Sarcomatoid carcinoma presenting as cancers of unknown primary: a clinicopathological portrait.

BACKGROUND: Sarcomatoid carcinoma of unknown primary (SCUP) is a rare entity of either poorly differentiated carcinoma with sarcoma-like differentiation or a true mixed lineage neoplasm. Limited data regarding clinicopathological profile and management exists. METHODS: We retrospectively reviewed the MD Anderson Cancer of Unknown Primary database and tumor registry to identify 48 SCUP patients between 2001 and 2017. Patient characteristics, pathology, molecular diagnostics, treatments, and outcomes were obtained. Kaplan-Meier method was used to estimate overall survival (OS) and compared using log rank test. RESULTS: Median age at diagnosis was 59 years (range 27-86). Majority of patients were female (58%) and presented with ≥3 metastatic sites (52%), commonly lymph node (50%), bone (42%), lung (27%), and liver (21%). First line treatment included chemotherapy (35%), surgery (27%), and radiation (24%). Gemcitabine and docetaxel (18%) was the most common chemotherapy regimen. Median OS for entire cohort was 11 months (95% CI: 5.6 to 16.4). Poor performance status (PS), > 1 metastatic site, elevated lactate dehydrogenase (LDH), and high neutrophil-to-lymphocyte ratio (NLR) were significantly associated with worse OS on univariate analyses. On multivariate analyses, poor PS (HR 8.7; 95%CI: 3.0-25.0; p <  0.001) and high NLR (HR 3.4; 95%CI: 1.3-8.8; p = 0.011) emerged as independent prognostic factors for OS. CONCLUSIONS: SCUP is a rare presentation with an aggressive clinical course and limited survival. Diagnosis is difficult to make and requires careful review and synthesis of histology, immunohistochemistry, and molecular diagnostics. Chemotherapy resistance remains a challenge. Early mutational profiling is warranted, and clinical trial participation should be encouraged for this subset.

[A Case of Cervical Lymph Node Metastasis from an Unknown Primary Cancer Controlled with Immunotherapy, Chemotherapy, and Surgery].

We present a case of cervical lymph node metastasis from an unknown primary cancer that was controlled with immunotherapy, chemotherapy, and surgery. The patient, a 61-year-old man, was referred to our department for treatment of a lesion in the left cervical lateral area. At the initial visit, the mass was covered by reddened skin and was elastic, hard, and immobile on palpation. The presence of a malignant disease such as malignant lymphoma or lymphadenitis because of infection by tubercle bacillus or Epstein-Barr virus was suspected on the basis of the clinical and magnetic resonance imaging findings. Biopsy and resection of the cervical mass was performed under general anesthesia. Because the pathological diagnosis during surgery indicated squamous cell carcinoma, the surgical approach was changed to neck dissection. Head, neck, and thoracic computed tomography and other examinations were performed to locate the primary cancer, but its origin remained unknown. Postoperative therapy consisted of chemotherapy and immunotherapy. The patient has been followed up for 4 years and 10 months without any evidence of recurrence.

Risk of cancer of unknown primary after hospitalization for autoimmune diseases.

Cancer of unknown primary (CUP) is a heterogeneous syndrome diagnosed at metastatic sites. The etiology is unknown but immune dysfunction may be a contributing factor. Patients with autoimmune diseases were identified from the Swedish Hospital Discharge Register and linked to the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for subsequent CUP and compared with subjects without autoimmune diseases. A total of 789,681 patients were hospitalized for any of 32 autoimmune diseases during years 1964-2012; 2,658 developed subsequent CUP, giving an overall SIR of 1.27. A total of 16 autoimmune diseases were associated with an increased risk for CUP; polymyositis/dermatomyositis showed the highest SIR of 3.51, followed by primary biliary cirrhosis (1.81) and Addison's disease (1.77). CUP risk is known to be reduced in long-time users of pain-relieving nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin. For patients with ankylosing spondylitis and with some other autoimmune diseases, with assumed chronic medication by NSAIDSs, CUP risks decreased in long-term follow-up. The overall risk of CUP was increased among patients diagnosed with autoimmune diseases, which call for clinical attention and suggest a possible role of immune dysfunction in CUP. The associations with many autoimmune diseases were weak which may imply that autoimmunity may not synergize with CUP-related immune dysfunction. However, long-term NSAID medication probably helped to curtail risks in some autoimmune diseases and CUP risks were generally higher in autoimmune diseases for which NSAIDs are not used and for these CUP appears to be a serious side effect.

Rapid development of migratory, linear, and serpiginous lesions in association with immunosuppression.

A 78-year-old Bulgarian woman presented to the National Institutes of Health (NIH) with a diagnosis of poorly differentiated metastatic carcinoma of unknown origin. The prior month she had been seen at a hospital in Bulgaria for weight loss and a right inguinal mass. NIH pathology review confirmed a poorly differentiated carcinoma with extensive necrosis suggesting squamous cell carcinoma. She was enrolled in a treatment trial at NIH with metastatic disease invading the lungs and lymph nodes (mediastinum, abdomen, and pelvis) and a chemotherapy regimen was started of gemcitabine, carboplatin, and lenalidomide with dexamethasone as an antiemetic. The patient returned on day 8, and a rash of 2 days duration was noted. Immediately before arriving at the dermatology clinic, she developed altered mental status with aphasia and was admitted for neurologic observation. The altered mental status resolved and evaluation revealed only small-vessel ischemia. The patient was also experiencing diarrhea and was found to have elevated transaminases (4- to 7-fold over normal). Chemotherapy was held because of the transaminase abnormalities and altered mental status. The following day, the patient was seen by dermatology for a progressive asymptomatic eruption.

Improved prognosis and evidence of enhanced immunogenicity in tumor and circulation of high-risk melanoma patients with unknown primary.

BACKGROUND: Melanoma of unknown primary (MUP) represents a poorly understood group of patients both clinically and immunologically. We investigated differences in prognosis and candidate immune biomarkers in patients with unknown compared with those with known primary melanoma enrolled in the E1609 adjuvant trial that tested ipilimumab at 3 and 10 mg/kg vs high-dose interferon-alfa (HDI). PATIENTS AND METHODS: MUP status was defined as initial presentation with cutaneous, nodal or distant metastasis without a known primary. Relapse-free survival (RFS) and overall survival (OS) rates were estimated by the Kaplan-Meier method. Stratified (by stage) log-rank test was used to compare RFS and OS by primary tumor status. Gene expression profiling (GEP) was performed on the tumor biopsies of a subset of patients. Similarly, peripheral blood samples were tested for candidate soluble and cellular immune biomarkers. RESULTS: MUP cases represented 12.8% of the total population (N=1699) including 11.7% on the ipilimumab arms and 14.7% on the HDI arm. Stratifying by stage, RFS (p=0.001) and overall survival (OS) (p=0.009) showed outcomes significantly better for patients with unknown primary. The primary tumor status remained prognostically significant after adjusting for treatment and stage in multivariate Cox proportional hazards models. Including only ipilimumab-treated patients, RFS (p=0.005) and OS (p=0.023) were significantly better in favor of those with unknown primary. Among patients with GEP data (n=718; 102 MUP, 616 known), GEP identified pathways and genes related to autoimmunity, inflammation, immune cell infiltration and immune activation that were significantly enriched in the MUP tumors compared with known primaries. Further investigation into infiltrating immune cell types estimated significant enrichment with CD8 +and CD4+T cells, B cells and NK cells as well as significantly higher major histocompatibility complex (MHC)-I and MHC-II scores in MUP compared with known primary. Among patients tested for circulating biomarkers (n=321; 66 unknown and 255 known), patients with MUP had significantly higher circulating levels of IL-2R (p=0.04). CONCLUSION: Patients with MUP and high-risk melanoma had significantly better prognosis and evidence of significantly enhanced immune activation within the TME and the circulation, supporting the designation of MUP as a distinct prognostic marker in patients with high-risk melanoma.

Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas.

PURPOSE: Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown. EXPERIMENTAL DESIGN: Patients with melanoma were prospectively offered tumor sequencing of 341-468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables. RESULTS: A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months. CONCLUSIONS: Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor-refractory melanoma.

Malignancy and myositis: novel autoantibodies and new insights.

PURPOSE OF REVIEW: Currently available data support the idea that inflammatory myopathies, particularly dermatomyositis, are paraneoplastic diseases. Cancer screening is usually recommended in patients with these conditions, but there is no consensus regarding how and how often screening should be performed. This review will address recent advances in our understanding of the relationship between cancer and myositis and describe new data regarding the best approach for cancer screening in myositis patients. RECENT FINDINGS: A newly described autoantibody to a 155-kDa nuclear protein, identified as transcription intermediary factor 1-gamma (TIF1-γ), has proven useful for cancer screening in patients with dermatomyositis. Occult tumor detection by PET/computed tomography (PET/CT) seems to be a good alternative to broad conventional screening. A combination of both methods, detection of autoantibodies against p155 and PET/CT study, may be the best approach to ascertain the presence of occult malignancy in patients with dermatomyositis. SUMMARY: Advances in immunology and imaging techniques are increasing the accuracy of occult malignant cancer detection in dermatomyositis patients. Nevertheless, the diagnosis of cancer in this population remains elusive in some cases. Further investigation is needed to improve our knowledge of the link between myositis and cancer.

Clinical and immune profiling for cancer of unknown primary site.

BACKGROUND: Immune checkpoint inhibitors (ICIs) confer a survival benefit in many cancer types. Given that the survival outcome for cancer of unknown primary site (CUP) remains poor, we investigated the potential of CUP for immunotherapy. METHODS: A total of 164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients) who were treated between January 2009 and March 2017 was identified from a review of medical records at Kindai University Hospital. They included 92 patients for whom pretreatment tumor tissue was available both for determination of programmed cell death-ligand 1 expression and tumor-infiltrating lymphocyte (TIL) density by immunohistochemistry (IHC) and for immune-related gene expression profiling (irGEP). The results of irGEP for CUP were compared with published data for ICI-treated solid cancers classified into progressive disease (PD) and non-PD subsets according to their best response to ICIs. RESULTS: The median overall survival of all CUP patients was 29.3 months (95% confidence interval [CI], 15.7-not reached) and 7.1 months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P = 0.002-0.067; CUP versus non-PD, P = 0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P = 0.008, false discovery rate = 0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented. CONCLUSIONS: The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.

Malignancy dominated with rheumatic manifestations: A retrospective single-center analysis.

Paraneoplastic rheumatic syndromes comprise a heterogeneous group of disorders characterized by typical rheumatic manifestations but without direct invasion by the tumor or metastases. The clinical features and malignancy-associated risk factors of 21 patients with paraneoplastic rheumatic syndromes, including 11 men and 10 women with a mean age of 56.3 ± 13.1 years, were characterized by a retrospective review. All patients were diagnosed with malignancy within 2 years of rheumatism diagnosis. Patients suffering from solid malignancies accounted for the majority (62%); hematological malignancies were observed in the remainder. Arthritis (48%), lymph node enlargement (38%), skin rash (38%), weight loss (29%), fever/chills (24%), fatigue (24%), muscle soreness (24%) and smoking history (29%) were common findings. Except for 8 patients (38%) who tested positive for anti-nuclear antibody (ANA) and 9 positive for rheumatoid factor (RF), all patients tested negative for anti-extractable nuclear antigen (ENA) antibodies. Rheumatic disorders with a typical clinical presentation in older patients and nonspecific systemic features should alert clinicians to search for an occult malignancy. Patients with rheumatic disease must be closely followed to screen for malignancies, particularly within 2 years of rheumatism diagnosis.

The role of P501S and PSA in the diagnosis of metastatic adenocarcinoma of the prostate.

BACKGROUND: Adenocarcinoma of the prostate can present as metastatic carcinoma with no known primary. Prostatic origin can be confirmed in most of these cases by immunohistochemistry for prostate-specific antigen (PSA) and prostate-specific acid phosphatase. In a small subset of high-grade prostate carcinomas, both markers are negative and therefore are not helpful for confirming prostatic origin. Recently, novel marker proteins that are preferentially expressed in prostate tissue were identified. One such marker is P501S or prostein, a 553-amino acid protein that is localized to the Golgi complex. It is expressed in both benign and neoplastic prostate tissues, but not in any other normal or malignant tissue examined to date. Owing to its apparent specificity, prostein may be a good marker to demonstrate prostatic origin in metastatic prostate cancer. DESIGN: Five-micron sections of a tissue microarray were subjected to immunohistochemistry with a monoclonal mouse anti-P501S (clone 10E3, Dako, Carpintera, CA) antibody and a monoclonal mouse anti-PSA (clone ER-PR8, Dako, Carpintera, CA) antibody. The tissue microarray contains 78 cases of metastatic prostatic adenocarcinoma, 20 cases of primary prostatic adenocarcinoma, and 20 cases of benign prostate tissue from the peripheral zone as well as samples of benign brain, pancreas, kidney, thyroid, testis, skeletal muscle, and fibroconnective tissue. RESULTS: Similar staining (intensity and extent) was identified for both markers in the majority of metastatic tumors (11 distant sites, 42 pelvic lymph nodes), in all 20 primary tumors and in all benign prostate and nonprostate tissues. The P501S stain had perinuclear cytoplasmic (Golgi) distribution even in poorly differentiated tumors and metastases. Two distant metastases were negative for PSA but retained focal weak positivity for P501S. Two other distant metastases were weakly PSA positive, but strongly P501S positive. Metastases in the pelvic lymph nodes were positive for both markers in 53 cases and 1 lymph node metastasis was strongly PSA positive but P501S negative. In summary, 67 of the 69 cases (97%) of metastatic prostate carcinomas were PSA positive, whereas 68 of the 69 cases showed at least focal weak reactivity for P501S (99%). None of the tumors were negative for both markers. CONCLUSIONS: Immunohistochemistry for P501S is a sensitive and highly specific marker for identifying prostate tissue. The large majority of metastatic prostatic adenocarcinomas are P501S positive (99%). A small subset of metastatic prostatic adenocarcinoma shows significant differences in staining intensity and extent for PSA and P501S and, therefore, combined use of these markers may result in increased sensitivity for detecting prostatic origin.

[Tumors of unknown origin: Case report].

IgG4 related disease is a recently recognized chronic fibrotic, inflammatory condition, caused by infiltrating IgG4 positive plasma cells that can cause tumor like disease in almost any organ in the body. Typical histopathology is lymphoplasmocytic infiltration of IgG4 positive cells, storiform fibrosis and obliterative phlebitis. Glucocorticoids alone or in combination with B-cell depletion with rituximab causes often good, lasting response. We present here a lady with recurrent lung infiltration that simulated pneumonia and later tumor of the lung. She was also earlier diagnosed with lump in the breast that was found to contain similar IgG4 positive plasma cells that was also demonstrated in the lung biopsy. She responded very well to rituximab given on 2 occasions. Three years after this treatment she is in total remission. Key words: IgG4 related disease, rituximab treatment, plasmacytoma of breast, tumor of lung Correspondence: Arni Jon Geirsson, arnijon@landspitali.is.

Validation of Human Papillomavirus as a Favourable Prognostic Marker and Analysis of CD8+ Tumour-infiltrating Lymphocytes and Other Biomarkers in Cancer of Unknown Primary in the Head and Neck Region.

BACKGROUND: Human papillomavirus (HPV) is a favourable prognostic factor in oropharyngeal cancer. Moreover, we and others reported that HPV-positive cancer of unknown primary in the head and neck region (HNCUP) has better outcome than HPV-negative HNCUP. However, not all studies concord. Here, our previous finding was investigated in a new cohort and additional biomarkers were analyzed. MATERIALS AND METHODS: A total of 19 HNCUPs diagnosed 2008-2013 were analyzed for HPV DNA by polymerase chain reaction assay (PCR) and p16 by immunohistochemistry (IHC). Thereafter, 69 HNCUPs diagnosed between 2000-2013 were analyzed for HPV16 mRNA by PCR (if HPV16DNA-positive) and cluster of differentiation 8 positive (CD8+) tumour-infiltrating lymphocytes (TILs) and human leukocyte antigen (HLA) class I-expression using IHC. RESULTS: HPV DNA, alone and in combination with p16 overexpression, was validated as a favourable prognostic factor in HNCUP. HPV16 mRNA was present in most HPV16 DNA-positive cases, confirming HPV-driven carcinogenesis in HNCUP. High CD8+ TIL counts indicated favourable prognosis. CONCLUSION: HPV status is useful for the management of patients with HNCUP and the role of CD8+ TILs should be further explored.

Direct evidence on the immune-mediated spontaneous regression of human cancer: an incentive for pharmaceutical companies to develop a novel anti-cancer vaccine.

To develop an effective pharmaceutical treatment for a disease, we need to fully understand the biological behavior of that disease, especially when dealing with cancer. The current available treatment for cancer may help in lessening the burden of the disease or, on certain occasions, in increasing the survival of the patient. However, a total eradication of cancer remains the researchers' hope. Some of the discoveries in the field of medicine relied on observations of natural events. Among these events is the spontaneous regression of cancer. It has been argued that such regression could be immunologically-mediated, but no direct evidence has been shown to support such an argument. We, hereby, provide compelling evidence that spontaneous cancer regression in humans is immunologically-mediated, hoping that the results from this study would stimulate the pharmaceutical industry to focus more on cancer vaccine immunotherapy. Our results showed that patients with >3 primary melanomas (very rare group among cancer patients) develop significant histopathological spontaneous regression of further melanomas that they could acquire during their life (P=0.0080) as compared to patients with single primary melanoma where the phenomenon of spontaneous regression is absent or minimal. It seems that such regression resulted from the repeated exposure to the tumor which mimics a self-immunization process. Analysis of the regressing tumors revealed heavy infiltration by T lymphocytes as compared to non-regressing tumors (P<0.0001), the predominant of which were T cytotoxic rather than T helper. Mature dendritic cells were also found in significant number (P<0.0001) in the regressing tumors as compared to the non regressing ones, which demonstrate an active involvement of the different arms of the immune system in the multiple primary melanoma patients in the process of tumor regression. Also, MHC expression was significantly higher in the regressing versus the non-regressing tumors (P <0.0001), which reflects a proper tumor antigen expression. Associated with tumor regression was also loss of the melanoma common tumor antigen Melan A/ MART-1 in the multiple primary melanoma patients as compared to the single primary ones (P=0.0041). Furthermore, loss of Melan A/ MART-1 in the regressing tumors significantly correlated with the presence of Melan A/ MART-1-specific CTLs in the peripheral blood of these patients (P=0.03), which adds to the evidence that the phenomenon of regression seen in these patients was immunologically-mediated and tumor-specific. Such correlation was also seen in another rare group of melanoma patients, namely those with occult primary melanoma. The lesson that we could learn from nature in this study is that inducing cancer regression using the different arms of the immune system is possible. Also, developing a novel cancer vaccine is not out of reach.

Paraneoplastic cerebellar degeneration. Case report and literature review.

Paraneoplastic cerebellar degeneration (PCD) presents with acute or subacute onset of ataxia, dysarthria, and intention tremor. In patients older than 50 years, acute or subacute cerebellar degeneration is paraneoplastic in origin in 50% of cases. Paraneoplastic cerebellar degeneration most often precedes a potentially curable remote malignancy. Less often, PCD occurs in a patient with a known malignancy or heralds the onset of a recurrence. The presence of specific antibodies in serum samples helps to guide identification of the occult underlying malignancy. Physicians should entertain the diagnosis of PCD when older patients present with signs of cerebellar degeneration without an obvious cause. A systematic evaluation, including the selection of appropriate imaging and laboratory studies, will often enable physicians to identify the responsible cancer. However, because PCD can precede a cancer by months to years, periodic reevaluation is needed when the cancer remains occult.

[Changes of immunologic parameters in patients with simple bone metastases treated with 89SrCl2].

OBJECTIVE: To investigate the influence of (89)SrCl(2) (strontium-89 chloride) on immune functions in patients with simple bone metastases. METHODS: Twenty-five patients diagnosed as simple bone metastases with un-detectable primary tumors were treated with (89)SrCl(2). The CD4(+), CD8(+), CD4(+)/CD8(+) lymphocyte subsets were assessed before and after (89)SrCl(2) treatment. Twenty normal individuals served as controls. RESULTS: The CD4(+), CD8(+) and CD4(+)/CD8(+) in the control group were (38.83 +/- 8.95)%, (32.19 +/- 8.51)% and 1.29 +/- 0.47, respectively. In patients, they were (31.12 +/- 8.12)%, (41.75 +/- 10.91)% and 0.84 +/- 0.22 before treatment, and (36.21 +/- 8.71)%, (35.08 +/- 10.14)% and 1.19 +/- 0.27 after treatment, respectively (P < 0.05). The patients were divided into treatment effective and non-effective groups by pain score. Before treatment, the immunologic parameters in the two groups had no significant differences (P > 0.05). After treatment, the frequencies of CD4(+) and CD8(+) subsets, CD4(+) to CD8(+) ratios and the number of metastatic foci in the effective group were (37.81 +/- 5.18)%, (33.17 +/- 6.38)%, 1.33 +/- 0.31 and 6.64 +/- 3.11, respectively, while in the treatment non-effective group, they were (32.09 +/- 5.72)%, (39.99 +/- 5.38)%, 0.82 +/- 0.22 and 9.87 +/- 3.46, respectively (P < 0.05). CONCLUSION: The immune functions in patients with simple bone metastases are inhibited. Treatment with (89)SrCl(2) may improve their immunity to certain extent. The degree of recovery in the treatment effective patients was better than that in the treatment non-effective cases.

Incidence of Malignancies in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Diagnosed Between 1991 and 2013.

OBJECTIVE: To investigate the incidence of malignancies during longitudinal followup of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), and to examine the effect of immunosuppressive therapy on malignancy risk in these patients. METHODS: The study population consisted of patients with histopathologically confirmed AAV, diagnosed between 1991 and 2013 at a large university hospital. The mean duration of followup was 10 years. Malignancy incidence was assessed using the Dutch National Pathology Database. Incidence rates from the Netherlands Cancer Registry were used to compare malignancy incidence in the AAV cohort to that in the general Dutch population. RESULTS: Thirty-six of 138 patients with AAV developed a total of 85 malignancies during a mean followup of 9.7 years. The sex-, age-, and calendar year-adjusted malignancy risk was 2.21-fold higher (95% confidence interval [95% CI] 1.64-2.92) than that in the general population. Non-melanoma skin cancers occurred most frequently (standardized incidence ratio 4.23 [95% CI 2.76-6.19]). The incidence rates of other malignancies were not significantly increased. Malignancy risk was associated with the duration of cyclophosphamide (CYC) therapy and, interestingly, was not increased in patients who had received CYC for <1 year. CONCLUSION: Patients with AAV have a higher risk of malignancy than the general population, but this risk is accounted for solely by non-melanoma skin cancers. Over the years, the risk of other malignancies-specifically bladder and hematologic malignancies-has decreased in patients with AAV. This finding reflects ongoing efforts to reduce CYC exposure by developing new treatment regimens.