MINI REVIEW

Malignant lymphomas represent a leading cause of mortality amongst young population (aged between 20 and 39 yo) ranking second after cardiac disease. Recently there have been major improvements in establishing the physiopathological pattern of the disease, diagnostic tools and treatment options. Advances in biological, molecular genetics and genetic sequencing which were a far cry few years ago have filled in the gaps in better understanding this disease (1).

Among neoplasms of the head and neck region, lymphomas come in second in frequency. They can develop from local lymph nodes or as extranodal disease, the latter being the second most frequent after primary gastrointestinal lymphomas. They include abnormal proliferation of lymphatic tissue from the Waldeyer ring, nose, paranasal sinuses, larynx, pharynx or salivary glands. In these areas the MALT (mucosa associated lymphoid tissue) tissue is well developed and can represent a starting point for malignant proliferation especially in cases with chronic inflammation at this level (2-4).

Cases of extranodal malignant lymphomas are increasing, currently representing over 30% of all malignant lymphomas at the time of diagnosis. They present certain specific pathogenical, clinical and therapeutical aspects which allowed this group of lymphoproliferations to be given special attention in the recent years (5).

A key role in the evaluation of these patients has the clinical exam performed by the ENT specialist, careful inspection and palpation of the latero-cervical tumours together with the whole cervical region and endoscopic assessment of mucosal layer of the nasal cavity, rhinopharynx, oropharynx and larynx. Often these findings must be correlated with other paraclinical examinations and ultimately the positive diagnosis is given by the histopathological exam. This allows the clinician to ascertain a series of immunohistochimical and cytogenetic aspects of the malignant cell involved which can determine the evolution and prognosis of the patients. The best course of treatment can be decided only a after positive diqgnosis made by the pathologist (6,7).

The vast majority of extranodal lymphomas are nonHodgkin lymphomas. Frequently, head and neck literature includes otolaryngological lymphomas. Non-Hodgkin lymphomas of the superior respiratory-digestive tract are classified by frequency in 3 categories (Table 1).

There have been reported cases of lymphomas arising from salivary glands or from elements of the inner ear. These lymphomas can metastasize in the latero-cervical nodes making the differential diagnosis between a carcinoma which has metastasized or an extranodal malignant lymphoma challenging (8, 9).

Histological, and clinical heterogeneity of malignant lymphomas raise special problems on a therapeutic standpoint.

Treatment of these malignancies experienced significant changes over time; progress recorded in knowledge of cellular biology in recent years allowed the use of modern means of treatment aimed to stop the development of neoplastic process, hoping to achieve a disease cure. The main therapeutic means used in the therapy of malignant lymphomas are: conventional chemotherapy, radiation therapy, surgery and rescue treatment – “salvage” therapy, interferon therapy, monoclonal antibody therapy, bone marrow transplant, peptides treatment.

Conventional treatment in malignant lymphomas

The primary method of treatment in malignant lymphomas is represented by chemotherapy. Its use is supported by the fact that two thirds of non-Hodgkin lymphomas are disseminated diseases, diagnosed when already in stages III-IV.

Chemotherapy is used in most of the cases as polychemotherapy and only in selected cases as monotherapy (especially in elderly patients who present reduced malignancy lymphomas) (10).

Radiation therapy is used in well determined circumstances and with very precise techniques, in correlation with affected lymph nodes location. For a long period of time it represented the main therapeutic resource in localised forms of disease (stage I) which presented reduced malignancy histological aspect.

In most of the cases it serves as an adjuvant being associated with polychemotherapy. Radiotherapy (cobalt) as primary treatment has its justification in the particular forms involving bulky tumor masses.

In the case of non-Hodgkin’s malignant lymphomas of low malignancy extent, for advanced stages of the disease, multiple therapeutic approaches must be considered:

– Careful oversight “watch and wait“, without treatment in asymptomatic patients. It is a preferable attitude until the moment of disease advancement, apparition of massive lymphadenopathy or systemic manifestations.

– Moderate treatment. It is indicated for first-line treatment and palliative treatment. It includes the following:

* a. alkylating agents monotherapy: response in 50-80% of cases. They are especially represented by Cyclophosphamide and Chlorambucil.

Complete remission is obtained in about 6 to 12 months of treatment, with a mean duration of 24-36 months, the average survival being of 8 years. (11). It constitutes the version of choice in patients 65 aged or older.

*b. polychemotherapy: the standard cure is represented by CVP plan (Cyclophosphamide, Vincristine, Prednisone), with 80-90% response (complete and partial remissions). Using more aggressive cures has no positive impact on survival.

*c. chemotherapy and radiotherapy association. Radiotherapy is useful in patients who develop localized forms of disease (compressive, painful lymph nodes, spinal cord compression).

– Aggressive chemotherapy. Despite high percentage of remissions rates, it is rarely employed. Most studies show a constant tendency to relapse without major improvement of overall survival (12).

Main regimens used are: COPP (Cyclophosphamide, Oncovin, Procarbazine, Prednisone), CHOP – Bleo + IF (Cyclophosphamide, Adriablastin, Oncovin, Prednisone, Bleomycin, Interferon).

– Aggressive radiotherapy. It consists of total body and lymphoid irradiation. In this situation, complete remission is obtained in 100% of cases with the duration of relapse-free survival rate at 5 years of 60%.

– Other non-conventional therapeutic modalities: interferon alpha, bone marrow transplant, treatment with monoclonal antibodies with purine analogues;

– Indolent lymphomas type B benefit from these types of treatment: “Watch and wait strategy”, Fludarabine, anti-CD20 monoclonal antibodies (Rituximab, Gazivaro), CHOP, CHOP + Rituximab or Rituximab (R-CHOP).

The chemotherapy is the most important therapeutic tool in the malignant non-Hodgkin lymphomas with intermediate grade of malignancy. The radiation therapy is an adjuvant type of therapy. It’s applied in localized forms, without unfavourable prognostic factors and evolving forms bulky tumour masses initial or continuing after applying the
chemotherapy.

In the localized forms, the therapeutic schemes are:

* 3-4 chemotherapy cycles (CHOP) + targeted radiotherapy; survivals without success are recorded in 80% of cases;

* The radiotherapy targeted without any other treatment is indicated in the IA stages of disease or IE nonbulky and in stages II and IIE with 2 damage nonbulky sites immediately adjacent and without systemic symptoms.

Extranodal determinations require a special attention because of the immediate hidden associations (Waldeyer ring, the digestive tube) and the risk of relapse in the central nervous system from the sinuses lymphoma. In the primary extranodal lymphomas with a localization at the level of the Waldeyer ring, in addition to tissue sampling for histological analysis a surgical approach is preferable intended to remove as much of the lymphomatous tissue (tonsillectomy or the removal of tissue from other areas, the full removal of the lymph nodes) (13-15).

In the disseminated forms, the treatment of choice is the polychemotherapy, which must lead to a complete remission. The maximum doses are administered, and after achieving full remission it is required to implement only a few more chemotherapy cycles, prolonged therapy increasing toxicity, without superior results.

The standard cure is CHOP. The II and III generation cures, such as m-BACOD (Methotrexat Leucovorin, Bleomycin, Cyclophosphamide, Oncovin, Adriablastin, Dexamethasone), MACE/MOPP (ProPrednisone, Methotrexat, Adriablastine, Cyclophosphamide, Etoposide), MACOP-B (Leucovirin, Adriablastin, Methotrexat Cyclophosphamide, Oncovin, Prednisone, Bleomycin), COPBLAM III (Cyclophosphamide, Oncovin, Prednisone, Bleomycin, Adriablastin, Metulan) may be used for the achievement of improved therapeutic outcome.

Studies have shown increased toxicity and they don’t significantly demonstrated the benefit of using incisive cures compared to CHOP, both in terms of survival at 3 years and duration until the achievement of the success (16-18). High degree malignant lymphomas raise a difficult question in terms of first-line treatment, where there is no consensus so far.

In lymphoblastic lymphomas, the conventional chemotherapeutic schemes for aggressive lymphomas lead to excellent initial response rate but most of the patients relapse and eventually die with a progressive disease that does not respond to salvage chemotherapy.

There is a protocol for combined systemic chemotherapy associated with CNS prophylaxy comprising:

– induction with Cyclophosphamide, Doxorubicin, Prednisone, Vincristin, Methotrexat;

– CNS prophylaxis with Methotrexate; – consolidation with 4 cycles of the order of induction;

– oral maintenance therapy with Methotrexate and 6-Mercaptopurine for 12 months. At 3 years, the percentage of patients without success is 58% (19).

The next therapeutic scheme can be used: RCHOP, R-ICE (Rituximab, Ifosfamid, Carboplatin, Etoposid) ESHAP (Etoposide, Methylprednisolone, Citarabin, Cisplatin), EPOCH (Etoposid, Prednisolone, Cyclophosphamide, Oncovin, Hidroxidaunorubicin). There have been utilized different therapeutic schemes modelled on the treatment of acute lymphoblastic leukemias.

A problem in the study remains the bone marrow transplant which, if conducted after getting the first complete remission, can favourably influence the patient’s prognosis.

For small non-cleaved-cell lymphoma and Burkitt’s lymphoma in children, modern protocols include only multiagent chemotherapy and contain Cyclophosphamide in combination with Doxorubicin, Methotrexate, Cytarabine and/or Vincristine.

In adult patients, therapy begins with aggressive chemotherapy (BACT-Carmustine, Cytarabine, Cyclophosphamide, 6-Thioguanina or BEAMCarmustine, Cytarabine, Etoposide, Melphalane), followed by autologous or allogeneic bone marrow transplant (10).

The use of 3rd generation therapeutic protocols allows complete remissions in approximately 50% of cases aggressive non-Hodgkin’s lymphomas. There are 10-15% of cases refractory to treatment, and 20-30% of cases relapse, relatively early, after obtaining full remission.

CONCLUSIONS

In the context of the efforts made for the correct diagnosis and therapy in malignant lymphomas with an expression in the head and neck area, the complex approach, with the integration of the clinical, morphological and cytogenetic elements, the interdisciplinary collaboration of the ENT surgeon with the pathologist, haemato-logist, oncologist, radiotherapist, nutritionist and psychologist is mandatory in order to establish the best approach for the patient with malignant head and neck lymphoma.

This article was published in the Archives of the Balkan Medical Union

REFERENCES

1. Vlãdãreanu Ana-Maria – Actualitati in limfoamele maligne nonhodgkiniene, Ed. Amaltea, 13-16, 2002
2. Greer P, John P: Wintrobe’s Clinical Hematology, 12th ed., Lippincott Williams and Wilkins, 2009, 2071-2130
3. Essadi I, Ismaili N, Tazi E, Elmajjaoui S, Saidi A, Ichou M, Errihani H, Primary lymphoma of the head and neck: two cases reports and review of the literature, Cases J, 2008, 1(1): 426
4. Vlãdãreanu AM, Limfoamele in corelatie cu virusurile limfotrope, Ed Medicala Amaltea, Bucuresti, 2007, 159-205
5. Oltean G: Limfoamele maligne cu debut extraganglionar, Ed. Veritas, Targu-Mures, 2001, 112-133
6. Vlãdãreanu Ana-Maria: Limfoamele în corelaåie cu virusurile limfotrope, Ed. Medicalã Amaltea, Bucureşti, 17-61; 2007
7. Tuşaliu M, Zainea V: Malignant Lymphoma with tonsillar onset-comments on a clinical case, Arch.Balkan.Med.Union, 48(4): 435-439; 2013
8. Jaffe ES, Harris NL, Stein H, Vardiman JW – World Health Organization Classification of Tumors: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, Lyon, IARC, Press, 162-167, 2001
9. Feller AC, Diebold J: Histopathology of Nodal and Extranodal Non-Hodgkin’s lymphomas, Springer, 6.3:213-227, 410; 2004
10. Salles G, Shipp M A, Coiffier B: Chemotherapy of NonHodgkin’s Aggressive Lymphomas, Semin.Hematol., 31, 1: 4649; 1994
11. Case D C: Clinical experience with oral idarubicin in lowgrade non-Hodgkin’s Lymphomas, Res.Clin.Forums.,18, 3: 3541; 1996
12. Parker S L, Tong T, Bolden S, et al: Cancer statistics,1996, CA Cancer J.Clin., 65:5-27; 1996
13. Tuşaliu M, Zainea V: Indications and surgical techniques in malignant sinonasal lymphomas, Arch.Balkan.Med.Union, 49(1):87-93, 2014
14. Robbins KT, Kong JS, Fuller LM, Goepfert H: A comparative analysis of lymphomas involving Waldeyer’s ring and the nasal cavity and paranasal sinuses, J.Otolaryncol. 1985, 14:7-13
15. Tuşaliu M, Mogoanta CA, Dobrea CM, Zainea V: Clinical and histological aspects with therapeutic implications in head and neck lymphomas, Rom J Morphol Embryol 2015, 56(2): 499504
16. Clavio M, Rossi E, Truini M,et al: Anaplastic Large Cell Lymphoma: A Clinicopathologic Study of 53 Patients, Leukemia and Lymphoma, 22:319-327;1996
17. Schmitz N, Linch D C, Dreger P, et al: Randomised trial of filgrastim-mobilized peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients, Lancet, 347:353-357;1996
18. Gaynor E R, Dahlbarg S, Fisher R I: Factor affecting reduced survival of the elderly with intermediate and high grade lymphoma: An analysis of SWOG-516 (INT 0067) – The National High Priority Lymphoma Study – a randomised comparison of CHOP vs mBACOD vs ProMACE-CytaBOM vs MACOP (abstract 1250), Proc.Am.Soc.Clin.Oncol., 13:370;1994
19. Fisher R I, Gaynor E R, Dahlberg S, et al: Comparison at a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma, N.Engl.J. Med.,328-1002;1993