Cases Fund.

Ms. Williams takes Yani to the park, the library and school events and helps him with his homework. “She is phenomenal,” Ms. Hawkins said.

Ms. Williams began working with the family in the fall of 2005.

Five months later, while the apartment was being fixed, Ms. Hawkins received a past-due rent notice. She owed $455. She also owed $589.06 for an electric bill. “I did not know I still had to pay” the rent for a home that was unlivable, she said.

She was told that she was still responsible for $92 a month, her portion of the subsidized rent, she said. On her income of $558 a month in public assistance, plus $200 in food stamps and $92 in public aid for Yani, she just did not have the money.

Ms. Williams approached the bureau for help, and through the Neediest Cases Fund the outstanding bills were covered. “I am so grateful,” said Ms. Hawkins, who had worked in earlier years, primarily in retail or secretarial jobs.

She is paying the $92 a month rent to remain qualified for subsidized housing. Her apartment has been largely repaired, but she wants to live in her mother’s building and is No. 135 on the waiting list.

Her mother said, “I need to have her near me.”

“But those things we go through,” said Ms. Hawkins, taking everything in stride.

“I am just grateful that God sees fit to bless me day to day,” she said. “He allowed me to have this beautiful child. And he allows me to breathe the breath of life every day. Every day that I take in one, I am glad. But for the grace of God, that could’ve been my last breath just a minute ago.”

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The multicentric form of CD is morphologically identical to the plasma cell variant. Although this type of CD is most common in individuals infected with HIV, reports of this disease have also been described in patients who have undergone renal transplantation or received immunosuppression therapy, such as cyclosporin A.8 The multicentric form is associated with HHV-8 infection. Fever, hepatosplenomegaly, peripheral lymphadenopathy, edema, and pulmonary symptoms, as well as secondary tumors related to HHV-8 infection (eg, Kaposi sarcoma, non-Hodgkin lymphoma, or plasmablastic lymphoma) are common, especially with coexisting HIV disease.2 Like the plasma cell variant, the pathogenesis of multicentric disease stems from high levels of IL-6; however, it is virally mediated.4 Human herpesvirus 8 encodes a viral IL-6 (v-IL-6), which induces endogenous human IL-6 production.4 Multicentric disease follows an aggressive course in patients with HIV and may represent a medical emergency.2 Treatment includes chemotherapy, and the HHV-8 viral load is monitored in conjunction with chemotherapy to assess the effectiveness of treatment.

The etiology of CD is unknown. It has been hypothesized that the 2 variants may represent a continuum of the same disease, that is, the plasma cell variant evolving into the hyaline-vascular variant; however, most investigators consider the 2 variants to be distinct entities.4 Interestingly, Menke et al7 found an aberrant immunophenotypical population of mantle zone B lymphocytes in all the variants of CD.

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Castleman’s disease is a rare lymphoproliferative disorder of uncertain cause characterized by a distinctive pattern of hypervascular lymphoid hyperplasia (1). Although it is usually reported as a solitary mediastinal mass, involvement of other anatomic sites has been reported, with the head and neck being the second most common area (2). We describe a case of hyaline-vascular-type Castleman’s disease located in the retropharyngeal space.

A 34-year-old woman initially presented with a 5-year history of painless swelling on the right side of her oropharynx and a 2-year history of a slightly enlarging mass on the right side of her neck. Her medical history was unremarkable.

Unenhanced CT scans showed a large, well-circumscribed, solid mass in the right retropharyngeal space, which was isodense to the muscle. The mass showed homogeneous, strong enhancement on the contrast-enhanced CT scans

One month later, MR imaging was performed. On the MR images, the mass was located within the right retropharyngeal space, displacing the parapharyngeal fat anteriorly, the pharyngeal mucosal space medially, the styloid process anterolaterally, and the carotid space laterally. It was isointense to the muscle on the T1-weighted images (Fig 1B). There was a nonenhancing linear hypointense signal in an arborizing pattern within the mass on T1- and T2-weighted images (Fig 1C and D). The mass occupied the right retropharyngeal and parapharyngeal space from below the skull base to the hyoid bone level on the contrast-enhanced T1-weighted coronal image (Fig 1E). There was a small lymph node with a 1-cm diameter in the right internal jugular chain just below the main mass.

Excision of the neck mass was performed via a transcervical approach. A 5 x 8-cm, well-encapsulated, ovoid mass was removed without much difficulty. Histopathologic evaluation revealed Castleman’s disease (giant lymph node hyperplasia) of the hyaline-vascular type (Fig 1F). The mass was thought to arise from the lateral retropharyngeal lymph node. The small lymph node just below the main mass was proved reactive hyperplasia without tumor cells.

In 1956, Castleman et al (3) described a group of patients with large thymoma-like masses in the anterior mediastinum, which they called mediastinal lymph node hyperplasia. The cause of Castleman’s disease is uncertain; it is thought to be inflammatory or hamartomatous in nature (4, 5). Two distinct histologic variants are recognized (4). The most common is the hyaline-vascular type (more than 90% of the cases), which consists of small lymphoreticular follicles distributed within a hypervascular hyalinized stroma. The plasma cell type is less common (fewer than 10% of the cases) and consists of larger lymphoreticular nodules that are separated by sheets of plasma cells and a somewhat less vascular stroma. Patients with the hyaline-vascular-type disease are usually asymptomatic, but they may complain of symptoms caused by the compression of adjacent structures or may present with a palpable mass. Systemic manifestations are commonly seen in the plasma cell type and include fever, anemia, and hyperglobulinemia.

Castleman’s disease is usually limited to one site, although an aggressive multicentric form has been described. The most common site is the mediastinum (approximately 70%). Additional sites of occurrence include the axilla, retroperitoneum, mesentery, vulva, pancreas, pelvis, and neck (1, 4). Fewer than 10% of cases arise in the head and neck (6-11). In our case, the tumor was located within the right retropharyngeal space. It was thought to arise from a retropharyngeal node, probably the lateral group, which is located at the anterolateral aspect of the prevertebral muscle, although a carotid space origin could not be completely excluded. Several cases of Castleman’s disease involving the retropharyngeal or parapharyngeal space, medial to the carotid sheath, as in our case, have been reported (7-9).

The typical CT findings of Castleman’s disease are a well-marginated, homogeneous, and densely enhancing mass (6, 7), although ring enhancement can also be seen (1, 10). The hyaline-vascular variant tends to show more prominent enhancement on CT scans, most likely because of its greater vascularity (1, 10).

Typically, Castleman’s disease appears on MR images as low-to-intermediate signals compared with muscle on T1-weighted images and high signals on T2-weighted images (7, 9). In a few previous reports (12, 13), linear, arborizing, hypointense signals within the mass have been attributed to calcification, fibrous septations, vessels, or sinus histiocytosis. The linear hypointense signals seen on MR images in our case were proved perivascular lamellar fibrosis on pathologic correlation (Fig 1G). These linear hypointense signals could be an important clue to the diagnosis of Castleman’s disease, although they occur infrequently.

The MR imaging differential diagnoses for Castleman’s disease include paraganglioma and schwannoma. Paragangliomas in this area usually displace the internal carotid artery anteriorly because the tumor arises around the vagus nerve. Furthermore, paragangliomas have multiple focal and serpentine areas of low signal intensity, representing vascular flow voids within the mass, especially in large lesions. Schwannomas that arise from the vagus nerve and the sympathetic chain usually displace the internal carotid artery anteriorly because these nerves are posterior to this vessel. Frequently, schwannomas have inhomogeneous signal intensity due to cystic change. These features could be the clue to the differential diagnosis, with Castleman’s disease in the retropharyngeal or parapharyngeal space.

Complete surgical excision is the treatment of choice for Castleman’s disease in the head and neck, with a 100% control rate for the hyaline-vascular type. The plasma cell type, however, requires excision with close follow-up and possible systemic chemotherapy (14). Malignant transformation or association with other malignancies is rare and includes plasmacytoma, malignant lymphoma, and Kaposi’s sarcoma (15). Its malignant potential, although rare, raises suggestions of a relationship with an immune dysfunction or even primary lymphoproliferative disorder (16).

Castleman’s disease is a rare mass, which may involve the retropharyngeal space. On CT scans, it appears as a well-marginated, homogeneously enhancing mass. It has an isointense signal compared with muscle on T1-weighted MR images and a hyperintense signal compared with muscle on T2-weighted MR images, with homogeneous, strong enhancement. Linear hypointense signals in an arborizing pattern may be present within the mass. Castleman’s disease should be considered in the differential diagnosis of masses involving the retropharyngeal space.

1.                    Chaloupka JC, Castillo M, Hudgins P. Castleman disease in the neck: atypical appearance on CT. AJR Am J Radiol 1990;154:1051-1052[Free Full Text]

2.                    Frizzera G. Castleman’s disease: more questions than answers. Hum Pathol 1985;16:202-205[Medline]

3.                    Castleman B, Iverson L, Menendez VP. Localized mediasinal lymph node hyperplasia resembling thymoma. Cancer 1956;9:822-830[Medline]

4.                    Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer 1972;29:670-683[Medline]

5.                    Johnson JT, Oral A, Nalesnik M, Roscoe GJ, Whiteside TL. Giant lymph node hyperplasia: clinical and immunohistologic correlation of an intermediate variant. Ear Nose Throat J 1985;64:249-254[Medline]

6.                    Koslin DB, Berland LL, Sekar BC. Cervical Castleman disease: CT study with angiographic correlation. Radiology 1986;160:213-214