Gingival enlargement as an early diagnostic indicator in therapy-related acute myeloid leukemia: A rare case report and review of literature.

Treatment for Hodgkin's lymphoma (HL) has resulted in excellent survival rates but is associated with increased risks of secondary therapy-related acute myeloid leukemia (t-AML). Gingival enlargement associated with bleeding and ulceration is the most common rapidly appearing oral manifestations of leukemic involvement. An 8 months pregnant patient reported with generalized gingival enlargement, with localized cyanotic and necrotic papillary areas. Co-relating the hematological report with the oral lesions and her past medical history of HL, a diagnosis of t-AML secondary to treatment for HL was made by the oncologist. As oral lesions are one of the initial manifestations of acute leukemia, they may serve as a significant diagnostic indicator for the dental surgeons and their important role in diagnosing and treating such cases. Furthermore, this case report highlights the serious complication of t-AML subsequent to HL treatment and the important role that a general and oral health care professional may play in diagnosing and treating such cases.

INTRODUCTION

Hodgkin's lymphoma (HL) is a malignancy of the lymphatic system, occurring in all age groups, with young adults most often affected.[1] It has become one of the best curable adult malignancies with the introduction of highly effective multi-agent chemotherapy (CT) protocols and the optimization of radiation fields and doses. The systemic CT for HL involving mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) resulted in greater proportions of remission and cure ratios.[2] The combination of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), reported by Bonadonna et al.,[3] was primarily considered a salvage treatment for patients with advanced disease and was considered an alternative protocol for relapsed HL after MOPP.

HL survivors often suffer from treatment-related late effects such as heart failure, infertility, chronic fatigue, and secondary malignancies.[456] Therapy-related acute myeloid leukemia (t-AML) represents one of the most severe late-effects after treatment for HL. Treatment for a pre-existing condition using CT, radiation or immunosuppressive therapy, or a combination of these may lead to the devastating complication of t-AML.[7] Although a causal relationship is implied, the mechanism remains to be proven. This risk is multifactorial and is thought to arise as a direct consequence of mutational events induced by the primary leukemogenic effect of therapy.[78] Currently comprising 10-20% of all cases of acute myeloid leukemia (AML), t-AML is relatively resistant to conventional leukemia therapies.[79] The life-threatening complications of this disorder are the result of persistent and profound cytopenias due to the failure of normal hematopoiesis regardless of the fraction of myeloblasts accumulating in the bone marrow or blood. There has been general agreement that patients with t-AML have shorter survivals than patients with de novo AML and it is often poor despite prompt diagnosis and treatment.[9] Nearly all t-AML patients died rapidly (about 8-10 months) after diagnosis.[10]

The risk of leukemia in patients who have been treated with radiotherapy (RT) alone is minimal, while CT with alkylating agents (MOPP) bears the most significant risk.[3111213] Since the 1980s, MOPP-only CT had been gradually replaced by ABVD, which contained less alkylating agents, and thus led to a lower risk of developing t-AML.[11] There are only a few reports worldwide on the incidence of hematologic malignancies following ABVD.[101214]

AML is an abnormal clonal proliferation of immature myeloid cells, with infiltration into spleen, lymph nodes, central nervous system, skin, and gingiva. It is further classified into four groups by the World Health Organization in 1997,[15] as: (1) AML with recurrent cytogenetic translocations; (2) AML with myelodysplasia related features; (3) therapy-related AML and myelodysplastic syndromes; and (4) AML not otherwise specified. Oral lesions may be the presenting feature of acute leukemia and the most common oral findings include gingival enlargement, local abnormal color or gingival hemorrhage, petechiae, ecchymoses, mucosal ulceration, and oral infections.[16] Oral manifestations of the disease lead majority of these patients to consult the dentist and in most of the cases the underlying disease is diagnosed from clinical findings during periodontal examination.[17]

To the best of our knowledge, this is the first case report of a pregnant patient treated for HL with ABVD and RT, subsequently developing AML, and presenting to us with generalized gingival enlargement. This report also gives a brief literature review on the topic of therapy related AML.

CASE REPORT

A 28-year-old female patient at her 8th month of gestation, reported to the Department of Periodontology, on 21st June 2011, with a chief complaint of swelling and dull aching pain in her gums since 10 days. The patient first noticed the swelling 2 months back, prior to which she was asymptomatic. The swelling was accompanied with pain and bleeding on brushing. The patient did not give any significant past medical history and her routine blood investigations for pregnancy were normal. Extra-oral examination revealed mild, slightly tender, bilateral submandibular lymphadenopathy. On intraoral examination, there was generalized papillary and marginal gingival enlargement in both her jaws. The gingiva was inflamed with moderate deposits of plaque and calculus with localized bleeding on probing. The patient appeared very fatigued and weak, and hence the decision to perform gingival biopsy was postponed. Given the history and oral findings, a provisional diagnosis of pregnancy gingival enlargement was made. The patient requested for an appointment after a week as she had prior engagements. Hence, a treatment plan was formulated which included oral prophylaxis and the patient was advised chlorhexidine mouthwash (0.2%) twice daily, for a period of 2 weeks.

On 27th June 2011, the patient reported with increased gingival pain and swelling accompanied with fever. On examination, there was severe generalized gingival overgrowth with localized necrosis and sloughing involving the interdental papilla in relation to tooth #3. Interdental and marginal gingiva in relation to teeth #10 and 11 revealed the first instance of an abnormal color change and had become more erythematous, boggy, and cyanotic [Figure 1]. Routine blood investigations were advised. The hematological findings are presented in Table 1. Peripheral blood smear revealed 90% myeloblasts with large round nucleus, coarse chromatin and ill-defined nucleoli with moderately pale blue cytoplasm [Figures 2 and 3]. Hematology clinic diagnosed the case as AML M4/M5 (French-American-British Classification, 2000). After observing the hematological report, the patient was further probed for her past medical history, on which she disclosed that she had taken systemic CT for HL 4 years back. Considering her medical status (8th month of pregnancy), she was referred to her consulting obstetrician and oncologist for any required immediate needful treatment. The oncologist informed us that the patient was diagnosed for Malignant HL 4 years back in May 2007, for which she had received CT with six cycles of ABVD and RT (40 Grays) for 1 month. Co-relating the past medical history with present findings, the case was diagnosed as therapy-related AML (t-AML). The clinical photographs from the day the necrotic areas were observed till the delivery of the baby showed classical gingival changes [Figures 4 and 5].

Figure 1

Clinical photographs of patient (a-d) on 27th June 2011, exhibiting generalized gingival enlargement with localized necrotic and cyanotic areas

Table 1

Hematological findings of the patient

Figure 2

Photomicrograph showing immature white blood cells with large nuclei (Leishman's stain; ×40)

Figure 3

Photomicrograph showing monoblasts with large indented nucleus, prominent 1-2 nucleoli and royal blue cytoplasm (Leishman's stain; ×100)

Figure 4

Clinical photographs of patient (a-d) on 30th June 2011, exhibiting generalized gingival enlargement with spread of cyanotic areas to papillary areas of teeth #12 and 13

Figure 5

Clinical photographs of patient (a-d) on 5th July 2011, with more severe gingival enlargement and necrotic gingivae in relation to teeth #12, 13 and 14

Further on supervision with her obstetrician, on 21st July 2011, the patient delivered a healthy baby without any complications. After few days of delivery, the patient was put on CT with vincristine, daunorubicin and cytarabine for AML. However, the patient did not respond well to the treatment and died 3 months later.

DISCUSSION

The fact that gingival hyperplasia are sometimes the initial manifestation of leukemic infiltration, implies that dental professionals must be sufficiently familiarized with its clinical manifestations.[18] Gingival hyperplasia is commonly seen with the AML subtypes: Acute monocytic leukemia (M5) (66.7%), acute myelomonocytic leukemia (M4) (18.5%), and acute myelocytic leukemia (M1, M2) (3.7%).[19] Leukemic gingival enlargements occur in AML because gingival tissue supports continuous trafficking of myeloid cells and contains specialized post-capillary venules for egress of these cells into the tissues at the sites of gingivitis or periodontitis.[20] The change in gingival morphology and its cyanotic appearance and sloughing may result from reactive hyperplasia, dense leukemic infiltration of connective tissue and compression of local vasculature causing ischemia.[19] During pregnancy, hormonal changes (increase in progesterone and estrogen levels) induce changes in vascular permeability, leading to gingival edema and an increased inflammatory response to dental plaque.[21] In the present case, the first symptom of sudden marked gingival enlargement and localized necrosis, along with the hematological and peripheral smear findings confirmed this as a case of AML.

Combination of CT and RT greatly improved survival rates in Hodgkin's disease, but increased the risk of secondary malignancies.[22] MOPP and ABVD are the CT protocols widely used for the first-line treatment of HL patients.[3] These regimens include leukemogenic DNA-breaking alkylating agents, namely mechlorethamine in MOPP and dacarbazine in ABVD.[23] Secondary leukemias induced by these drugs mostly occur 3-8 years after exposition and are often preceded by a pre-leukemic phase that is characterized by myelodysplasia. Topoisomerase-II-inhibitors (adriamycin) represent another drug class with leukemogenic potential used in the treatment of HL and they are characterized by a more rapid development (2 years) of t-AML after exposure.[24] The 15 year actuarial risk for developing leukemia after combined modality therapy was 9.5% for MOPP versus 0.7% for ABVD.[25]

The risk of leukemia appears to correlate with the number of cycles of the drug regimens taken. Patients who received six cycles of two alkylating agents such as in MOPP had approximately 2% of 15-year cumulative risk of AML.[2326] Brusamolino et al.[13] had reported that patients who received four cycles of ABVD had a less than 1% 15-year cumulative risk of developing acute leukemia. Also, Chronowski et al.[27] reported that none of the 19 patients who received four to six cycles of ABVD developed acute leukemia.

RT alone has been associated with a less than 0.4% 15-year cumulative incidence rate of leukemia.[13] Administration of RT additional to CT marginally increases overall second malignancy risks in advanced stages of HL.[28] This is a unique case, since our patient received six cycles of ABVD for HL treatment and RT for 1 month, and later developed AML after 4 years. The main rationale for such a combined approach has been to improve a relapse-free survival.[27] It has not yet been possible to determine whether the development of t-AML is a stochastic event, occurring by chance, or whether certain individuals are at higher risk; perhaps due to a heritable predisposition,[29] or because of the hormonal misbalance in pregnancy. The identification of such an underlying pre-existing conditions would help the screening and counseling of patients at the time of treatment for their primary disease.

A number of potential factors explain the poor outcome of patients with t-AML.[30] Persistence of the primary malignant disease, particularly metastatic cancer or lymphoma, causes morbidity and mortality independent of the bone marrow failure caused by leukemia. Injury to normal hematopoietic stem cells, organs and their vascular supply from prior treatment may compromise the ability of these patients to receive intensive CT. Finally, the high frequency of unfavorable cytogenetic aberrations arising during or after CT-RT appears to result in the rapid emergence of CT resistance in t-AML stem cells.

Clinical outcome of t-AML patients who had received ABVD-based CT for HL treatment was poor with an overall survival of only 4 months.[10] Other studies by Neugut et al.[31] have reported an estimated survival time at 12 months of 10% for t-AML. But our patient unfortunately succumbed to the complications and died within 4 months of diagnosis of t-AML. The incidence and prognosis of t-AML after HL treatment may change in the coming years. Response-adapted treatment strategies that are currently being evaluated will potentially lead to a decrease of cumulative CT and radiation doses in many HL patients. Use of allogeneic stem cell transplantation will probably have a positive impact on the prognosis of the young patients diagnosed with t-AML.[32] More rational would be to substitute alkylating and topoisomerase II inhibitors in the CT regimen by cytostatic drugs without leukemogenic potential, such as the anti-metabolites.[32]

There is a need for continuous monitoring for patients with Hodgkin disease. The risks of second malignancies are small compared with the benefits that intensive RT and CT have brought to the treatment of Hodgkin's disease. However, further observation and refinement of treatments are needed to reduce these adverse long-term side-effects.

CONCLUSION

This case illustrates the need to be vigilant for second hematologic malignancies during long-term follow-up after ABVD therapy for HL. Given the poor prognosis of these second malignancies, more quantitative information on the effect primary treatment agents have on second cancer risks would help to prevent these fatal complications.

Although, physicians most commonly diagnose AML, dentists were responsible for initiating the diagnosis of 25% of acute myelogenous leukemia and 33% of acute myelomonocytic leukemia.[14] The dental practitioner should have an awareness of diagnostic signs and complications associated with leukemia to enable early diagnosis, timely and prompt referral for subsequent management.