current recommendations for multidrug therapy ( mdt ) of leprosy follow a fixed duration of treatment regardless of clearance of skin lesions or presence or absence of acid - fast bacilli in the skin . a fairly high percentage of patients with leprosy who complete recommended duration of multi - drug therapy are left with residual skin lesions which are a great source of anxiety to the patient and the family . a small percentage of patients go on to develop new lesions after completion of treatment which may be either late reactions or relapse . hardly any literature exists on the histological findings in biopsies taken from patients who have completed mdt . this article describes histomorphological findings in patients with treated leprosy who underwent skin biopsies after completion of mdt because they either had persistent lesions or developed new lesions on follow - up . histology of treated leprosy may show findings that are diagnostic for leprosy ( histology active ) or findings that by themselves are not diagnostic for leprosy ( histology inactive ) but may be used as clues in confirming that the persistent skin lesions are histologically inactive and need no further treatment . awareness of histomorphological changes that occur in skin lesions of leprosy after completion of treatment can aid the pathologist to determine whether the lesions are active or inactive histologically and assist the clinician to convince the patient that his disease is inactive and does not need further treatment . current recommendations for multidrug therapy ( mdt ) of leprosy follow a fixed duration of treatment ( 6 months for pauci and 12 months for multibacillary leprosy ) regardless of clearance of skin lesions or presence or absence of acid - fast bacilli in the skin . a fairly high percentage of patients with leprosy who complete recommended fixed duration of mdt are left with residual skin lesions , which are a great source of anxiety to the patient and the family . a small number of patients go on to develop new lesions after completion of the course of treatment which are regarded as either late reactions or relapse . many of such patients who are under treatment from dermatologists in private , undergo skin biopsy to assess hardly any literature exists on the histologic findings in biopsies taken from patients who have completed chemotherapy . this article describes the histomorphological findings in skin lesions of leprosy patients who had completed course of treatment but had either persistence of lesions or developed new lesions on follow - up and underwent biopsies for assessing the biopsy of persistent lesions in treated leprosy may show : 
 findings still diagnostic of leprosy , i.e. persistence of granulomas or in the absence of granulomas , selective lymphocytic infiltration of nerves , arrectores pilorum muscles , eccrine structures , etc . such findings are reported as persistence of  activity of the disease.findings that by themselves are not diagnostic for leprosy , but when considered in conjunction with the history of anti - leprosy treatment taken by the patient can be used as clues for diagnosis of treated leprosy . findings still diagnostic of leprosy , i.e. persistence of granulomas or in the absence of granulomas , selective lymphocytic infiltration of nerves , arrectores pilorum muscles , eccrine structures , etc . such findings are reported as persistence of  activity of the disease . findings that by themselves are not diagnostic for leprosy , but when considered in conjunction with the history of anti - leprosy treatment taken by the patient can be used as clues for diagnosis of treated leprosy . this article will focus on the second group of findings that show subtle but characteristic changes that may be used for diagnosis of treated leprosy and confirm these can be subdivided into : 
 epidermal changes.alterations in dermal stroma.morphological changes in the inflammatory infiltrate . epidermal changes : 
 flat epidermis with prominent melanin in a lesion that is clinically hypopigmented [ figures 1 and 2]:lesions of treated leprosy that clinically are hypopigmented and show a dry surface often show prominent melanin in the basal layer without any increase in the number of melanocytes at the dermoepidermal junction . at first glance the histology is suggestive of a pigmented lesion , however , the lesion biopsied is always hypopigmented clinically . prominent melanin in the basal layer in a clinically hypopigmented patch is a clue to treated , histologically inactive hansen 's disease.spike of lymphocytes in the epidermis or eccrine ductal epithelium [ figure 3]:a single small collection of epitheliotropic lymphocytes in the epidermis or eccrine ductal epithelium ( acrosyringium ) may be seen in a lesion of treated leprosy . the dermis is devoid of any inflammation or granulomas and the sections may be passed of as normal skin . there is no atypia of the lymphocytes or psoriasiform epidermal hyperplasia as seen in mycosis fungoides . such cases usually have had borderline leprosy and have received full course of mdt.a single focus of epidermotropic lymphocytes in a flat epidermis in the absence of dermal inflammation is a clue to treated , borderline hansen 's disease . alterations in dermal stroma : 
 edema of perivascular and periadnexal adventitial dermis with scatter of noncohesive lymphoplasmacytic cells and increased numbers of mast cells [ figure 4 ] : the adventitial dermis surrounding the vessels and adnexal structures in the dermis shows a pale edematous appearance that reflects resolving inflammation with alteration in the characteristics of the inflammatory cells , lymphocytes are replaced by plasmacytoid cells with abundant amphophilic cytoplasm . also seen are increased numbers of mast cells scattered amidst the regenerating stroma.fibromyxoid changes of dermis [ figure 5]:this may take the form of extensive myxoid appearance of the upper and mid - dermis with pale fibrillary collagen separated by myxoid material , fibroplasia with scattered fibroblasts , upper dermal telangiectasia and perivascular and periadnexal lymphoplasmacytic infiltrate . a second pattern is blue - gray mucin deposition between the collagen bundles in the upper and mid - dermis that may resemble mucin deposits in collagen vascular diseases like lupus erythematosus [ figure 6].morphea - like dermal changes [ figure 7]:histopathological findings that mimic morphea may be seen in lesions of treated leprosy , with a flat epidermis which has prominent melanin in the basal layer , a thickened sclerotic dermis with paucity of adnexal structures and no granulomas or significant inflammatory infiltrate . important to note that patients with morphea - like dermal changes post - treatment show granulomas in the pretreatment biopsies without sclerosis of dermal collagen . morphological changes in inflammatory infiltrate : 
 lymphoplasmacytoid appearance of infiltrate [ figure 8]:the lymphocytes that in pretreatment biopsies are seen as tight cohesive collections around vascular and adnexal structures are replaced by plasmacytoid cells with abundant amphophilic cytoplasm scattered in the pale edematous stroma of the adventitial dermis . similar changes may be seen surrounding residual granulomas of treated leprosy.uniformly foamy histiocytes with fragmented and granular acid - fast material [ figure 9]:in multibacillary leprosy macrophages may be present in large numbers even after completion of mdt . these develop uniformly foamy cytoplasm that on staining with fite - faraco stain show no solid viable bacilli but abundant fragmented and granular acid - fast debris . such macrophages laden with lipids derived from the mycobacteria can be easily differentiated from an active nontreated case of bl / ll leprosy in which the histiocytes have solid staining amphophilic cytoplasm and occasional variably sized foamy cells . the uniformly foamy histiocytes of treated multibacillary leprosy are seen surrounding vascular and adnexal structures and may even be seen interstitially and be mistaken for a xanthoma . flat epidermis with prominent melanin in a lesion that is clinically hypopigmented [ figures 1 and 2]:lesions of treated leprosy that clinically are hypopigmented and show a dry surface often show prominent melanin in the basal layer without any increase in the number of melanocytes at the dermoepidermal junction . at first glance the histology is suggestive of a pigmented lesion , however , the lesion biopsied is always hypopigmented clinically . prominent melanin in the basal layer in a clinically hypopigmented patch is a clue to treated , histologically inactive hansen 's disease.spike of lymphocytes in the epidermis or eccrine ductal epithelium [ figure 3]:a single small collection of epitheliotropic lymphocytes in the epidermis or eccrine ductal epithelium ( acrosyringium ) may be seen in a lesion of treated leprosy . the dermis is devoid of any inflammation or granulomas and the sections may be passed of as normal skin . there is no atypia of the lymphocytes or psoriasiform epidermal hyperplasia as seen in mycosis fungoides . such cases usually have had borderline leprosy and have received full course of mdt.a single focus of epidermotropic lymphocytes in a flat epidermis in the absence of dermal inflammation is a clue to treated , borderline hansen 's disease . flat epidermis with prominent melanin in a lesion that is clinically hypopigmented [ figures 1 and 2 ] : lesions of treated leprosy that clinically are hypopigmented and show a dry surface often show prominent melanin in the basal layer without any increase in the number of melanocytes at the dermoepidermal junction . at first glance the histology is suggestive of a pigmented lesion , however , the lesion biopsied is always hypopigmented clinically . prominent melanin in the basal layer in a clinically hypopigmented patch is a clue to treated , histologically spike of lymphocytes in the epidermis or eccrine ductal epithelium [ figure 3 ] : a single small collection of epitheliotropic lymphocytes in the epidermis or eccrine ductal epithelium ( acrosyringium ) may be seen in a lesion of treated leprosy . the dermis is devoid of any inflammation or granulomas and the sections may be passed of as normal skin . there is no atypia of the lymphocytes or psoriasiform epidermal hyperplasia as seen in mycosis fungoides . a single focus of epidermotropic lymphocytes in a flat epidermis in the absence of dermal inflammation is a clue to treated , borderline hansen 's disease . alterations in dermal stroma : 
 edema of perivascular and periadnexal adventitial dermis with scatter of noncohesive lymphoplasmacytic cells and increased numbers of mast cells [ figure 4 ] : the adventitial dermis surrounding the vessels and adnexal structures in the dermis shows a pale edematous appearance that reflects resolving inflammation with alteration in the characteristics of the inflammatory cells , lymphocytes are replaced by plasmacytoid cells with abundant amphophilic cytoplasm . also seen are increased numbers of mast cells scattered amidst the regenerating stroma.fibromyxoid changes of dermis [ figure 5]:this may take the form of extensive myxoid appearance of the upper and mid - dermis with pale fibrillary collagen separated by myxoid material , fibroplasia with scattered fibroblasts , upper dermal telangiectasia and perivascular and periadnexal lymphoplasmacytic infiltrate . a second pattern is blue - gray mucin deposition between the collagen bundles in the upper and mid - dermis that may resemble mucin deposits in collagen vascular diseases like lupus erythematosus [ figure 6].morphea - like dermal changes [ figure 7]:histopathological findings that mimic morphea may be seen in lesions of treated leprosy , with a flat epidermis which has prominent melanin in the basal layer , a thickened sclerotic dermis with paucity of adnexal structures and no granulomas or significant inflammatory infiltrate . important to note that patients with morphea - like dermal changes post - treatment show granulomas in the pretreatment biopsies without sclerosis of dermal collagen . edema of perivascular and periadnexal adventitial dermis with scatter of noncohesive lymphoplasmacytic cells and increased numbers of mast cells [ figure 4 ] : the adventitial dermis surrounding the vessels and adnexal structures in the dermis shows a pale edematous appearance that reflects resolving inflammation with alteration in the characteristics of the inflammatory cells , lymphocytes are replaced by plasmacytoid cells with abundant amphophilic cytoplasm . also seen are increased numbers of mast cells scattered amidst the regenerating stroma . fibromyxoid changes of dermis [ figure 5 ] : this may take the form of extensive myxoid appearance of the upper and mid - dermis with pale fibrillary collagen separated by myxoid material , fibroplasia with scattered fibroblasts , upper dermal telangiectasia and perivascular and periadnexal lymphoplasmacytic infiltrate . a second pattern is blue - gray mucin deposition between the collagen bundles in the upper and mid - dermis that may resemble mucin deposits in collagen vascular diseases like lupus erythematosus [ figure 6 ] . morphea - like dermal changes [ figure 7 ] : histopathological findings that mimic morphea may be seen in lesions of treated leprosy , with a flat epidermis which has prominent melanin in the basal layer , a thickened sclerotic dermis with paucity of adnexal structures and no granulomas or significant inflammatory infiltrate . important to note that patients with morphea - like dermal changes post - treatment show granulomas in the pretreatment biopsies without sclerosis of dermal collagen . morphological changes in inflammatory infiltrate : 
 lymphoplasmacytoid appearance of infiltrate [ figure 8]:the lymphocytes that in pretreatment biopsies are seen as tight cohesive collections around vascular and adnexal structures are replaced by plasmacytoid cells with abundant amphophilic cytoplasm scattered in the pale edematous stroma of the adventitial dermis . similar changes may be seen surrounding residual granulomas of treated leprosy.uniformly foamy histiocytes with fragmented and granular acid - fast material [ figure 9]:in multibacillary leprosy macrophages may be present in large numbers even after completion of mdt . these develop uniformly foamy cytoplasm that on staining with fite - faraco stain show no solid viable bacilli but abundant fragmented and granular acid - fast debris . such macrophages laden with lipids derived from the mycobacteria can be easily differentiated from an active nontreated case of bl / ll leprosy in which the histiocytes have solid staining amphophilic cytoplasm and occasional variably sized foamy cells . the uniformly foamy histiocytes of treated multibacillary leprosy are seen surrounding vascular and adnexal structures and may even be seen interstitially and be mistaken for a xanthoma . lymphoplasmacytoid appearance of infiltrate [ figure 8 ] : the lymphocytes that in pretreatment biopsies are seen as tight cohesive collections around vascular and adnexal structures are replaced by plasmacytoid cells with abundant amphophilic cytoplasm scattered in the pale edematous stroma of the adventitial dermis . uniformly foamy histiocytes with fragmented and granular acid - fast material [ figure 9 ] : in multibacillary leprosy macrophages may be present in large numbers even after completion of mdt . these develop uniformly foamy cytoplasm that on staining with fite - faraco stain show no solid viable bacilli but abundant fragmented and granular acid - fast debris . such macrophages laden with lipids derived from the mycobacteria can be easily differentiated from an active nontreated case of bl / ll leprosy in which the histiocytes have solid staining amphophilic cytoplasm and occasional variably sized foamy cells . the uniformly foamy histiocytes of treated multibacillary leprosy are seen surrounding vascular and adnexal structures and may even be seen interstitially and be mistaken for a xanthoma . scanning view with flat pigmented epidermis and thickened nerve with surrounding lymphocytic infiltrate in subcutis . ( h and e , 40 ) flat epidermis with uniformly increased melanin in the basal layer without increased melanocytes at dermoepidermal junction . ( hande , 400 ) single focus of epidermotropic lymphocytes in the basal and spinous layers of the flat epidermis . ( h and e , 400 ) perivascular edema with many mast cells , fibroplasia and lymphoplasmacytic cells . ( h and e , 400 ) myxoid pale appearance of reticular dermis with scattered fibrocytes and lympho - plasmacytoid infiltrate . ( h and e , 100 ) interstitial mucin deposits that appear as blue - gray stringy material between the collagen bundles . ( h and e , 400 ) morphea - like appearance with flattened pigmented epidermis and thick sclerotic dermis that is paucicellular and pauciadnexal . ( h and e , 100 ) numerous plasmacytoid cells with abundant amphophilic cytoplasm scattered in a pale edematous stroma . ( h and e , 400 ) uniformly foamy ( xanthomatous ) histiocytes in treated bl / ll hansen 's . many patients of leprosy who complete prescribed courses of mdt are left with residual lesions that may clinically be active or inactive at the time of release from treatment ( rft ) . governmental agencies and ngos engaged in the treatment and follow - up of leprosy patients do not recommend skin biopsies post - treatment , however , patients undergoing treatment with private dermatologists often undergo skin biopsies to assess activity of the disease for visible skin lesions and/or persistent neural symptoms like loss of sensations or tingling / numbness which are a source of great anxiety to the patient and the families given the great social stigma associated with this disease . biopsies from such patients are received because of the following reasons : 
 skin lesions are still clinically active.lesions although clinically inactive still persist and are a source of anxiety to the patient.new lesions develop.there are no skin lesions but neural symptoms persist.delayed reactions / relapse.persistent reactions . lesions although clinically inactive still persist and are a source of anxiety to the patient . how does a histopathologist deal with such biopsies ? hardly any literature exists on the histological findings in treated leprosy and on criteria for  active versus  inactive disease . biopsies from persistent skin lesions of treated leprosy may show findings that are still diagnostic of leprosy , i.e. , presence of epithelioid cell granulomas that selectively involve adnexal and neural structures in tuberculoid / bt leprosy or collections of histiocytes that harbor acid - fast bacilli or fragmented acid fast debris . in multibacillary leprosy finding of viable solid staining afb is suggestive of a relapse , however , in paucibacillary leprosy it is very difficult to differentiate histologically between a reaction and a relapse . some authorities advocate use of quantitative evaluation of granulomas ( granuloma fraction and bacillary index of granuloma ) and comparison of before and after biopsies . in most cases , however , pretreatment biopsies are not available for comparison . also sampling errors can occur as different areas in the same biopsy do show differences in granuloma fraction and the pre and post - treatment biopsies can not be from the same site . further more , patients tend to change doctors and conceal history of previous treatments , especially in a disease like leprosy . therefore , assessment of post - treatment histology of skin lesions is best done using qualitative and morphological findings . morphological changes seen in treated leprosy include : 
 ill - formed , noncohesive , opened out granulomas with intercellular edema separating the epithelioid cells [ figure 10].scatter of lymphoid cells in an edematous fibroblastic stroma . ( in active untreated leprosy the stroma is normal and uninvolved and the granulomas and lymphocytes are selectively restricted to adnexal and neural structures ) [ figure 11].histiocytic granulomas made up of uniformly foamy histiocytes and containing fragmented and granular acid - fast bacillary debris . ill - formed , noncohesive , opened out granulomas with intercellular edema separating the epithelioid cells [ figure 10 ] . ( in active untreated leprosy the stroma is normal and uninvolved and the granulomas and lymphocytes are selectively restricted to adnexal and neural structures ) [ figure 11 ] . histiocytic granulomas made up of uniformly foamy histiocytes and containing fragmented and granular acid - fast bacillary debris . ill formed , noncohesive , opened out granuloma with intercellular edema separating the epithelioid cells . ( h and e , 400 ) interstitial scatter of lymphocytes in fibroblastic stroma with resolving granulomas . ( h and e , 100 ) such findings suggest that the patient has received treatment , however , the granulomas persist and histologically the lesion is still active. on the other hand , many biopsies from persistent lesions , post - mdt , do not show granulomas or histiocytes and can not be diagnosed as leprosy based on the current histological findings . these cases , however , do show subtle morphological findings that are seen only in lesions of treated leprosy and such findings can be used in conjunction with history of previous diagnosis and treatment of leprosy to confirm that the disease is inactive , has been adequately treated , and does not need further continuation of mdt . the morphological findings described in this article have not been described before and they possibly reflect postinflammatory changes and regenerative responses of the dermis . changes in immune status that occur with mdt may also play a role especially in the finding of epitheliotropic lymphocytes in the epidermis . upgrading of adhesion molecules like icam 1 on keratinocytes is associated with epidermotropism of lymphocytes in inflammatory conditions with improved cmi and a th1 response that releases interferon-. healing and resolution of inflammation in treated leprosy does not normally lead to promiment fibrosis as is seen in other granulomatous diseases of the skin , like tuberculosis , leishmaniasis , etc . this is because inflammation in leprosy favors selectively the papillary and adventitial dermis that abuts the epidermis and epithelial adnexal structures respectively . postinflammatory changes in the adventitial dermis do not lead to prominent fibrosis unlike the dense fibrosis that is seen in resolving and treated lesions of lupus vulgaris or tuberculosis verrucosa cutis where the reticular dermis is the seat of granulomatous inflammation . the finding of morphea - like dermal sclerosis and mucin deposits in the dermis are unusual findings for treated leprosy which may lead to diagnostic confusion . interestingly such patients never show dermal sclerosis in the pretreatment biopsies but show granulomas , histologically typical of leprosy , and are never diagnosed as morphea clinically . therefore , it is unlikely that such patients may have had morphea to begin with and the changes of dermal sclerosis seen in post - mdt biopsies represent postinflammatory changes of the reticular dermis . the alteration of morphology of the cellular infiltrate , i.e. , plasmacytoid lymphocytes may represent persistent innate immune responses , as plasmacytoid lymphocyte transformation is known to occur in viral infections with heightened innate immune responses . uniformly foamy histiocytes reflect complete killing of mycobacteria and correlates with granular acid - fast material without solid staining organisms . no explanation can be offered for the hyperpigmentation of basal layer of the epidermis , but this finding serves to differentiate between other hypopigmented lesions that clinically may be considered in the differential diagnoses . the findings described in this article are based on the personal experience of the author and may reflect personal bias . this is a retrospective and descriptive study of findings that the author finds useful for making diagnoses of histologically inactive disease in cases of leprosy . not all biopsies show these findings and amongst the described clues some like basal cell hyperpigmentation in hypopigmented patches and plasmacytoid appearance of cells are common while dermal changes like morphea - like appearance and mucin in the dermis are rare . the common factor , however , is that all these patients have had leprosy diagnosed on clinicopathological grounds and have completed recommended courses of mdt before the post - treatment biopsies were taken . it is important to understand that these findings by themselves , are not diagnostic for leprosy and are of value only in patients with leprosy who have completed mdt . to conclude , many patients with leprosy who complete fixed duration of mdt continue to have persistence of skin lesions , or develop new lesions . activity of disease and the morphological findings described in this article are helpful to confirm the diagnosis of treated , histologically