CASE IN POINT

SQUAMOUS CELL CARCINOMA OF THE ANUS IN A PATIENT WITH CHRONIC LYMPHOCYTIC LEUKEMIA

Wen S. Lai, MD and Jonathan E. Dowell, MD

Many studies suggest a link between this type of leukemia and the development of additional primary , but an association with anal has been largely overlooked.

he idea that patients with pletely understood, it’s believed for three years and had become leukemia may be pre- that inherent constant over the past two months. disposed to developing in CLL may play a key role. Here, His medical history was notable T additional primary malig- we present the first detailed case only for low risk, Rai stage 0 CLL nancies was first suggested in 1878, report of a patient with CLL who that had been found incidentally at when Whipman reported a case of developed squamous cell carci- another hospital seven years earlier in a patient with noma of the anus. This case sug- and had never required treatment. underlying leukemia.1 Since then, gests that the risk of anal cancer, as On , the pa- numerous publications have sup- with other types of malignancies, tient had no palpable lymphade- ported the association between may be increased in patients with nopathy and no evidence of liver or leukemia and other malignancies, CLL and further implicates abnor- spleen enlargement. Digital rectal particularly in patients with mal immune function as the proba- examination revealed a firm mass chronic lymphocytic leukemia (CLL). ble cause of the propensity toward along the left wall of the anal canal Although the pathogenetic additional malignancies associated approximately 3 to 4 cm from the mechanism for this link is not com- with a CLL diagnosis. anal verge. A complete blood count revealed an elevated white blood INITIAL EXAM cell count of 76 x 103/µL (normal, 4 Dr. Lai is a staff in the general internal A 77-year-old man presented to the to 11 x 103/µL), a low hemoglobin medicine department and Dr. Dowell is the chief of the hematology and department, both at Dallas VA Medical Center, Dallas, level of 10.6 g/dL (normal, 13 to the Dallas VA Medical Center, Dallas, TX. In addi- TX reporting rectal pain during 17.3 g/dL), and a normal platelet tion, Dr. Lai and Dr. Dowell are both assistant pro- defecation and streaks of bright red count of 2.3 x 105/µL. A white blood fessors in the internal medicine department at the University of Texas Southwestern Medical Center at blood on the stool. These symp- cell differential showed 99% Dallas. toms had occurred intermittently lymphocytes and 1% neutrophils

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(normal, 37% to 80% neutrophils Given that CLL is relatively com- nosis, could result in an increased and 20% to 45% lymphocytes). mon and typically affects elders, it detection of additional malignan- Peripheral blood immunopheno- might seem reasonable to dismiss cies. If this were the case, however, typing demonstrated a distinct pop- an association between CLL and one would expect that most of the ulation of lymphocytes comprising additional primary as co- second malignancies would be dis- approximately 95% of the sample incidental. Yet convincing epide- covered around the time of CLL di- cells. Consistent with a diagnosis of miologic data link CLL with agnosis. Yet both SEER reviews B cell CLL, these cells expressed subsequent malignancies. Two found that the heightened cancer CD5, CD19, CD20, and CD23 glyco- large reviews of the National risk was constant across all time in- proteins and failed to express CD10. Cancer Institute’s Surveillance, tervals after CLL was diagnosed,3,4 Colonoscopy confirmed the , and End Results suggesting that ascertainment bias presence of a 3-cm fungating mass (SEER) database found an elevated is not a significant contributor to along the left wall of the anal ca- risk of second cancers—specifi- this phenomenon. nal. revealed squamous cally, lung cancer, malignant A second possibility is that a cell carcinoma. A computed tomog- , brain tumors, soft tis- common genetic or environmental raphy scan of the abdomen and sue , and Hodgkin’s dis- factor predisposes patients to both pelvis showed no pathologically ease—in patients with CLL.3,4 In CLL and the additional . enlarged lymphadenopathy or addition, a number of reports sug- After review of the SEER data on other evidence of metastatic gest that associated with CLL, disease. of the skin, which is not included in however, Greene and colleagues the SEER database, also occurs found no elevated risk of any type TREATMENT COURSE more frequently when CLL is pres- of leukemia following the diagnosis The patient’s anal mass was treated ent.4–10 Case reports of gastric of these tumors.3 The association, with concurrent cancer,11 Merkel cell tumor,12 ade- therefore, appears to be one-way, (cisplatin and 5-flurouracil) and ra- nocarcinoma of the ,13 which argues against a common diation therapy, which resulted in a and small-cell carcinoma of the etiology for both tumors. Greene complete tumor response. Three colon14 also have been published. and colleagues also point out that months after the completion of Ours is the first detailed case re- their finding suggests that a CLL- therapy, he remained disease free. port of a patient with CLL who de- associated “susceptibility state” veloped squamous cell carcinoma may result in the development of ABOUT THE CONDITION of the anus. Two earlier series, pub- additional primary malignancies. CLL—which is characterized by lished in 1965 and 1987, each re- The susceptibility state that has the clonal proliferation and accu- ported on a patient with CLL and been implicated most often for the mulation of neoplastic B lympho- anal cancer but did not provide increased risk of second cancers cytes in the blood, bone marrow, specifics of the cases (including associated with CLL is abnormal lymph nodes, and spleen—is ).7,10 Anal carcinoma is immune function. It’s possible that the most frequently diagnosed quite uncommon, representing only drugs used to treat CLL might play leukemia in Western countries. 0.003% of all cancer diagnoses.15 a role in this, but the data at pres- Classically, it is diagnosed in pa- Given this extremely low inci- ent are uncertain. In a 1990 report, tients in their sixties and has a male dence, it’s not surprising that the the French Cooperative Group on predominance. Due to the in- SEER reviews did not detect an in- Chronic Lymphocytic Leukemia creased frequency of blood count creased risk of anal cancer in pa- demonstrated a higher incidence of orders in recent years, approxi- tients with CLL. epithelial cancer among patients mately 60% of CLL diagnoses today What’s behind this increased with early stage, low risk CLL who are made when patients are asymp- risk of malignant disease in pa- were randomly assigned to receive tomatic. Prognosis for patients di- tients with CLL? Several hypothe- indefinite treatment with chloram- agnosed with CLL is variable, with ses have been proposed. First, it’s bucil 0.1 mg/kg/day (33 of 303 pa- some having a normal life span, been suggested that ascertainment tients, or 11%) than among those while others die within five years bias, as a result of the medical at- who were randomly assigned to of diagnosis.2 tention that comes with CLL diag- receive no treatment (19 of 309

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patients, or 6%).16 The authors, recurrent bacterial and atypical It’s at least plausible that similar however, did not define the statisti- and autoimmune phe- immunologic incompetence, as a cal significance of this finding. nomena.2 consequence of CLL, led to the de- Anecdotally, neither our patient Furthermore, the pattern of sec- velopment of anal cancer in our nor many of those with second ma- ond primary cancers observed in patient. One fact that argues lignancies reported in other small CLL is similar to that seen in pa- against our supposition, is the lack series ever had received treatment tients receiving chronic immuno- of a clear link between CLL and for their CLL. Furthermore, neither suppressive therapy following , which has a similar of the two large SEER reviews renal transplantation. Specifically, pathogenesis to anal cancer.3,4 demonstrated a clear association the frequencies of lung cancer, Even so, it seems reasonable, over- between CLL treatment and the malignant melanoma, and squa- all, to conclude that patients with risk of a second malignancy.3,4 But mous cell carcinoma of the skin are CLL may be at increased risk for virtually all of the data for these re- increased in both populations.19,20 anal cancer. ● views were accumulated before the In addition, it has been observed nucleoside analogues were com- that squamous cell carcinomas of The opinions expressed herein are monly employed in CLL, and these the skin far outnumber basal cell those of the authors and do not drugs are well known to possess carcinomas in patients with necessarily reflect those of Federal immunosuppressive effects. In fact, CLL and in those who’ve under- Practitioner, Quadrant HealthCom a case report published in 1997 gone renal transplantation—but Inc., the U.S. government, or any of its agencies. This article may discuss unlabeled or investiga- tional use of certain drugs. Please Until more definitive data become available, review complete prescribing infor- mation for specific drugs or drug we cannot assume that CLL treatment plays combinations—including indica- tions, contraindications, warn- more than a modest role in the increased risk ings, and adverse effects—before administering pharmacologic of second cancers. therapy to patients. showed remarkable progression of not in immunocompetent patients.10 REFERENCES 1. Whipham T. Splenic leukemia with carcinoma. squamous cell carcinoma of the These observations provide at least Trans Pathol Soc London. 1878;29:313–319. scalp following the institution of suggestive evidence that a similar 2. Rozman C, Montserrat E. Chronic lymphocytic leukemia [published correction appears in N fludarabine in a patient with long- perturbation in immune function is Eng J Med. 1995;333:1515]. N Eng J Med. standing CLL.17 Nevertheless, until responsible for the increased inci- 1995;333:1052−1057. 3. Greene MH, Hoover RN, Fraumeni JF Jr. Subse- more definitive data become avail- dence of second cancers seen in quent cancer in patients with chronic lympho- able, we cannot assume that CLL both of these patient groups. cytic leukemia—A possible immunologic mechanism. J Natl Cancer Inst. 1978;61: treatment plays more than a mod- It’s interesting to note that 337–340. est role in the increased risk of sec- chronic immunosuppression is a 4. Travis LB, Curtis RE, Hankey BF, Fraumeni JF Jr. Second cancers in patients with chronic lym- ond cancers. known for the develop- phocytic leukemia. J Natl Cancer Inst. 1992; The immunosuppression of CLL ment of squamous cell carcinoma 84:1422–1427. 21 5. Levi F, Randimbison L, Te VC, La Vecchia C. itself has been well described. The of the anus. Patients receiving im- Non-Hodgkin’s , chronic lymphocytic disease is characterized by im- munosuppression following renal leukaemias and skin cancers. Br J Cancer. 1996;74:1847–1850. paired B and T cell function, with transplantation have a significantly 6. Beresford OD. Chronic lymphatic leukaemia as- resultant hypogammaglobulinemia increased incidence of squamous sociated with malignant disease. Br J Cancer. 1952;6:339–344. and reduced spontaneous and an- cell carcinomas of the anogenital 7. Gunz FW, Angus HB. Leukemia and cancer in tibody-dependent cellular cyto- region.22,23 The risk is especially the same patient. Cancer. 1965;18:145–152. 18 8. Berg JW. The incidence of multiple primary can- toxicity. The clinical course of high in those with persistent hu- cers. I. Development of further cancers in pa- CLL frequently is complicated by man papillomavirus .23 tients with lymphomas, leukemias, and

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JANUARY 2005 • FEDERAL PRACTITIONER • 61 BLAST INJURIES

• Design and implement elec- necessarily reflect those of the site. December 30, 2003. Available at: www. emedicine.com/emerg/topic63.htm. Accessed tronic coding strategies to allow sponsors, Federal Practitioner, December 14, 2004. the VHA to identify blast in- Quadrant HealthCom Inc., the 8. Scott BA, Fletcher JR, Pulliam MW, Harris RD. The Beirut terrorist bombing. Neurosurgery. juries and track patients, health U.S. government, or any of its 1986;18:107–110. care utilization, and costs over agencies. Please review complete 9. Mellor SG, Cooper GJ. Analysis of 828 service- men killed or injured by explosion in Northern time. prescribing information for spe- Ireland 1970–84: The Hostile Action Casualty • Initiate a research agenda to cific drugs or drug combina- System. Br J Surg. 1989;76:1006–1010. 10. Peleg K, Aharonson-Daniel L, Michael M, enhance understanding of the tions—including indications, Shapira SC, and the Israel Trauma Group. Pat- effects of and efficacious treat- contraindications, warnings, and terns of injury in hospitalized terrorist victims. Am J Emerg Med. 2003;21:258–262. ments for blast injuries. adverse effects—before administer- 11. Blast injury FAQs. Defense and Veterans To accomplish these goals, addi- ing pharmacologic therapy to Brain Injury Center web site. Available at: www.dvbic.org/blastinjury.html. Accessed tional resources are needed. In the patients. December 13, 2004. meantime, however, we present 12. Jehel L, Paterniti S, Brunet A, Duchet C, Guelfi JD. Prediction of the occurrence and intensity of the JAHVH Blast Injury Program as REFERENCES post-traumatic stress disorder in victims 32 a first step in the process of devel- 1. Coupland RM, Meddings DR. Mortality associ- months after bomb attack. Eur Psychiatry. ated with use of weapons in armed conflicts, 2003;18:172–176. oping such a comprehensive sys- wartime atrocities, and civilian mass shootings: Literature review. BMJ. 1999;319(7207):407–410. tem of patient care and outcomes 2. Explosions and Blast Injuries: A Primer for research. ● Clinicians. Atlanta, GA: Center for Disease Con- Case Reports Wanted! trol and Prevention; March 2003 [last update]. Available at: www.bt.cdc.gov/masstrauma Do you have an interesting or The research reported here was /explosions.asp. Accessed December 13, 2004. unusual case to share with your supported by the VHA. Further 3. Leibovici D, Gofrit ON, Stein M, et al. Blast in- colleagues? Send your short case juries: Bus versus open-air bombings—A com- report and discussion to: support was provided by the De- parative study of injuries in survivors of open-air fense and Veterans Brain Injury versus confined-space explosions. J Trauma. Editor 1996;41:1030–1035. Federal Practitioner Center and the James A. Haley 4. Wrightman JM, Gladish SL. Explosions and blast injuries. Ann Emerg Med. 2001;37:664–678. 26 Main Street Veterans’ Hospital, Tampa, FL. 5. Elsayed NM. Toxicology of blast overpressure. Chatham, NJ 07928-2402 Toxicology. 1997;121:1–15. 6. Mayorga MA. The pathology of primary blast See our Guidelines for Authors on page The opinions expressed herein are overpressure injury. Toxicology. 1997;121:17–28. 12 of this issue. those of the authors and do not 7. Lavonas E. Blast injuries. eMedicine web

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