Imaging characteristics of abdominal tumor in association with paraneoplastic pemphigus

ARTICLE

Auteur(s) : Qing-yu LIU^1,a liu.qingyu@163.com, Ming-chun CHEN^2,a, Xiao-hong CHEN³, Ming GAO¹, Hui-jun HU¹, Hai-gang LI⁴

¹ Department of Radiology, The Second Affiliated Hospital of Sun Yat-sen University, 107 Yan Jiang Xi Road, 510120 Guangzhou, China

² Department of Dermatology, The Second Affiliated Hospital of Sun Yat-sen University, 107 Yan Jiang Xi Road, 510120 Guangzhou, China

³ Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhong Shan Er Road, 510080 Guangzhou, China

⁴ Department of Pathology, The Second Affiliated Hospital of Sun Yat-sen University, 107 Yan Jiang Xi Road, 510120 Guangzhou, China

Reprints: Q. LIU

^a Qing-yu LIU and Ming-chun CHEN contributed equally to this work.

Paraneoplastic pemphigus (PNP), a mucocutaneous autoimmune disease, was first reported by Anhalt et al. in 1990 [1]. The main distinctive clinical and pathological manifestations of PNP include polymorphic mucocutaneous eruption, concurrent internal neoplasia, refractory to corticosteroids alone or in combination with immunosuppressive drugs, and microscopic evidence of necrosis of individual keratinocytes and vacuolar interface changes [2-4]. Its etiological factor is an autoimmune response stimulated by autoantibodies secreted from the associated tumor against epidermal antigens, and cellular cytotoxicity-mediated autoimmunity may also be involved in mucocutaneous impairment [2, 5].

The majority of PNP patients are associated with benign or malignant lymphoproliferative tumors, such as non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Castleman's diseases etc [2-4]. Early detection and removal of the associated tumor is the key to the treatment of PNP [2]. Imaging modality (CT, MR or PET/CT) is the examination of choice for tumor detection and differentiation. Imaging manifestations help radiologists and/or referring physicians in PNP understanding [6]. At present, there are few reports on imaging findings of tumor associated with PNP, especially tumor localized in the abdomen [6]. In this study, we collected the clinical data of 6 cases of PNP, and retrospectively analyzed the imaging manifestations of an abdominal tumor associated with PNP.

Materials and methods

Between January 2005 and November 2009, a total of 8 cases of PNP were treated at our hospitals. Of the 8 cases, 6 were associated with abdominal tumor. The existence of the associated abdominal tumor was found by routine ultrasonography check-up, and further confirmed by CT or PET/CT. In our study, the diagnosis of PNP was confirmed according to the diagnostic criteria described by Camisa et al. [7]. Mucocutaneous biopsy was performed in all 6 cases, and final diagnosis of the associated abdominal tumor was confirmed by postoperative pathologic examination. Informed consent was obtained from all patients.

Abdominal tumor was detected by whole-body PET/CT examination (Biograph 16HR; Siemens Medical Solutions, Erlangen, Germany) in one patient. After fasting for more than 6 hrs, patients received an intravenous administration of 7.4 MBq/kg body-weight dose of ¹⁸fluorine–deoxyglucose (¹⁸F-FDG). After resting for 45-60 min, PET/CT examination was performed to acquire PET and CT images. CT scanning parameters were as follows: 120 kV voltage, 130-270 mA current, 5.0 mm slice thickness. CT data were used for low-noise attenuation correction of PET emission data and for fusion with attenuation corrected PET images. PET images were reconstructed iteratively with an ordered subsets expectation maximization algorithm.

Abdominal tumor was detected by 64-slice multidetector CT scanners in 5 cases. CT imaging was performed using a Toshiba Aquilion 64 (Toshiba Medical systems, Tokyo, Japan) or Siemens Sensation 64 (Siemens Medical Solutions, Erlangen, Germany) multidetector CT scanner. The scan parameters were as follows: 64 × 0.5 mm or 64 × 0.6 mm beam collimation, 120 kVp, 200-350 effective mAs, 5.0 mm slice thickness reconstructions. After a precontrast scan, 80-100 mL of non-ionic iodinated contrast material (Ultravist; 300 mg I/mL, Schering, Berlin, Germany) was administered at a rate of 3.5 mL/s via the antecubital vein. Abdominal dual-phase dynamic CT scan was performed in 2 patients at 20-35 sec (hepatic arterial phase, HAP) and 65-75 sec (portal venous phase, PVP) after injection, respectively. In three patients, an abdominal dynamic CT scan was performed at 25 sec (HAP), 65 sec (PVP), 120 sec (equilibrium phase, EP), and 220 sec (delayed phase, DP) after injection, respectively.

The clinical features were retrospectively reviewed. PET/CT and CT findings of tumors were retrospectively analyzed by two experienced radiologists. Imaging findings included as follows: (1) the location, shape, size, number, margin and presence of surrounding structure compression or invasion; (2) presence of radioactive ¹⁸F-FDG uptake; (3) density characteristics of tumors on CT images. On unenhanced CT images, the density of tumor was classified as hypo-, iso-, or hyper-attenuation with respect to the adjacent muscles. The degree of enhancement was assessed subjectively and classified as follows: mild enhancement, when the density of the tumor was similar to that of adjacent muscles; moderate enhancement, when higher than muscles and lower than major arteries (abdominal aorta or iliac artery); marked enhancement, when similar to the density of major arteries (abdominal aorta or iliac artery).

Results

The associated abdominal tumors in these 6 PNP patients were all Castleman's disease, which was confirmed pathologically. All six cases of Castleman's disease were hyaline-vascular type, including one male and five females, with a median age of 29 years (16-56 years).

The initial symptoms of these six PNP patients were oral mucosa and lip erosions and/or ulcers with severe pain (figures 1A, B). Of these 6 cases, 4 cases were simultaneously associated with conjunctival congestion and erosion, and 5 with perineal mucosa swelling, erosion or ulceration (figure 1C). All these 6 patients suffered from polymorphous skin lesions. Four cases showed severe erosions on the palms and/or soles with hemorrhagic crusting appearance (figures 1A, B), a clinical feature that is unusual for pemphigus vulgaris. Mucocutaneous biopsy specimens showed vacuolar degeneration of basal cell layer. Blisters, clefting, acantholysis and necrosis of individual keratinocytes in the epidermis were seen in all six cases (figure 1D). After removal of the tumors, all 6 patients showed significant symptom improvement or resolution, and still survive free of disease.

Imaging features of 6 cases of abdominal tumors associated with PNP are listed in table 1. Out of the six cases of Castleman's disease, five were found in the retroperitoneum (including 3 cases in the left side and 2 cases in the right side) and one in the left iliac fossa. All 6 cases of Castleman's disease presented with solitary, oval and well-defined masses, without invasion of surrounding tissues. Precontrast CT scan revealed hypo-attenuation in all 6 cases of Castleman's disease, and two of them were associated with punctate or “arborizing” pattern calcification (figures 2A, 3A).

Table 1 Imaging features of 6 cases of tumor associated with PNP.

Note: RR: right retroperitoneum; LR: left retroperitoneum; LP: left pelvis; HV type: hyaline-vascular type; HAP: hepatic arterial phase; PVP: portal venous phase. EP: equilibrium phase. DP: delayed phase.

Out of the six cases of Castleman's disease, one case was located behind the head of the pancreas, and PET revealed inhomogeneous FDG uptake, with a maximum standard uptake value of 4.7 (figure 2).

Among the 5 cases receiving a dynamic enhanced CT scan, inhomogeneous marked enhancement (n = 3) or moderate enhancement (n = 2) with hypo-attenuation areas of patchy shape were presented in HAP (figures 3 and 4). Moderate enhancement (n = 2) or marked enhancement (n = 3) were noted in PVP, and intratumoral hypo-attenuation areas which pathologically proved to be abundance of fibrotic components reduced in 3 cases (figure 3). However, intratumoral hypo-attenuation areas, which proved pathologically to be cystic degeneration and necrotic changes, depicted no enhancement in another 2 cases in PVP (figure 4). Three cases presented persistent marked enhancement in EP and DP, and intratumoral fibrotic hypo-attenuation areas gradually disappeared in two cases (figure 3).

Discussion

PNP is an extremely rare mucocutaneous autoimmune disease. From 1990 to 2002, only 163 cases of PNP were reported in English documents [8]. PNP is a kind of mucocutaneous disease resulting from an intercellular adhesion disorder, mainly due to autoantibodies secreted from an associated tumor against epithelial proteins, although cell-mediated autoimmunity (for example cytotoxic T lymphocytes, natural killer cells and macrophages) may also be involved in the pathogenesis of PNP [5]. Oral lesions are typically one of the most consistent features of PNP. Exquisitely diffuse, severe and painful oral blisters, erosions or ulcerations may involve any oral mucosal surface, and may result in a hemorrhagic, crusted appearance. Furthermore, conjuctival or perineal mucosa is usually involved. Skin lesions are polymorphous and include bullae, erythematous papules or plaques. A significant interesting clinical feature of PNP is severe erosions on the palms and/or soles with hemorrhagic crusting appearance, which is unusual for pemphigus vulgaris [2, 4]. PNP should be suggested in pemphigus patients with extensive and severe oral erosions/ulcerations and bilateral conjuctival involvement, microscopic evidence of necrosis of individual keratinocytes and vacuolar interface changes, or resistance of the mucocutaneous lesions to intensive therapy [2-4]. In PNP-suspected patients, the referring physicians may play a key role in directing imaging investigation towards the existence of an underlying tumor [9, 10].

The main concurrent tumor of PNP is a lymphoproliferative neoplasm which might be malignant or benign. In Western countries, the majority of tumors associated with PNP are malignant, including non-Hodgkin lymphoma (NHL) (38.6%), chronic lymphocytic leukemia (CLL) (18.4%) [8]. However, in China, most tumors associated with PNP are benign abdominal Castleman's disease, while rarely cases of NHL and CLL [2, 9]. Zhu et al. documented a frequency of 64.7% (11/17) retroperitoneal Castleman's disease in PNP patients [2]. The prognosis for patients associated with abdominal Castleman's disease is poor when respiratory involvement is found [2, 4]. Early detection and removal of associated abdominal tumors is the key to the treatment of PNP, the mortality due to bronchiolitis obliterans can be significantly low when early resection of the Castleman's tumor is performed [2].

Castleman's disease is a very rare benign lymphoproliferative lesion. The most frequent involved site is the chest (70%), followed by the neck (14%), abdomen (12%) and axillary region (4%) [11]. However, the associated Castleman's disease in PNP patients is mainly located at the retroperitoneum or pelvic cavity [2, 9, 10], while the mediastinum is rarely involved [2, 9]. It was reported by Wang et al. [9] that 73.1% (19/26) of Castleman's disease associated with PNP is located in the retroperitoneum, while only 26.9% (7/26) is in the mediastinum.

Castleman's disease associated with PNP is all localized type, presenting a solitary mass, and most cases are hyaline-vascular type (19/24, 79.2%), while mixed-type or plasma cell type is rarely reported (5/24, 20.8%) [9]. In our study, all 6 cases of abdominal Castleman's disease associated with PNP were localized and of hyaline-vascular type.

Castleman's disease usually presents with a solitary, non-invasive mass with a round, oval or spindle shape. Various forms of calcification are one of the imaging characteristics of Castleman's disease (including punctate, radial, branch or “arborizing” pattern), with a calcification rate up to 31% [12, 13]. Calcification might result from calcium deposits in small blood vessels and their branches with hyaline degeneration and fibrosis [13]. In our study, out of the 6 cases of Castleman's disease associated with PNP, calcification was observed in two cases.

It was reported in the literature that hyaline-vascular Castleman's disease is characterized by marked enhancement in HAP with the enhancement mode similar to that of large arteries, and persistent enhancement in DP [13]. Most of Castleman's disease associated with PNP showed similar enhancement patterns in our study, moderate or marked enhancement in HAP with persistent enhancement in EP and DP. These characteristic enhancement patterns indicate the rich blood supply of tumors and the slow clearance of contrast agents, and are closely related with the abundance of capillary proliferation, angiotelectasis and a rich feeding artery [13]. A similar enhancement pattern on dynamic MRI scan was reported by Irsutti et al. [6] in one case of Castleman's disease associated with PNP in 1999.

Enhancement uniformity of Castleman's disease depends on the size of tumors, and tumors usually present homogeneous enhancement if the tumor diameter < 5.0 cm, while hypo-attenuation areas of patchy shape on CT image are seen due to abundant fibrous tissues, if the tumor diameter > 5.0 cm [12, 13]. In all 5 cases of Castleman's disease performed with CT scan in our study, the tumor diameter was above 5.0 cm. All five cases showed hypo-attenuation areas in HAP, and three cases were due to the existence of a fibrous tissue-rich area while two cases were due to necrotic and cystic degeneration. Intra-tumoral fibrous tissue-rich areas were reduced in PVP and gradually disappeared in EP and DP, this enhancement pattern is one of the characteristic imaging features of Castleman's disease [12, 13].

Absence of necrosis or cystic degeneration is another feature of Castleman's disease, which might be attributed to a rich blood supply, good collateral circulation, as well as the low susceptibility of lymphoid follicles to necrosis [13]. However, larger tumors might result in necrosis and cystic degeneration. In our study, necrosis and cystic degenerations were observed in two cases (with a size of 7.8 cm and 8.5 cm, respectively).

Although Castleman's disease is benign, different levels of radioactive FDG uptake can be observed in PET/CT, and even a maximum standard uptake value up to 6.2 has been reported [14, 15], indicating that Castleman's disease may be hypermetabolic [16]. In our study, an ¹⁸F-FDG uptake up to 4.7 was found in one case of Castleman's disease associated with PNP. Although PET/CT can be used in the evaluation of metabolic activity in Castleman's disease, the value of PET/CT in the qualitative diagnosis of Castleman's disease should be further studied.

Because of a higher incidence of lymphoma associated with PNP in western countries, abdominal Castleman's disease associated with PNP should be differentiated from lymphoma in the abdomen. Treatment strategies and responses between lymphoma and Castleman's disease associated with PNP are significantly different. For abdominal Castleman's disease, surgical excision plays important role in the treatment of PNP, and may result in resolution of PNP, mucocutaneous lesions obviously alleviate or even disappear [4, 9], while for lymphoma, treatment includes chemotherapy or radiotherapy, and symptoms generally do not resolve, despite the apparent control or cure of the malignant process [4, 17]. Lymphoma mainly presents multiple lymphadenopathy with confluence, and without marked enhancement in HAP, persistent enhancement in DP or calcification, which is significantly different from Castleman's disease. In addition, retroperitoneal sarcoma should also be differentiated from Castleman's disease because retroperitoneal sarcoma may also be associated with PNP [18, 19].

Conlusion

In summary, PNP is a relatively rare, special type of pemphigus with distinctive clinical and pathological manifestations. Most of the associated abdominal tumors of PNP are Castleman's disease. For suspected cases of PNP, careful and comprehensive examination should be performed to detect the existence of an abdominal tumor. Imaging examination plays an important role in the detection and qualitative diagnosis of Castleman's disease.

Disclosure

Financial support: none. Conflict of interest: none.

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